Subgroups of patients with young-onset type 2 diabetes in India reveal insulin deficiency as a major driver
Author Name: Rashmi Prasad, Olof Asplund, Sharvari Shukla, Rucha Wagh, et al , Publication Year: 2022 , Journal Name: Diabetologia
Abstract: Aim/hypothesis: Five subgroups were described in European diabetes patients using a data driven machine learning approach on commonly measured variables. We aimed to test the applicability of this phenotyping in Indian individuals with young-onset type 2 diabetes.
Methods: We applied the European-derived centroids to Indian individuals with type 2 diabetes diagnosed before 45 years of age from the WellGen cohort (n = 1612). We also applied de novo k-means clustering to the WellGen cohort to validate the subgroups. We then compared clinical and metabolic-endocrine characteristics and the complication rates between the subgroups. We also compared characteristics of the WellGen subgroups with those of two young European cohorts, ANDIS (n = 962) and DIREVA (n = 420). Subgroups were also assessed in two other Indian cohorts, Ahmedabad (n = 187) and PHENOEINDY-2 (n = 205).
Results: Both Indian and European young-onset type 2 diabetes patients were predominantly classified into severe insulin-deficient (SIDD) and mild obesity-related (MOD) subgroups, while the severe insulin-resistant (SIRD) and mild age-related (MARD) subgroups were rare. In WellGen, SIDD (53%) was more common than MOD (38%), contrary to findings in Europeans (Swedish 26% vs 68%, Finnish 24% vs 71%, respectively). A higher proportion of SIDD compared with MOD was also seen in Ahmedabad (57% vs 33%) and in PHENOEINDY-2 (67% vs 23%). Both in Indians and Europeans, the SIDD subgroup was characterised by insulin deficiency and hyperglycaemia, MOD by obesity, SIRD by severe insulin resistance and MARD by mild metabolic-endocrine disturbances. In WellGen, nephropathy and retinopathy were more prevalent in SIDD compared with MOD while the latter had higher prevalence of neuropathy.
Conclusions /interpretation: Our data identified insulin deficiency as the major driver of type 2 diabetes in young Indians, unlike in young European individuals in whom obesity and insulin resistance predominate. Our results provide useful clues to pathophysiological mechanisms and susceptibility to complications in type 2 diabetes in the young Indian population and suggest a need to review management strategies.
Pre-conceptional Maternal Vitamin B12 Supplementation Improves Offspring Neurodevelopment at 2 Years of Age: PRIYA Trial
Author Name: Naomi D’souza , Rishikesh Behere, Bindu Patni, Madhavi Deshpande, et al , Publication Year: 2021 , Journal Name: Frontiers in Pediatrics
Abstract: Background: The first thousand days window does not include the pre-conceptional period. Maternal pre-conceptional health has a profound influence on early embryonic development (implantation, gastrulation, placentation etc). Nutrition provided by B-complex vitamins is important for fetal growth, especially neural development. We report effects of a maternal pre-conceptional vitamin B12 and multi micronutrient (MMN) supplementation on offspring neurodevelopmental performance.
Methods: In the Pune Rural Intervention in Young Adolescents trial (PRIYA), adolescents (N = 557, 226 females) were provided with vitamin B12 (2 μg/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayley's Scale of Infant Development (BSID-III) at 24–42 months of age to investigate effects on offspring neurodevelopment.
Results: Participants had similar baseline B12 levels. The levels improved in the B12 supplemented groups during pre-conception and pregnancy (28 weeks gestation), and were reflected in higher cord blood holotranscobalamin (holo-TC) levels compared to the placebo group. Neurodevelopmental outcomes in the B12 alone group (n = 21) were better than the placebo (n = 27) in cognition (p = 0.044) and language (p = 0.020) domains (adjusted for maternal baseline B12 levels). There was no difference in neurodevelopmental outcomes between the B12 + MMN (n = 26) and placebo group. Cord blood Brain Derived Neurotrophic Factor (BDNF) levels were highest in the B12 alone group, though not significant.
Conclusion: Pre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening during pre-conception.
Maternal Vitamin B12 Status During Pregnancy and Its Association With Outcomes of Pregnancy and Health of the Offspring: A Systematic Review and Implications for Policy in India
Author Name: Rishikesh V. Behere, Anagha S. Deshmukh, Suhas Otiv, Mohan D. Gupte et al. , Publication Year: 2021 , Journal Name: Frontiers in Endocrinology
Abstract: Vitamins B12 and folate participate in the one-carbon metabolism cycle
and hence regulate fetal growth. Though vitamin B12 deficiency is widely prevalent, the
current public health policy in India is to supplement only iron and folic acid for the prevention
of anaemia. Prompted by our research findings of the importance of maternal vitamin B12
status for a healthy pregnancy, birth and offspring health outcomes, we evaluated available
literature evidence using a systematic review approach, to inform policy. A systematic search was performed for relevant Indian studies in the
MEDLINE/PubMed and IndMed databases. We selected studies reporting maternal
vitamin B12 status (dietary intake or blood concentrations), and/or metabolic markers
of vitamin B12 deficiency (homocysteine, methylmalonic acid) or haematological indices
during pregnancy and their associations with outcomes of pregnancy, infancy or in later
life. Intervention trials of vitamin B12 during pregnancy were also included. Quality of
evidence was assessed on the Grading of Recommendations Assessment, Development,
and Evaluation (GRADE) system. We followed the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) statement. Of the 635 articles identified, 46 studies met the inclusion criteria (cohort studies-
26, case-control studies-13, RCT’s -7). There is a high prevalence of vitamin B12
deficiency in Indian women during pregnancy (40-70%) (3 studies). Observational
studies support associations (adjusted for potential sociodemographic confounders,
maternal body size, postnatal factors) of lower maternal B12, higher homocysteine or
an imbalance between vitamin B12-folate status with a higher risk of NTDs (6 studies),
pregnancy complications (recurrent pregnancy losses, gestational diabetes, preeclampsia)
(9 studies), lower birth weight (10 studies) and adverse longer-term health
outcomes in the offspring (cognitive functions, adiposity, insulin resistance) (11 studies). Vitamin B12 supplementation (7 RCT’s) in pregnancy showed a beneficial effect on
offspring neurocognitive development and an effect on birth weight was inconclusive.
There is a high quality evidence to support the role of low maternal vitamin B12 in higher
risk for NTD and low birth weight and moderate-quality evidence for higher risk of
gestational diabetes and later life adverse health outcomes (cognitive functions, risk for
diabetes) in offspring. In the Indian population low maternal vitaminB12 status, is associated with
adverse maternal and child health outcomes. The level of evidence supports adding
vitamin B12 to existing nutritional programs in India for extended benefits on outcomes in
pregnancy and offspring health besides control of anaemia.
Efficacy of B12 Fortified Nutrient Bar and Yogurt in Improving Plasma B12 Concentrations— Results From 2 Double-Blind Randomized Placebo Controlled Trials
Abstract: Dietary vitamin B12 (B12) deficiency is common in Indians. Long-term compliance to
tablet supplementation is poor in asymptomatic individuals. To study efficacy of B12 fortified nutrient bar and yogurt in improving plasma B12
concentrations in children and adults. Two double-blind, placebo-controlled directly observed therapy randomized controlled
trials were conducted for 120 days: (1) Healthy children (10-13 years) were fed nutrient bar fortified
with B12 (2 mg), multiple micronutrients B12 (1.8 mg) or placebo. (2) Healthy adults (18-50 years) were
fed yogurt fortified with B12 (2 mg) or Propionibacterium (1 108 cfu/g) or placebo. B12, folate,
homocysteine, and hemoglobin concentrations were measured before and post intervention. We randomized 164 children and 118 adults; adherence was 96% and 82%, respectively.
In children, B12 fortified bars increased B12 concentrations significantly above baseline (B12 alone
þ91 pmol/L, B12þ multiple micronutrients þ82 pmol/L) compared to placebo. In adults, B12 fortified
yogurt increased B12 significantly (þ38 pmol/L) but Propionibacterium and placebo did not. In both trials,
homocysteine fell significantly with B12 supplementation. Rise of B12 and fall of homocysteine were influenced by dose of B12 and folic acid. There was no significant difference in change of anthropometry
and hemoglobin between groups.
B12 fortified foods are effective in improving B12 status in Indian children and adults.
They could be used to improve B12 status in the national programs for children, adolescents, and
women of reproductive age. They could also be used as over-the-counter products.
Transient systemic inflammation in adult male mice results in underweight progeny
Author Name: Sushama Rokade, Manoj Upadhya, Dattatray S. Bhat, Nishikant Subhedar et al. , Publication Year: 2021 , Journal Name: American Journal Reproductive Immunology
Abstract: While the testes represent an immune-privileged
organ, there is evidence
that systemic inflammation is accompanied by local inflammatory responses. We
therefore examined whether transient systemic inflammation caused any inflammatory
and functional consequences in murine testes. Using a single systemic administration of Toll-like
receptor (TLR)
agonists [lipopolysaccharide (LPS) or peptidoglycan (PG) or polyinosinic-polycytidylic
acid (polyIC)] in young adult male mice, we assessed testicular immune-inflammatory
landscape and reproductive functionality. Our findings demonstrated a significant induction of testicular TNF-α,
IL-1β
and IL-6
transcripts within 24 h of TLR agonist injection. By day 6, these cytokine
levels returned to baseline. While there was no change in caudal sperm counts at
early time points, eight weeks later, twofold decrease in sperm count and reduced testicular
testosterone levels were evident. When these mice were subjected to mating
studies, no differences in mating efficiencies or litter sizes were observed compared
with controls. Nonetheless, the neonatal weights of progeny from LPS/PG/polyIC-treated
sires were significantly lower than controls. Postnatal weight gain up to three
weeks was also slower in the progeny of LPS/polyIC-treated
sires. Placental weights
at 17.5 days post-coitum
were significantly lower in females mated to LPS-and
polyIC-treated
males. Given this likelihood of an epigenetic effect, we found lower testicular
levels of histone methyltransferase enzyme, mixed-lineage
leukaemia-1,
in mice given
LPS/PG/polyIC 8 weeks earlier.
Conclusion: Exposure to transient systemic inflammation leads to transient local inflammation
in the testes, with persistent sperm-mediated
consequences for foetal
development.
COVID-19 Patients Admitted to a Tertiary Care Hospital in Pune, India and Predictors of Requirement for Intensive Care Treatment
Author Name: Urvi Bhooshan Shukla, Sharvari Rahul Shukla, Sachin Bhaskar Palve, Rajiv Chintaman Yeravdekar et al. , Publication Year: 2021 , Journal Name: Journal of The Association of Physicians of India
Abstract: To study associations of severity of COVID-19 disease with clinical features and laboratory markers. 2. To develop
a model to predict the need for ICU treatment. This is an analysis of clinical course in 800 consecutive patients from a dedicated COVID-19 tertiary care hospital in
Pune, India (8th April to 15th June 2020). We obtained clinical and laboratory information, severity grading and progress from
hospital records. We studied associations of these characteristics with need for ICU management. We developed a predictive
model of need for ICU treatment among first 500 patients and tested its sensitivity and specificity in the following 300 patients.
Maternal vitamin B12, folate during pregnancy and neurocognitive outcomes in young adults of the Pune Maternal Nutrition Study (PMNS) prospective birth cohort: study protocol
Abstract: The Developmental Origins of Health and
Disease (DOHaD) hypothesis proposes that intrauterine
and early life exposures significantly influence fetal
development and risk for disease in later life. Evidence
from prospective birth cohorts suggests a role for maternal
B12 and folate in influencing neurocognitive outcomes
in the offspring. In the Indian setting, B12 deficiency is
common during the pregnancy while rates of folate
deficiency are lower. The long-term
influences of maternal
nutrition during the pregnancy on adult neurocognitive
outcomes have not been examined. The Pune Maternal
Nutrition Study (PMNS) is a preconceptional birth cohort
into its 24th year and is considered a unique resource to
study the DOHaD hypothesis. We found an association
between maternal B12 status in pregnancy and child’s
neurocognitive status at 9 years of age. We now plan to
assess neurocognitive function and MRI measurements of
brain structural–functional connectivity at young adult age
to study its association with maternal nutritional exposures
during the pregnancy.
Low vitamin B-12–high folate status in adolescents and pregnant women may have deleterious effects on health of the offspring
Author Name: Rishikesh V Behere, Chittaranjan S Yajnik , Publication Year: 2021 , Journal Name: Am J Clin Nutr
Abstract: We read with interest the paper by Bailey et al. (1) and the associated
editorial by Molloy (2). They report a significant interaction between
low vitamin B-12 and high folate status in relation to lower cognitive
functioning in elderly participants of the NHANES cohort. There is
a suggestion that unmetabolized folic acid might be related to such outcomes, raising a concern about dose of folic acid in fortified foods
and supplements. We wish to highlight the possible detrimental effects of maternal
imbalance of these 2 vitamins (low vitamin B-12–high folate) on the
health of the offspring, both in the short term and long term. Indians
are predominantly vegetarian because of multigenerational cultural
and socioeconomic influences. Low intake of animal-origin foods
in a predominantly vegetarian population contributes to low vitamin
B-12–high folate status. The national anemia-control program (now
called Intensified-National Iron Plus Initiative) provides iron and
folic acid but no vitamin B-12 to children, adolescents, and women of
reproductive age. Obstetricians use large-dose folic acid supplements
(5 mg) for the prevention of neural tube defects (NTDs) and other
purported benefits (although the recommended dose for prevention
of a first occurrence of NTDs is only 400 μg).
Biosocial life-course factors associated with women's early marriage in rural India: The prospective longitudinal Pune Maternal Nutrition Study
Author Name: Akanksha Marphatia, Jonathan Wells, Alice Reid, Chittaranjan Yajnik , Publication Year: 2021 , Journal Name: American Journal of Biological Anthropology
Abstract: Objectives
By convention, women's early marriage is considered a sociocultural decision sensitive to factors acting during adolescence such as poverty, early menarche, and less education. Few studies have examined broader risk factors in the natal household prior to marriage. We investigated whether biosocial markers of parental investment through the daughters' life-course were associated with early marriage risk in rural India. We used an evolutionary perspective to interpret our findings.
Materials and Methods
A prospective cohort recruited mothers at preconception. Children were followed from birth to age 21 years. Multivariable logistic regression models estimated odds ratios of marrying early (<19 years) associated first with wealth, age at menarche and education, and then with broader markers of maternal phenotype, natal household characteristics, and girls' growth trajectories. Models adjusted for confounders.
Results
Of 305 girls, 71 (23%) had married early. Early married girls showed different patterns of growth compared to unmarried girls. Neither poverty nor early menarche predicted early marriage. Girls' non-completion of lower secondary school predicted early marriage, explaining 19% of the variance. Independent of girls' lower schooling, nuclear household, low paternal education, shorter gestation, and girls' poor infant weight gain were associated with marrying early, explaining in combination 35% of the variance.
Discussion
Early marriage reflects “future discounting,” where reduced parental investment in daughters' somatic and educational capital from early in her life favors an earlier transition to the life-course stage when reproduction can occur. Interventions initiated in adolescence may occur too late in the life-course to effectively delay women's marriage.
Poor In Utero Growth and Reduced b-Cell Compensation and High Fasting Glucose from Childhood Are Harbingers of Glucose Intolerance in Young Indians
Author Name: Chittaranjan S. Yajnik, Souvik Bandopadhyay, Aboli Bhalerao, Dattatray S. Bhat et al. , Publication Year: 2021 , Journal Name: Diabetes Care
Abstract: India is a double world capital of early-life undernutrition and type 2 diabetes.
We aimed to characterize life course growth and metabolic trajectories in those
developing glucose intolerance as young adults in the Pune Maternal Nutrition
Study (PMNS).
RESULTS
At 18 years (N = 619), 37% of men and 20% of women were glucose intolerant
(prediabetes n = 184; diabetes n = 1) despite 48% being underweight (BMI <18.5
kg/m2). Glucose-intolerant participants had higher fasting glucose from childhood.
Mothers of glucose-intolerant participants had higher glycemia in pregnancy.
Glucose-intolerant participants were shorter at birth. Insulin sensitivity
dec-reased with age in all participants, and those with glucose intolerance had
consistently lower compensatory insulin secretion from childhood. Participants
in the highest quintile of fasting glucose at 6 and 12 years had 2.5- and 4.0-fold
higher risks, respectively, of 18-year glucose intolerance; this finding was replicated
in two other cohorts.
CONCLUSION
Inadequate compensatory insulin secretory response to decreasing insulin sensitivity
in early life is the major pathophysiology underlying glucose intolerance in thin
rural Indians. Smaller birth size, maternal pregnancy hyperglycemia, and higher glycemia
from childhood herald future glucose intolerance, mandating a strategy for
diabetes prevention from early life, preferably intergenerationally.
Abstract: Vitamin B12 is a fascinating nutrient in that it is made by microbes but is essential for human
metabolism. Humans can get it only from animal origin foods. Dietary deficiency rather than
an absorption defect (Pernicious anemia, intrinsic factor defect) is the commonest cause of
deficiency in the world, contributed by cultural and economic imperatives. Indians have a
large prevalence of subclinical B12 deficiency due to vegetarianism. Birth cohort with longterm
serial follow-up (Pune Maternal Nutrition Study) has helped reveal the life-course evolution
of B12 deficiency: genetics, transplacental and lactational transfer from the mother,
influence of family environment, rapid childhood and adolescent growth, and low consumption
of milk all made a contribution. A novel association of low maternal B12 status was with
fetal growth restriction and increased risk factors of diabetes in the baby. After demonstrating
adequate absorption of small (2 μg) dose of vitamin B12, and a noticeable improvement
of metabolic parameters in a pilot trial, we planned a supplementation trial in adolescents
to improve outcomes in their babies (a primordial prevention called Pune Rural Intervention
in the Young Adolescent). The results are awaited. The long-term effects in the babies born
in the trial will contribute to a better understanding of the Developmental Origins of Health
and Disease. Vitamin B12 is arguably the most fascinating of the nutrients. It is synthesized
only by prokaryotic microbes and thus contributed to the metabolism of the living
from early days of life on earth [1] . Its synthesis is complex and involves around
30 steps. Not all microbes are equipped to synthesize it and some are dependent on an external supply. Vitamin B12-producing bacteria symbiont in some of the
algae are an additional source of the vitamin [2] . Animals eat bacteria and their
products and store vitamin B12 in their tissues; it enters the human food cycle
when products of animal origin are eaten by the humans. The common nutritional
source of the vitamin for humans is thus meat, liver, eggs, fish, and milk.
Those who do not eat animal origin foods (due to ethical, religious, cultural, and
socioeconomic reasons) are thus at a high risk of becoming deficient. Long-term
use of drugs like metformin (for type 2 diabetes) and proton pump inhibitors (for
acid peptic disease) and H. pylori infection also contribute to vitamin B12 deficiency
by interfering different aspects of B12 absorption or metabolism.
Fetal adiposity epidemic in the modern world: a thrifty phenotype aggravated by maternal obesity and diabetes
Author Name: Chittaranjan Yajnik, Parag Yajnik , Publication Year: 2020 , Journal Name: American Journal of Clinical Nutrition
Abstract: Along with the ongoing struggle to overcome undernutrition,
infectious disease, and low birth weight in many countries, we are
facing a rising epidemic of obesity, diabetes, and big babies (1).
The large infants have excess fat in the body (adiposity) which is
thought to be the harbinger of the obesity and diabetes epidemics.
Controlling fetal adiposity may be the only solution to the vicious
intergenerational cycle of obesity and diabetes. We now have a
double duty to solve this double burden of malnutrition. Fetal growth and body composition are driven by genetics
and epigenetics, the latter being the route for the intrauterine
environment to exert its influence. Study of rare monogenic
conditions has helped us understand the role of genes and environment
in fetal growth but the major influences are polygenic
and epigenetic (2, 3). The intrauterine environment thus becomes
the major modifiable influence on fetal growth. It is composed
of maternal nutrition (including dietary requirements, dietary
intake, and nutritional status), metabolism, disease, pollutants,
and other factors. Maternal diabetes has long been known to
influence fetal adiposity, vividly described by Pedersen in the
1950s: “Most conspicuous is obesity, the round cherub’s cheeks,
buried eyes, and short neck…” (4). This visual descriptionmisses
the fat in the intra-abdominal (visceral) tissue.
Type 1 diabetes genetic risk score is discriminative of diabetes in non- Europeans: evidence from a study in India
Author Name: James Harrison, Divya Sri Priyanka Tallapragada, Alma Baptist, Seth Sharp et al. , Publication Year: 2020 , Journal Name: Nature
Abstract: As of 2015 there were 490,000 children <15 years of age living with type 1 diabetes (T1D) globally, with >100,000
in India1. Despite this, almost all large genetic, biomarker and phenotype studies focus on T1D in people of
European ancestry. The extent of overlapping genetic risk for T1D between different ethnic populations is not
well described. Rising obesity rates and the recognition that T1D can occur at any age make the discrimination
between T1D and type 2 diabetes (T2D) an increasingly difficult challenge. The discrimination of diabetes subtypes
is more challenging in the Indian population due to the higher prevalence of early-onset T2D at a lower
body mass index (BMI) than in European populations2. It is vital to identify the correct diabetes subtype as optimal
treatment differs between T1D and T2D.
We and others have previously shown that a T1D genetic risk score (T1D GRS) comprising of between 9 and
67 SNPs can be a useful tool to aid the discrimination between T1D and T2D or controls in Europeans3–6. The
majority of the discriminative power of the T1D GRS is in the first 9 SNPs when ranked by effect size3. These 9
SNPS include SNPs tagging the high-risk HLA DR3-DQ2.5 (DR3)/DR4-DQ8 (DR4) alleles and the highly protective
HLA DR15-DQ6.2 (DR15) allele. In this study we aimed to assess if the T1D GRS developed in Europeans
discriminates T1D from T2D and controls in Indians and could aid diabetes classification in this population.
Maternal B12, Folate and Homocysteine Concentrations and Offspring Cortisol and Cardiovascular Responses to Stress
Author Name: Ghattu V. Krishnaveni, Sargoor R. Veena, Matt Johnson, Kalyanaraman Kumaran et al. , Publication Year: 2020 , Journal Name: J Clin Endocrinol Metab
Abstract: We examined the hypothesis that low plasma vitamin B12 (B12) and high folate
and homocysteine concentrations in the mother are associated with higher hypothalamic–
pituitary–adrenal axis (cortisol) and cardiovascular responses during the Trier Social Stress Test
for Children (TSST-C) in an Indian birth cohort. Adolescents (n = 264; mean age: 13.6 years), whose mothers’ plasma B12, folate
and total homocysteine concentrations had been measured during pregnancy, completed
5-minutes each of public speaking and mental arithmetic tasks in front of 2 unfamiliar “judges”
(TSST-C). Baseline and poststress salivary cortisol concentrations were measured. Heart rate,
blood pressure, stroke volume, cardiac output, and total peripheral resistance were measured
continuously at baseline, during the TSST-C, and for 10 minutes after the TSST-C using a finger
cuff; beat-to-beat values were averaged for these periods, respectively. Maternal low B12 status (plasma B12 < 150 pmol/L) was associated with greater
cortisol responses to stress in the offspring (P < .001). Higher homocysteine concentrations
were associated with greater offspring heart rate response (P < .001). After adjustment for
multiple comparisons, there were nonsignificant associations between higher maternal folate
concentrations and offspring total peripheral resistance response (P = .01). Our findings suggest that maternal 1-carbon nutritional status may have long-term
programming implications for offspring neuroendocrine stress responses.
Birth weight, childhood and adolescent growth and diabetes risk factors in 21-year-old Asian Indians: the Pune Children’s Study
Author Name: Kalyanaraman Kumaran, Himangi Lubree, Dattatray S. Bhat, Suyog Joshi et al. , Publication Year: 2020 , Journal Name: Journal of Developmental Origins of Health and Disease
Abstract: Our objective was to investigate associations of body size (birth weight and bodymass index (BMI))
and growth in height, body fat (adiposity) and lean mass during childhood and adolescence, with
risk markers for diabetes in young South Asian adults. We studied 357 men and women aged
21 years from the Pune Children’s Study birth cohort. Exposures were 1) birth weight, 21-year
BMI, both of these mutually adjusted, and their interaction, and 2) uncorrelated conditional measures
of growth in height and proxies for gain in adiposity and lean mass frombirth to 8 years (childhood)
and 8 to 21 years (adolescence) constructed from birth weight, and weight, height, and
skinfolds at 8 and 21 years. Outcomes were plasma glucose and insulin concentrations during
an oral glucose tolerance test and derived indices of insulin resistance and secretion. Higher 21-year
BMIwas associated with higher glucose and insulin concentrations and insulin resistance, and lower
disposition index. After adjusting for 21-year BMI, higher birth weight was associated with lower
120-min glucose and insulin resistance, and higher disposition index. In the growth analysis, greater
adiposity gain during childhood and adolescence was associated with higher glucose, insulin and
insulin resistance, and lower disposition index, with stronger effects from adolescent gain. Greater
childhood lean gain and adolescent height gain were associated with lower 120-min glucose and
insulin. Consistent with other studies, lower birth weight and higher childhood weight gain
increases diabetes risk. Disaggregation of weight gain showed that greater child/adolescent adiposity
gain and lower lean and height gain may increase risk.
Do components of adult height predict body composition and cardiometabolic risk in a young adult South Asian Indian population? Findings from a hospital-based cohort study in Pune, India: Pune Children’s Study
Author Name: Kalyanaraman Kumaran, Suyog M Joshi, Chiara Di Gravio, Himangi Lubree et al. , Publication Year: 2020 , Journal Name: BMJ Open
Abstract: We investigated whether the relationship
between components of height and cardiovascular disease
(CVD) risk may be explained by body composition. We also
examined relationships between parental heights and
offspring CVD risk. We studied 357 young adults and their
parents in the Pune Children’s Study. Primary and
secondary outcomes: we measured weight, total height,
leg length, sitting height, plasma glucose, insulin and
lipids, and blood pressure (BP). Total and regional lean and
fat mass were measured by dual X-ray
absorptiometry. Leg length was inversely related, and sitting
height was directly related to BMI. Total height and leg
length were directly related to lean mass, while sitting
height was directly related to both lean and fat mass. Leg
length was inversely related to systolic BP and 120 min
glucose, independent of lean and fat mass. Sitting height
was directly related to systolic BP and triglycerides; these
relationships were attenuated on adjustment for lean
and fat mass. When examined simultaneously, greater
leg length was protective and greater sitting height was
associated with a more detrimental CVD risk profile. Shorter adult leg length and greater sitting
height are associated with a more adverse CVD risk factor
profile. The mechanisms need further study, but our
findings suggest a role for lean and fat mass.
Author Name: Chittaranjan Yajnik , Publication Year: 2019 , Journal Name: Nutrition Foundation of India Bulletin
Abstract: Worldwide, the prevalence of diabetes in adults has progressively
1 increased from 4.7% in 1980, to 5.1% in 2003, to 6.0% in 2007 and
2 8.8% in 2017 as reported by the International Diabetes Foundation .
India has also seen a parallel rise in the incidence of diabetes. A
comparison of two surveys in Tamil Nadu (conducted using similar
methods) ten years apart (2006 and 2016), reported that diabetes
prevalence in persons 18-65 years of age had increased significantly
during the decade in a city (from 18.6% to 21.9%), in a town (16.4%
3 to 20.3%), and in peri-urban villages (9.2% to 13.4%) . Traditionally, diabetes was considered as a disease of the affluent
and a person’s susceptibility to it was attributed to having the thrifty
4 genotype . This genotype was thought to have evolved over millions
of years out of periodic availability of food (‘famine or feast’) to help
store calories (as body fat) to tide over the famine. It was suggested
that with regular availability of food in modern times, the genotype
produces obesity and led to diabetes. The precipitating factors
proposed were rapid urbanization, unhealthy diets and increasingly
sedentary lifestyles. This was evident as early as 1985 in a Southall
survey which showed that migrant Indians had a much higher
5 prevalence of diabetes as compared to local Europeans . In recent
times, however, it is apparent that people of lower socio-economic
status are also increasingly being affected, and developing countries
carry approximately 80% of the burden of diabetes, with China and
2 India being the world’s diabetes capitals . A recent population-based
ICMR-INDIAB study in 15 states of India reported the overall
prevalence of diabetes at 7.3% and pre-diabetes at 24.7% (ADA
6 criteria) . The interesting finding was that in some of the states, the
prevalence was higher in the urban poor as compared to the higher
income group. The Indian Global Burden of Disease (GBD) report
2017, compared literature-reported diabetes prevalence in the
years 1990 and 2016 and calculated the increase in diabetes burden
over 25 years. The remarkable finding was that the highest increase
in diabetes prevalence was in the states which have suffered
financial, geographic or socio-political difficulties over many
decades. Today, developing countries face a ‘double burden’ of
malnutrition: persistent problems of undernutrition including low
birth weight, stunting and infections, at the same time as increasing
prevalence of obesity, diabetes and other non-communicable
diseases (NCDs). It appears that rapid socioeconomic development
is not well tolerated by populations which faced deprivation in the
7 past . These facts have generated interest to investigate if nongenetic
factors also contribute to increased susceptibility to
diabetes and other NCDs.
Racial/ethnic differences in the burden of type 2 diabetes over the life course: a focus on the USA and India
Author Name: Sherita H. Golden, Chittaranjan Yajnik, Sanat Phatak, Robert L. Hanson et al. , Publication Year: 2019 , Journal Name: Diabetologia
Abstract: Type 2 diabetes is a common disease worldwide, but its prevalence varies widely by geographical region and by race/ethnicity.
This review summarises differences in the frequencies of type 2 diabetes according to race, ethnicity, socioeconomic position,
area of residence and environmental toxins. Type 2 diabetes susceptibility often begins early in life, starting with genetic
susceptibility at conception and continuing in later life, via in utero, childhood and adult exposures. Early-life factors may lead
to overt type 2 diabetes in childhood or in later life, supporting the concept of developmental origins of health and disease. The
causes of the racial/ethnic differences in incidence of type 2 diabetes are not well understood. Specifically, the relative contributions
of genetic and environmental factors to such differences are largely unknown. With a few exceptions in isolated
populations, there is little evidence that differences in frequencies of known type 2 diabetes susceptibility genetic alleles account
for racial/ethnic differences, although the search for genetic susceptibility has not been uniform among the world’s racial/ethnic
groups. In the USA, race/ethnicity is associated with many other risk factors for type 2 diabetes, including being overweight/
obese, diet and socioeconomic status. Some studies suggest that some of these factors may account for the race/ethnic differences
in prevalence of type 2 diabetes, although there is inadequate research in this area. A better understanding of the impact of these
factors on type 2 diabetes risk should lead to more effective prevention and treatment of this disease. This has not yet been
achieved but should be a goal for future research.
Developmental undernutrition, offspring obesity and type 2 diabetes
Author Name: Aryeh D. Stein, Okezi E. Obrutui, Rishikesh V. Behere, Chittaranjan S. Yajnik. , Publication Year: 2019 , Journal Name: Diabetologia
Abstract: The Developmental Origins of Health and Disease (DOHaD) paradigm posits that a mismatch between circumstances at or
around conception and in later life leads to metabolic dysregulation and the development of obesity and diabetes. In this review
we highlight three strands of evidence: prospective studies of patterns of growth from birth to adulthood, historical studies of
exposure to famine at defined points during gestation and early life, and nutrition intervention studies. We conclude that, while
much is still unknown, it is becoming clearer that the combination of early-life undernutrition and later development of obesity is
associated with increased risk of diabetes. There is a need to support public health programmes aimed at intergenerational
(primordial) prevention of diabetes and other non-communicable disease.
Role of blood glucose and fat profile in lung function pattern of Indian type 2 diabetic subjects
Author Name: Morteza A. Khafaie, Sundeep S. Salvi, Chittaranjan S. Yajnik, Fakher Rahim et al. , Publication Year: 2019 , Journal Name: Multidisciplinary Respiratory Medicine
Abstract: It has been hypothesized that changes in lung function can occur in patients with
diabetes. Nevertheless, it is unclear how much of this correlation links with biomarkers of metabolism disorder. We
have investigated the association between hypoglycaemic and fat profile with lung function in Indian diabetic
subjects. Pulmonary function test including predicted forced vital capacity (% FVC), predicted forced
expiratory volume in 1 second (% FEV1) and FEV1/FVC ratio were assessed. We also examined fat profile,
glucose, HbA1c, hemoglobin and other hematological parameters. Four hundred sixty-five subjects aged 55 ± 11 participated in the study. Predicted forced vital capacity, % FEV1
and FEV1/FVC ratio was 85.88 ± 13.53, 85.87 ± 14.06 and 82.03 ± 6.83, respectively. Also, approximately 8 to 17% of the
participant reported having at least one chronic respiratory symptom or lung disease. We found that high glycaemic
measures (i.e. fasting and post-meal plasma glucose) are linked with dyspnea. In addition, HDL (high-density
lipoprotein) concentration was directly associated with % FVC. It is difficult to draw a clear conclusion about the cause-effect relationship or clinical impact
based on this study alone. However, identification of clinically meaningful elements for developing a screening
program is critical.
A physiological dose of oral vitamin B-12 improves hematological, biochemicalmetabolic indices and peripheral nerve function in B-12 deficient Indian adolescent women
Author Name: Chittaranjan S. YajnikID , Rishikesh V. Behere, Dattatray S. BhatID, Nilam Memane et al. , Publication Year: 2019 , Journal Name: PLOS ONE
Abstract: Vitamin B-12 deficiency is often considered synonymous with pernicious anemia, a rare
condition in which severe malabsorption of the vitamin requires high-dose parenteral treatment.
In developing countries such as India, inadequate dietary intake of B-12 due to sociocultural
factors leads to widely prevalent asymptomatic low B-12 status. In this scenario,
lower doses of oral B-12 may be effective, safer and more affordable. To examine the effects of oral B-12 treatment at physiological doses on hematological and biochemical
indices and peripheral nerve function in B-12 deficient rural Indian adolescent women. Thirty-nine women with B-12 deficiency who were excluded from a community based B-12
supplementation trial (Pune Rural Intervention in Young Adolescents (PRIYA)) received oral
B-12 2μg/day, either alone (n = 19) or with multiple micronutrients (UNIMAPP formula +
20gm milk powder, n = 20) for 11 months. Hematological indices, nutrients (B-12, folate),
metabolites (homocysteine) and peripheral nerve function (SUDOSCAN, Impetomedical,
Paris and sensory nerve conduction velocity (NCV) of median and sural nerves) were
assessed at baseline and after 11 months of B-12 treatment. Results were similar in the two treatment allocation groups, which were therefore combined.
At baseline, all women had B-12 concentration <100pmol/L, 79% were anemic and 33% had macrocytosis, but none had neuropathy. After 11 months of treatment, B-12 levels
increased, while folate did not change. The prevalence of anemia fell to 59% and mean corpuscular
volume (MCV) and plasma homocysteine concentrations decreased. Sudomotor
nerve function in the feet improved by an average of 14.7%, and sensory conduction velocity
in median and sural nerves increased by 16.2% and 29.4% respectively. We document clinically beneficial effects of supplementation with a physiological dose of
oral B-12 in asymptomatic rural Indian adolescent women with very low B-12 status. These
findings support a public health approach to tackle the widely prevalent low B-12 status in
young Indians.
Demographic and clinical profile of youth onset diabetes patients in India—Results from the baseline data of a clinic based registry of people with diabetes in India with young age at onset—[YDR-02]
Author Name: Pradeep Praveen, Sri Venkata Madhu, Mohan Viswanathan, Siddhartha Das et al. , Publication Year: 2019 , Journal Name: Pediatric Diabetes
Abstract: We here report the demographic and clinical profile of the patients
enrolled in the Indian Council of Medical Research funded Registry of people with
diabetes in India with young age at onset (YDR) from 1 January 2000 to 31 July 2011. The YDR registry recruits all diabetes cases (newly diagnosed or treated)
reporting on or after 1 January 2000 with age of diagnosis ≤25 years, and residing
within the assigned geographical area of the reporting centres. A baseline proforma
was used to obtain information on demographic and clinical details at registration. The registry has enrolled 5546 patients (49.5% male; 50.5% female) with
youth onset diabetes from 205 reporting centres linked to 8 regional collaborating
centres (RCC) across India. T1DM (63.9%; n = 3545) and T2DM (25.3%; n = 1401)
were the commonest variants of youth onset diabetes, though their relative proportion
varied across RCCs. The mean (SD) age at diagnosis for T1DM was 12.9 (6.5)
years, while that for T2DM was 21.7 (3.7) years. Nearly half the T1DM patients were
registered within 6 months of the onset of disease. Most cases of T2DM (47.3%) were registered after 3 years from their date of diagnosis. 56.1% of patients had at
least one episode of hospitalization at registration. The observations from YDR registry indicate the need to establish a surveillance
system in India to monitor diabetes in youth, not only to understand its complex
etiology and natural history but also due to its detrimental socio economic impact.
Food Access and Nutritional Status of Rural Adolescents in India: Pune Maternal Nutrition Study
Author Name: Anjali V. Ganpule-Rao, Devesh Roy, Bhushana A. Karandikar, Chittaranjan S. Yajnik et al. , Publication Year: 2019 , Journal Name: American Journal of Preventive Medicine
Abstract: The relationships among food access, foods consumed, and nutritional status and
health in developing countries are not well understood. Between 2013 and 2018, differences in the
rural food environment and access to food, nutritional status, and body size in the rural villages
where the Pune Maternal Nutrition birth cohort was recruited were measured and analyzed. Food access measures included the number of shops per 1,000 population, water availability,
and distance from the highway. A total of 418 adolescents (223 boys, 195 girls) aged 18 years
had diet assessed by a quantitative food frequency questionnaire; height, weight, and waist
measured; body fat percentage determined by dual x-ray absorptiometry; and blood biomarkers
(vitamin B12 and hemoglobin) assayed. By village, the number of shops per 1,000 population ranged from 3.85 to 23.29. Boys and
girls from the 2 villages with the highest food access, year-round water availability, and closest to
the highway were heavier and had higher BMI, waist circumference, and body fat percentage compared
with those from the lowest tertile of food access (p<0.05 for all, adjusted for SES). Across all
villages, dietary diversity was poor and B12 insufficiency and anemia were prevalent. With easier
access to food, consumption of staple foods decreased and outside food increased. On multivariate
regression analysis, higher BMI of the adolescents was significantly associated with higher food
access, along with higher weight at birth, socioeconomic scores, and daily energy consumption. Results demonstrate a strong link between rural food access, foods consumed, and
measures of nutritional status in an undernourished, mostly vegetarian, rural population.
The double burden of malnutrition: aetiological pathways and consequences for health
Author Name: Jonathan Wells, Ana Lydia Sawaya, Rasmus Wibaek, Martha Mwangome et al. , Publication Year: 2019 , Journal Name: Lancet
Abstract: Malnutrition has historically been researched and addressed within two distinct silos, focusing either on
undernutrition, food insecurity, and micronutrient deficiencies, or on overweight, obesity, and dietary excess.
However, through rapid global nutrition transition, an increasing proportion of individuals are exposed to different
forms of malnutrition during the life course and have the double burden of malnutrition (DBM) directly. Longlasting
effects of malnutrition in early life can be attributed to interconnected biological pathways, involving
imbalance of the gut microbiome, inflammation, metabolic dysregulation, and impaired insulin signalling. Lifecourse
exposure to early undernutrition followed by later overweight increases the risk of non-communicable
disease, by imposing a high metabolic load on a depleted capacity for homoeostasis, and in women increases the risk
of childbirth complications. These life-course trajectories are shaped both by societal driving factors—ie, rapidly
changing diets, norms of eating, and physical activity patterns—and by broader ecological factors such as pathogen
burden and extrinsic mortality risk. Mitigation of the DBM will require major societal shifts regarding nutrition and
public health, to implement comprehensive change that is sustained over decades, and scaled up into the entire
global food system.
Origins of lifetime health around the time of conception: causes and consequences
Author Name: Tom Fleming, Adam Watkins, Miguel Velazquez, John Mathers, et al , Publication Year: 2018 , Journal Name: Lancet
Abstract: Background: Early life nutrition may affect individuals’ susceptibility
to adult non-communicable diseases (NCD). Psychological stress is a
well-recognised NCD risk factor. Recent evidence suggests that
impaired foetal nutrition alters neuro-endocrine pathways, and
hypothalamic-pituitary-adrenal axis feedback systems, resulting in
abnormal stress responses, and NCD risk. This study aims to examine
adolescent cortisol and cardiovascular stress responses in relation to
maternal nutrition and contemporaneous NCD risk markers.
Methods: The study sample will be drawn from three well-established
birth cohorts in India; the Parthenon cohort, Mysore (N=550,
age~20y), the SARAS KIDS prenatal intervention cohort, Mumbai
(N=300, age~10-12y) and the Pune Rural Intervention in Young Adults/
PRIYA cohort, Pune (N=100, age~22y). We will perform the ‘Trier Social
Stress Test (TSST)’, a well-accepted stress-test module which involves
participants performing 5-minutes each of public speaking and mental
arithmetic tasks in front of unfamiliar ‘judges’ (stressor). Repeated
measures of salivary cortisol and autonomic cardiovascular outcomes
relative to the stressor will be assessed. Measures of psychological
stress, cognitive function, blood pressure, glucose-insulin metabolism
and depression will be carried out. Mechanistic studies including DNA
methylation in gluco-corticoid receptor (NR3C1) and 11β-HSD2 gene
loci and neuroimaging will be carried out in a subsample. Qualitative
interviews and focus group discussions in a subsample of the
Parthenon cohort will explore the perception of stress and stressors
among the youth.
We will convert repeated measures into time-weighted averages
before analysis. We will carry out multivariable regression analysis to
test the associations. We will further refine the analyses using the
mixed-model regression and conditional analyses for the association
with repeated measures.
Ethics and dissemination: This study has been approved by the
research ethics committee of CSI Holdsworth Memorial Hospital,
Mysore. The findings will be disseminated locally and at international
meetings, and reports will be submitted to open access peer reviewed
journals.
IGF-I and IGFBP-3 concentrations at 2 years: associations with anthropometry and milk consumption in an Indian cohort
Author Name: Andrea S. Wiley, Suyog M Joshi, Himangi G. Lubree, Dattatray S. Bhat et al. , Publication Year: 2018 , Journal Name: European Journal of Clinical Nutrition
Abstract: To ascertain associations between plasma insulin-like growth factor I (IGF-I), insulin-like growth
factor-binding protein 3 (IGFBP-3) and their molar ratio at 2 y with neonatal size, infant growth, body composition at 2 y,
and feeding practices in an Indian cohort. A cohort of 209 newborns, with 122 followed at 2 y. Anthropometry was conducted at birth and 2 y. IGFI
and IGFBP-3 concentrations were measured in cord blood and at 2 y. Maternal and child diet was assessed by food
frequency questionnaires and maternal interviews. Multivariate regression was used to test for associations adjusting for
confounding factors. Mean 2 y plasma IGF-I and IGFBP-3 concentrations and IGF-I/IGFBP-3 were 49.4 ng/ml (95% CI: 44.1, 54.8),
1953.8 ng/ml (CI: 1870.6, 2036.9) ng/ml, and 0.088 (CI: 0.081, 0.095), respectively. IGF-I and IGF-I/IGFBP-3 were
positively associated with current length, but not body mass index or adiposity. IGF-I was higher among those with greater
change in length since birth. IGF-I concentrations were higher in children who drank the most milk (>500 vs. <250 ml
per day: 65.6 vs. 42.8 ng/ml, p < 0.04), received other milk <6 months compared to ≥6 months (56.3 vs. 44.8 ng/ml, p <
0.05), and in those whose mothers consumed milk daily vs. less frequently in late pregnancy (56.4 vs. 42.7 ng/ml, p < 0.01).
In multivariate regression, 2 y IGF-I concentration and IGF-I/IGFBP-3 were each positively associated with current length
and milk intake. IGFBP-3 was not related to anthropometry or milk intake. Plasma IGF-I concentrations and IGF-I/IGFBP-3 at 2 y are positively associated with length at 2 y and current
milk intake.
Before the beginning: nutrition and lifestyle in the preconception period and its importance for future health
Author Name: Judith Stephenson, Nicola Heslehurst, Jennifer Hall, Danielle A J M Schoenaker et al. , Publication Year: 2018 , Journal Name: Lancet
Abstract: A woman who is healthy at the time of conception is more likely to have a successful pregnancy and a healthy child.
We reviewed published evidence and present new data from low-income, middle-income, and high-income countries
on the timing and importance of preconception health for subsequent maternal and child health. We describe the
extent to which pregnancy is planned, and whether planning is linked to preconception health behaviours.
Observational studies show strong links between health before pregnancy and maternal and child health outcomes,
with consequences that can extend across generations, but awareness of these links is not widespread. Poor nutrition
and obesity are rife among women of reproductive age, and differences between high-income and low-income
countries have become less distinct, with typical diets falling far short of nutritional recommendations in both
settings and especially among adolescents. Several studies show that micronutrient supplementation starting in
pregnancy can correct important maternal nutrient deficiencies, but effects on child health outcomes are disappointing.
Other interventions to improve diet during pregnancy have had little effect on maternal and newborn health outcomes.
Comparatively few interventions have been made for preconception diet and lifestyle. Improvements in the
measurement of pregnancy planning have quantified the degree of pregnancy planning and suggest that it is more
common than previously recognised. Planning for pregnancy is associated with a mixed pattern of health behaviours
before conception. We propose novel definitions of the preconception period relating to embryo development and
actions at individual or population level. A sharper focus on intervention before conception is needed to improve
maternal and child health and reduce the growing burden of non-communicable diseases. Alongside continued
efforts to reduce smoking, alcohol consumption, and obesity in the population, we call for heightened awareness of
preconception health, particularly regarding diet and nutrition. Importantly, health professionals should be alerted to
ways of identifying women who are planning a pregnancy.
Evaluation of tracer labelled methionine load test in vitamin B-12 deficient adolescent women
Author Name: Dattatray S. Bhat, Lourdes L. Gruca, Carole D. Bennett, Prachi Katre et al. , Publication Year: 2018 , Journal Name: PLOS ONE
Abstract: Methionine loading test (MLT) has been used primarily to identify defects in transsulfuration
of homocysteine in cystathionine beta synthase deficiency. It may not be as useful to evaluate
remethylation pathway, in vitamin B-12 and folate deficiencies. We used tracer isotope labelled MLT to interrogate transsulfuration and remethylation independently
in vitamin B-12 deficiency. We studied vitamin B-12 deficient women with a tracer labelled MLT before and eleven
months after treatment with vitamin B-12. The fractional contribution of [13C]homocysteine
to breath CO2 was used as a measure of transsulfuration, and difference in the intracellular
enrichment of [13C]methionine and that of [C2H3]methionine as a measure of remethylation
of homocysteine. Combined pre- and post-treatment results were analyzed to investigate
the association between plasma vitamin B-12 concentrations and measures of homocysteine
metabolism. The subjects were 17 years old, with a BMI of 19.4 kg/m2. Treatment with vitamin B-12,
2μg/day increased plasma B-12 from 93 (78.7, 106.2) [median (25th, 75th centiles)] to
161.5 (125.5, 226.2) pmol/L; 44% were below <150pmol/L after treatment. Fasting homocysteine
concentration was significantly lower and that of cysteine higher in subjects with
B-12 levels >150pmol/L. The tracer estimated transsulfuration of homocysteine was lower and remethylation higher with B-12 levels >150pmol/L when compared with those
<150pmol/L. The tracer labelled MLT in combination with fasting parameters is a robust way to estimate
parameters of methionine metabolism and can be used in the field where prime-constant
rate infusion studies cannot be done efficiently.
Life course programming of stress responses in adolescents and young adults in India: Protocol of the Stress Responses in Adolescence and Vulnerability to Adult Non-communicable disease (SRAVANA)
Abstract: Background: Early life nutrition may affect individuals’ susceptibility
to adult non-communicable diseases (NCD). Psychological stress is a
well-recognised NCD risk factor. Recent evidence suggests that
impaired foetal nutrition alters neuro-endocrine pathways, and
hypothalamic-pituitary-adrenal axis feedback systems, resulting in
abnormal stress responses, and NCD risk. This study aims to examine
adolescent cortisol and cardiovascular stress responses in relation to
maternal nutrition and contemporaneous NCD risk markers.
Methods: The study sample will be drawn from three well-established
birth cohorts in India; the Parthenon cohort, Mysore (N=550,
age~20y), the SARAS KIDS prenatal intervention cohort, Mumbai
(N=300, age~10-12y) and the Pune Rural Intervention in Young Adults/
PRIYA cohort, Pune (N=100, age~22y). We will perform the ‘Trier Social
Stress Test (TSST)’, a well-accepted stress-test module which involves
participants performing 5-minutes each of public speaking and mentalarithmetic tasks in front of unfamiliar ‘judges’ (stressor). Repeated
measures of salivary cortisol and autonomic cardiovascular outcomes
relative to the stressor will be assessed. Measures of psychological
stress, cognitive function, blood pressure, glucose-insulin metabolism
and depression will be carried out. Mechanistic studies including DNA
methylation in gluco-corticoid receptor (NR3C1) and 11β-HSD2 gene
loci and neuroimaging will be carried out in a subsample. Qualitative
interviews and focus group discussions in a subsample of the
Parthenon cohort will explore the perception of stress and stressors
among the youth.
We will convert repeated measures into time-weighted averages
before analysis. We will carry out multivariable regression analysis to
test the associations. We will further refine the analyses using the
mixed-model regression and conditional analyses for the association
with repeated measures.
Growth and body composition of children aged 2–4 years after exposure to community mobilisation women’s groups in Bangladesh
Author Name: Edward Fottrell, Naveed Ahmed, Badrun Nahar, Sanjit Kumer Shaha et al. , Publication Year: 2018 , Journal Name: Journal of Epidemiology and Community Health
Abstract: Background Women’s groups interventions in
Bangladesh reduced neonatal deaths by 38% and
improved hygienic delivery, newborn care practices and
breast feeding. We explore the longer-term impact of
exposure to women’s groups during pregnancy on child
growth at 2–4 years.
Methods We performed a cross-sectional survey of
child anthropometric measures (analysed as z-scores)
among children born to women who had participated
in the women’s groups interventions while pregnant,
compared with an age-matched and sex-matched
sample of children born to control mothers. Results
were stratified by maternal body mass index (BMI) and
adjusted for possible confounding effects of maternal
education, household asset ownership and, in a separate
model, mother-child height difference, a proxy for
improved survival of small babies in intervention groups.
Results Data were obtained from 2587 motherchild
pairs (91% response). After adjustment for asset
ownership, maternal education and potential survival
effects, children whose mothers were exposed to the
women’s group intervention had higher head (0.16
(0.04 to 0.28)), mid-upper arm (0.11 (0.04 to 0.19)),
abdominal (0.13 (0.00 to 0.26)) and chest (0.18 (0.08 to
0.29)) circumferences than their control counterparts. No
significant differences in subcutaneous fat (subscapular
and triceps skinfold thickness) were observed. When
stratified by maternal BMI, intervention children had
higher weight, BMI and circumferences, and these effects
decreased with increasing maternal BMI category.
Conclusions Women’s groups appear to have had
a lasting, positive impact on child anthropometric
outcomes, with most significant results clustering in
children of underweight mothers. Observed differences
are likely to be of public health significance in terms of
the nutritional and metabolic development of children.
Developmental origins of secondary school dropout in rural India and its differential consequences by sex: A biosocial life-course analysis
Author Name: Akanksha A. Marphatia, Alice M. Reid, Chittaranjan S. Yajnik , Publication Year: 2018 , Journal Name: International Journal of Educational Development
Abstract: We developed a biosocial life-course conceptual approach to investigate maternal and household predictors of
secondary school dropout, and to ascertain whether the consequences of dropout differ between girls and boys.
We analysed longitudinal biomedical data on 648 mother-child dyads from rural Maharashtra, India. Both
maternal (low education, early marriage age, shorter pregnancy duration) and household (low paternal education,
low socio-economic status) traits independently predicted dropout. Poor child growth and educational
trajectories also predicted dropout, mediating the association of only maternal education. Some girls married
despite completing secondary education, suggesting the value of education may be subordinated to the marriage
market.
Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus
Author Name: Benjamin M. Scirica, Deepak L. Bhatt, Eugene Braunwald, P. Gabriel Steg et al. , Publication Year: 2017 , Journal Name: The New England Journal of Medicine
Abstract: The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear.
We randomly assigned 16,492 patients with type 2 diabetes who had a history of,
or were at risk for, cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other
medications, including antihyperglycemic agents. The primary end point was a
composite of cardiovascular death, myocardial infarction, or ischemic stroke.
A primary end-point event occurred in 613 patients in the saxagliptin group and in
609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year
Kaplan–Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P=0.99 for superiority; P<0.001 for noninferiority); the results
were similar in the “on-treatment” analysis (hazard ratio, 1.03; 95% CI, 0.91 to
1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1059 patients in the saxagliptin group and in
1034 patients in the placebo group (12.8% and 12.4%, respectively, according to
2-year Kaplan–Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P=0.66).
More patients in the saxagliptin group than in the placebo group were hospitalized
for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007).
Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two
groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo
group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively).
DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic
events, though the rate of hospitalization for heart failure was increased. Although
saxagliptin improves glycemic control, other approaches are necessary to reduce
cardiovascular risk in patients with diabetes. (Funded by AstraZeneca and Bristol-Myers Squibb; SAVOR-TIMI 53 ClinicalTrials.gov number, NCT01107886.)
Abstract: With almost one-fifth of the world’s population living in India, the health status and the drivers of health loss are expected to vary between different parts of the country and between the states. Accordingly, effective efforts to improve population health in each state require systematic knowledge of the local health status and trends. While state-level trends for some important health indicators have been available in India, a comprehensive
Assessment of the diseases causing the most premature deaths and disability in each state,
The risk factors responsible for this burden, and their time trends have not been available in a single standardized framework. The India State-level Disease Burden Initiative was launched in October 2015 to address this crucial knowledge gap with support from the Ministry of Health and Family Welfare of the Government of India. This is a collaborative effort between the Indian Council of Medical Research, Public Health Foundation of India, Institute for Health Metrics and Evaluation, and experts and stakeholders from about 100 institutions across India.
Vitamin B-12, Folic Acid, and Growth in 6- to 30-Month-Old Children: A Randomized Controlled Trial
Author Name: Tor A. Strand, Sunita Taneja, Tivendra Kuma, Mari S. Manger et al. , Publication Year: 2017 , Journal Name: PEDIATRICS
Abstract: Folate and vitamin B-12 are important for growth. Many children in low- and
middle-income countries have inadequate intakes of these nutrients. We undertook a randomized, placebo controlled double-blind trial in 1000 North
Indian children, 6 to 35 months of age, providing twice the recommended daily allowance of
folic acid and/or vitamin B-12, or placebo, daily for 6 months. By using a factorial design, we
allocated children in a 1:1:1:1 ratio in blocks of 16. We measured the effect of giving vitamin
B-12, folic acid, or the combination of both on linear and ponderal growth. We also identified
predictors for growth in multiple linear regression models and effect modifiers for the effect of
folic acid or vitamin B-12 supplementation on growth. The overall effect of either of the vitamins was significant only for weight; children who
received vitamin B-12 increased their mean weight-for-age z scores by 0.07 (95% confidence
interval: 0.01 to 0.13). Weight-for-age z scores and height-for-age z scores increased
significantly after vitamin B-12 supplementation in wasted, underweight, and stunted
children. These subgrouping variables significantly modified the effect of vitamin B-12 on
growth. Vitamin B-12 status at baseline predicted linear and ponderal growth in children not
receiving vitamin B-12 supplements but not in those who did (P-interaction , .001). We provide evidence that poor vitamin B-12 status contributes to poor growth. We
recommend studies with larger doses and longer follow-up to confirm our findings.
Fetal growth trajectories in pregnancies of European and South Asian mothers with and without gestational diabetes, a populationbased cohort study
Author Name: Line Sletner, Anne Karen Jenum, Chittaranjan S. Yajnik, Kjersti Morkrid et al. , Publication Year: 2017 , Journal Name: PLOS ONE
Abstract: Our aim was to examine the impact of gestational diabetes (GDM), from before the GDM diagnosis
is made, on fetal growth trajectories, and to compare it in Europeans and South
Asians; two ethnic groups with dissimilar fetal growth patterns. We studied European (n = 349) and South Asian (n = 184) pregnant women, from the population-
based STORK-Groruddalen cohort in Oslo, Norway. Mothers were enrolled in early
pregnancy, screened for GDM in gestational week 28 ±2, and classified as ªnon-GDMº,
ªmild GDMº or ªmoderate/severe GDMº. We measured fetal head circumference, abdominal
circumference and femur length by ultrasound, and estimated fetal weight in gestational
week 24, 32 and 37, and performed corresponding measurements at birth. In non-GDM pregnancies, South Asian fetuses (n = 156) had a slower growth from gestational
week 24, compared with Europeans (n = 310). More than two thirds of the European
mothers later diagnosed with GDM were overweight or obese in early pregnancy, while this
was not observed in South Asians. Fetuses of GDM mothers tended to be smaller than
fetuses of non-GDM mothers in week 24, but thereafter grew faster until birth. This pattern
was especially pronounced in fetuses of South Asian mothers with moderate/severe GDM. In week 24 these fetuses had a -0.95 SD (95% CI: -1.53, -0.36) lower estimated fetal weight
than their non-GDM counterparts. In contrast, at birth they were 0.45 SD (0.09, 0.81) larger. Offspring of GDM mothers were smaller in mid pregnancy, but subsequently grew faster
until birth, compared with offspring of non-GDM mothers. This pattern was most prominent
in South Asian mothers with moderate to severe GDM. However, the most remarkable characteristic
of these fetuses was not a large size at birth, but the small size in mid pregnancy,
before the GDM diagnosis was set.
Abstract: The Pune Maternal Nutrition Study (PMNS) was established to prospectively study the relationship of
maternal nutrition to fetal growth and later cardiometabolic risk in the offspring. High homocysteine and low
vitamin B12 levels in pregnancy predicted lower birthweight and higher insulin resistance at 6 years in the
offspring. B12 deficiency was widespread in this population, due to low dietary intake. We therefore commenced a
community-based intervention study with the underlying hypothesis that vitamin B12 supplementation of
adolescent members of the PMNS cohort will improve birth weight, B12 status, and reduce future diabetes risk, in
their offspring. The individually randomised controlled trial commenced in September 2012, with boys and girls
randomized into 3 groups, to receive daily for at least 3 years or until the birth of their first child: 1) vitamin B12 2 μg;
or 2) vitamin B12 2 μg plus multiple micronutrients (MMN) plus 20 g of milk powder or 3) placebo. Iron and folic acid is
given to all participants. Compliance is assessed by monthly supplement counts. Adverse events are recorded using a
standardised questionnaire. The primary outcome is cord blood B12 concentration; based on 180–200 pregnancies in
the girls, the study has ~80% power to detect a 0.5 SD change in newborn B12, in the B12 supplementation groups
compared with controls, at the 5% significance level. Primary analysis will be by intention to treat. Our study tests a primordial prevention strategy through an intergenerational intervention started preconceptionally
in both boys and girls using physiological doses of micronutrients to improve immediate pregnancyrelated
and long-term cardio metabolic outcomes. The results will have significant public health implications in a
setting with widespread B12 deficiency but relative folate sufficiency. The randomised controlled trial design allows us
to be confident that our findings will be causally relevant. ISRCTN 32921044, applied on 14/09/2012. CTRI 2012/12/003212, registered on 02/12/2012.
Retrospectively registered.
Air pollution and respiratory health among diabetic and non-diabetic subjects in Pune, India—results from the Wellcome Trust Genetic Study
Author Name: Morteza Abdullatif Khafaie, Sundeep Santosh Salvi, Chittaranjan Sakerlal Yajnik, Ajay Ojha et al. , Publication Year: 2017 , Journal Name: Environmental Science and Pollution Research
Abstract: Diabetics may be more vulnerable to the harmful
effects of ambient air pollutants than healthy individuals. But,
the risk factors that lead to susceptibility to air pollution in
diabetics have not yet been identified.We examined the effect
of exposure to ambient PM10 on chronic symptoms and the
pulmonary function tests (PFT) in diabetic and non-diabetic
subjects. Also, to investigate possible determinants of susceptibility,
we recruited 400 type 2 diabetic and 465 healthy subjects
who were investigated for chronic respiratory symptoms (CRSs) and then underwent measurement of forced vital capacity
(FVC) and forced expiratory volume 1 (FEV1) according
to standard protocol. Percent predicted FEV1 and FVC
(FEV1% and FVC%, respectively) for each subject were calculated.
Particulate matter (PM10) concentrations at residence
place of subjects were estimated using AERMOD dispersion
model. The association between PM10 and CRSs was explored
using logistic regression. We also used linear regression
models controlling for potential confounders to study the
association between chronic exposure to PM10 and FEV1%
and FVC%. Prevalence of current wheezing, allergy symptom,
chest tightness, FEV1/FVC <70%, and physiciandiagnosed
asthma and COPD was significantly higher among
diabetic subjects than non-diabetics. There was no significant
difference between percent predicted value of PFT among
diabetic and non-diabetic subjects (P < 0.05). We estimated
that 1 SD increase in PM10 concentration was associated with
a greater risk of having dyspnea by 1.50-fold (95% CI, 1.12–
2.01). Higher exposure to PM10 concentration was also significantly
associated with lower FVC%. The size of effect for
1 SD μg/m3 (=98.38) increase in PM10 concentration was
3.71% (95% CI, 0.48–4.99) decrease in FVC%. In addition,
we indicated that strength of these associations was higher in
overweight, smoker, and aged persons. We demonstrated a
possible contribution of air pollution to reduced lung function
independent of diabetes status. This study suggests that decline
in exposure may significantly reduce disease manifestation
as dyspnea and impaired lung function. We conduct that
higher BMI, smoking, and older age were associated with
higher levels of air pollution effects.
Developmental origins of diabetes—an Indian perspective
Author Name: GV Krishnaveni and CS Yajnik. , Publication Year: 2017 , Journal Name: European Journal of Clinical Nutrition
Abstract: The developmental origins of health disease (DOHaD) hypothesis proposes that altered environmental influences (nutrition,
metabolism, pollutants, stress and so on) during critical stages of fetal growth predisposes individuals to diabetes and other noncommunicable
disease in later life. This phenomenon is thought to reflect permanent effects (‘programming’) of unbalanced fetal
development on physiological systems. Intrauterine programming may underlie the characteristic Indian ‘thin–fat’ phenotype and
the current unprecedented epidemic of diabetes on the backdrop of multigenerational maternal undernutrition in the country.
India has been at the forefront of the DOHaD research for over two decades. Both retrospective and prospective birth cohorts in
India provide evidence for the role of impaired early-life nutrition on the later diabetes risk. These studies show that in a
transitioning country such as India, maternal undernutrition (of micronutrients) and overnutrition (gestational diabetes) co-exist,
and expose the offspring to disease risk through multiple pathways. Currently, the Indian scientists are embarking on complex
mechanistic and intervention studies to find solutions for the diabetes susceptibility of this population. However, a few unresolved
issues in this context warrant continued research and a cautious approach.
Author Name: Ralph Green, Lindsay H. Allen, Anne-Lise Bjorke-Monsen, Alex Brito et al. , Publication Year: 2017 , Journal Name: DISEASE PRIMERS
Abstract: Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in
cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical
B12 deficiency with classic haematological and neurological manifestations is relatively uncommon.
However, subclinical deficiency affects between 2.5% and 26% of the general population depending
on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals
at all ages, but most particularly elderly individuals. Infants, children, adolescents and women
of reproductive age are also at high risk of deficiency in populations where dietary intake of
B12‑containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake,
inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired
cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status
include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally
increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify
clinical and subclinical deficiency remain debated. Management depends on B12 supplementation,
either via high-dose oral routes or via parenteral administration. This Primer describes the current
knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well
as shifting concepts about the prevalence, causes and manifestations of B12 deficiency
Understanding and acting on the developmental origins of health and disease in Africa would improve health across generations
Author Name: Shane A. Norris , Abdallah Daar, Dorairajan Balasubramanian, Peter Byass et al. , Publication Year: 2017 , Journal Name: Global Health Action
Abstract: Data from many high- and low- or middle-income countries have linked exposures during key
developmental periods (in particular pregnancy and infancy) to later health and disease.
Africa faces substantial challenges with persisting infectious disease and now burgeoning
non-communicable disease.This paper opens the debate to the value of strengthening the
developmental origins of health and disease (DOHaD) research focus in Africa to tackle critical
public health challenges across the life-course. We argue that the application of DOHaD
science in Africa to advance life-course prevention programmes can aid the achievement of
the Sustainable Development Goals, and assist in improving health across generations. To
increase DOHaD research and its application in Africa, we need to mobilise multisectoral
partners, utilise existing data and expertise on the continent, and foster a new generation of
young African scientists engrossed in DOHaD.
Abstract: Imputation is a computational method based on the principle of haplotype sharing allowing enrichment
of genome-wide association study datasets. It depends on the haplotype structure of the population
and density of the genotype data. The 1000 Genomes Project led to the generation of imputation
reference panels which have been used globally. However, recent studies have shown that populationspecific
panels provide better enrichment of genome-wide variants. We compared the imputation
accuracy using 1000 Genomes phase 3 reference panel and a panel generated from genome-wide data
on 407 individuals from Western India (WIP). The concordance of imputed variants was cross-checked
with next-generation re-sequencing data on a subset of genomic regions. Further, using the genomewide
data from 1880 individuals, we demonstrate that WIP works better than the 1000 Genomes phase
3 panel and when merged with it, significantly improves the imputation accuracy throughout the minor
allele frequency range. We also show that imputation using only South Asian component of the 1000
Genomes phase 3 panel works as good as the merged panel, making it computationally less intensive
job. Thus, our study stresses that imputation accuracy using 1000 Genomes phase 3 panel can be further
improved by including population-specific reference panels from South Asia.
Abstract: Previous studies have not adequately captured the heterogeneous nature of the diabetes epidemic in
India. The aim of the ongoing national Indian Council of Medical Research–INdia DIABetes study is to estimate the
national prevalence of diabetes and prediabetes in India by estimating the prevalence by state. We used a stratified multistage design to obtain a community-based sample of 57 117 individuals aged 20 years
or older. The sample population represented 14 of India’s 28 states (eight from the mainland and six from the northeast
of the country) and one union territory. States were sampled in a phased manner: phase I included Tamil Nadu,
Chandigarh, Jharkhand, and Maharashtra, sampled between Nov 17, 2008, and April 16, 2010; phase II included Andhra
Pradesh, Bihar, Gujarat, Karnataka, and Punjab, sampled between Sept 24, 2012, and July 26, 2013; and the northeastern
phase included Assam, Mizoram, Arunachal Pradesh, Tripura, Manipur, and Meghalaya, with sampling done between
Jan 5, 2012, and July 3, 2015. Capillary oral glucose tolerance tests were used to diagnose diabetes and prediabetes in
accordance with WHO criteria. Our methods did not allow us to differentiate between type 1 and type 2 diabetes. The
prevalence of diabetes in different states was assessed in relation to socioeconomic status (SES) of individuals and the
per-capita gross domestic product (GDP) of each state. We used multiple logistic regression analysis to examine the
association of various factors with the prevalence of diabetes and prediabetes. The overall prevalence of diabetes in all 15 states of India was 7·3% (95% CI 7·0–7·5). The prevalence of
diabetes varied from 4·3% in Bihar (95% CI 3·7–5·0) to 10·0% (8·7–11·2) in Punjab and was higher in urban areas
(11·2%, 10·6–11·8) than in rural areas (5·2%, 4·9–5·4; p<0·0001) and higher in mainland states (8·3%, 7·9–8·7)
than in the northeast (5·9%, 5·5–6·2; p<0·0001). Overall, 1862 (47·3%) of 3938 individuals identified as having
diabetes had not been diagnosed previously. States with higher per-capita GDP seemed to have a higher prevalence of
diabetes (eg, Chandigarh, which had the highest GDP of US$ 3433, had the highest prevalence of 13·6%, 12.8–15·2).
In rural areas of all states, diabetes was more prevalent in individuals of higher SES. However, in urban areas of some
of the more affluent states (Chandigarh, Maharashtra, and Tamil Nadu), diabetes prevalence was higher in people
with lower SES. The overall prevalence of prediabetes in all 15 states was 10·3% (10·0–10·6). The prevalence of
prediabetes varied from 6·0% (5·1–6·8) in Mizoram to 14·7% (13·6–15·9) in Tripura, and the prevalence of impaired
fasting glucose was generally higher than the prevalence of impaired glucose tolerance. Age, male sex, obesity,
hypertension, and family history of diabetes were independent risk factors for diabetes in both urban and rural areas. There are large differences in diabetes prevalence between states in India. Our results show evidence
of an epidemiological transition, with a higher prevalence of diabetes in low SES groups in the urban areas of the
more economically developed states. The spread of diabetes to economically disadvantaged sections of society is a
matter of great concern, warranting urgent preventive measures. Indian Council of Medical Research and Department of Health Research, Ministry of Health and Family
Welfare, Government of India.
Foetal programming in a diabetic pregnancy: long-term implications for the offspring
Author Name: G. V. Krishnaveni and C. S. Yajnik. , Publication Year: 2017 , Journal Name: CURRENT SCIENCE
Abstract: Maternal diabetes predisposes the growing foetus to
non-communicable disease risk later in life. Studies
show an increased risk of adiposity/obesity, type-2
diabetes and higher blood pressure in offspring of
diabetic mothers. Altered metabolic and neuroendocrine
functions, and epigenetic modification of genes
involved in these functions are some of the mechanisms
proposed for the offspring disease risk. Though
optimal management of diabetes during pregnancy
prevents its immediate complications, there is limited
evidence on the influence of glycaemic control on longterm
effects in the offspring. Future focus should be
on prevention of pregnancy diabetes through appropriate
maternal and child health policies in vulnerable
populations.
Keywords: Gestational diabetes, non-communicable
disease, offspring, pregnancy.
Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children’s health in India and Sub-Saharan Africa
Author Name: Giriraj R. Chandak, Matt J. Silver, Ayden Saffari, Karen A. Lillycrop et al. , Publication Year: 2017 , Journal Name: BMC Nutrition
Abstract: Animal studies have shown that nutritional exposures during pregnancy can modify epigenetic marks
regulating fetal development and susceptibility to later disease, providing a plausible mechanism to explain the
developmental origins of health and disease. Human observational studies have shown that maternal peri-conceptional
diet predicts DNA methylation in offspring. However, a causal pathway from maternal diet, through changes in DNA
methylation, to later health outcomes has yet to be established. The EMPHASIS study (Epigenetic Mechanisms linking
Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa, ISRCTN14266771) will investigate
epigenetically mediated links between peri-conceptional nutrition and health-related outcomes in children whose
mothers participated in two randomized controlled trials of micronutrient supplementation before and during pregnancy. The original trials were the Mumbai Maternal Nutrition Project (MMNP, ISRCTN62811278) in which Indian
women were offered a daily snack made from micronutrient-rich foods or low-micronutrient foods (controls), and the
Peri-conceptional Multiple Micronutrient Supplementation Trial (PMMST, ISRCTN13687662) in rural Gambia, in which
women were offered a daily multiple micronutrient (UNIMMAP) tablet or placebo. In the EMPHASIS study, DNA
methylation will be analysed in the children of these women (~1100 children aged 5–7 y in MMNP and 298 children
aged 7–9 y in PMMST). Cohort-specific and cross-cohort effects will be explored. Differences in DNA methylation
between allocation groups will be identified using the Illumina Infinium MethylationEPIC array, and by pyrosequencing
top hits and selected candidate loci. Associations will be analysed between DNA methylation and health-related
phenotypic outcomes, including size at birth, and children’s post-natal growth, body composition, skeletal development,
cardio-metabolic risk markers (blood pressure, serum lipids, plasma glucose and insulin) and cognitive function. Pathways
analysis will be used to test for enrichment of nutrition-sensitive loci in biological pathways. Causal mechanisms for
nutrition-methylation-phenotype associations will be explored using Mendelian Randomization. Associations between
methylation unrelated to supplementation and phenotypes will also be analysed.
Cobalamin Status from Pregnancy to Early Childhood: Lessons from Global Experience
Author Name: Rima Obeid, Michelle Murphy, Pol Solé-Navais and Chittaranjan Yajnik. , Publication Year: 2017 , Journal Name: Advances in Nutrition
Abstract: Low cobalamin intake and status during pregnancy or lactation have been linked to adverse maternal and perinatal health outcomes, whereas
low cobalamin status during early childhood is associated with impaired development in children. Women who begin pregnancy with depleted
stores (low or very low plasma cobalamin) will give birth to depleted infants who are likely to develop deficiency symptoms during the first few
weeks or months postpartum. Newly ingested cobalamin during pregnancy and lactation (from diet or supplements) is transferred to the child
and is not likely to correct cobalamin status in depleted women. The prevalence of low cobalamin status is high especially in low-income settings
or in populations with a low intake of animal products. Folate and cobalamin play interdependent roles in one-carbon metabolism. Although
folic acid supplementation during early pregnancy is widely recommended and practiced, cobalamin supplementation during pregnancy and
lactation has received little attention. Furthermore, the intake recommendations for pregnant and lactating women and in early life need
reevaluation in the light of newly available evidence in the field.
Abstract: There is growing evidence that air pollution is associated with increased risk of type 2 diabetes (T2DM). However,
information related to whether particulate matter (PM) contributing to worsened metabolic control in T2DM patients is
inconsistent. We examined the association of PM10 exposure with glucose-function parameters in young-onset T2DM
patients. We investigated the association between a year ambient concentration of PM10 at residential places, using
AERMOD dispersion model, with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), 2 h post meal plasma glucose
(2hPG), homeostasis model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-β) and disposition index
(DI) in 1213 diabetic patients from the Wellcome Trust Genetic study at the Diabetes Unit, KEM Hospital Research Center,
Pune, India. We used linear regression models and adjusted for a variety of individual and environmental confounding
variables. Possible effect modification by age, gender, waist-to-hip ratio (WHR) and smoking status were investigated.
Sensitivity analysis assessed the impact of relative humidity (RH) and temperature a day before examination and antidiabetic
and HHR medication (Hydralazine, Hydrochlorothiazide and Reserpine). We found that 1 SD increment in
background concentration of PM10 at residential places (43.83 μg/m3) was significantly associated with 2.25 mmol/mol and
0.38 mmol/l increase in arithmetic means of HbA1c and 2hPG, respectively. A similar increase in PM10 was also associated
with 4.89% increase in geometric mean of HOMA-IR. The associations remained significant after adjustment to RH and
temperature, and WHR and smoking enhanced the size of the effect. Our study suggests that long-term exposure to PM10 is
associated with higher glycaemia and insulin resistance. In context of our previous demonstration of association of SO2 and
NOx and plasma C-reactive protein, we suggest that air pollution could influence progression of diabetes complications.
Prospective studies and interventions are required to define mechanism and confirm causality.
Vitamin B12 supplementation influences methylation of genes associated with Type 2 diabetes and its intermediate traits
Author Name: Dilip K Yadav, Smeeta Shrestha, Karen A Lillycrop, Charu V Joglekar et al. , Publication Year: 2017 , Journal Name: Epigenomics
Abstract: We performed Infinium HumanMethylation450 BeadChip (Zymo Research, CA, USA) assay in
children supplemented with B12 and/or folic acid (n = 12 in each group) and investigated the functional
mechanism of selected differentially methylated loci. We noted significant methylation changes
postsupplementation in B12 (589 differentially methylated CpGs and 2892 regions) and B12 + folic acid
(169 differentially methylated CpGs and 3241 regions) groups. Type 2 diabetes-associated genes TCF7L2
and FTO; and a miRNA, miR21 were further investigated in another B12-supplementation cohort. We also
demonstrate that methylation influences miR21 expression and FTO, TCF7L2, CREBBP/CBP and SIRT1 are
direct targets of miR21-3p. B12 supplementation influences regulation of several metabolically
important Type 2 diabetes-associated genes through methylation of miR21. Hence, our study provides
novel epigenetic explanation for the association between disordered one carbon metabolism and risk of
adiposity, insulin resistance and diabetes and has translational potential.
Author Name: Chittaranjan S. Yajnik , Publication Year: 2017 , Journal Name: European Journal of Clinical Nutrition
Abstract: As an aspiring molecular biologist I learnt about the initiator
codon AUG, the f-Met-tRNA and Nomura’s ribosome cycle
in 1970 [1] but little did I know that methionine would
shadow me for the rest of my life! I was super excited about
Jacob and Monod’s Operon model which taught me how
nutrition and environment could guide the genome to
respond appropriately [2]. Low methionine status, hyperhomocysteinemia,
vitamin B12 deficiency and the associated
epigenetic foetal programming have dominated my
research in the quest to understand the high susceptibility of
Indians to diabetes [3]. Circumstances drove me to become
a doctor rather than a molecular biologist in 1971. My tryst with diabetes research began when I was
training in Medicine at the Sassoon General Hospital, Pune.
I was required to take nutritional history and measure body
mass index of diabetic patients. The scales used measured
weight in pounds and height in feet and inches. Unable to
afford a calculator, I used a log table to calculate the body
mass index (BMI) (kg/m2). The first ten patients revealed
that they were young and thin, unlike the textbook
description of a diabetic as old and obese. Discussions with
the boss resulted in a decision that passing the MD examination
was a priority rather than challenging the dogma!
After obtaining my MD, I applied to five leading diabetes
centres in the United Kingdom, and just when I was ready
to give up, Derek Hockaday offered me a registrar’s position
in Oxford. Later I learned that Sheikh Rashid of Dubai had
generously donated to diabetes research in Oxford, and I
was one of the beneficiaries.
Gut Microbial Diversity Assessment of Indian Type-2-Diabetics Reveals Alterations in Eubacteria, Archaea, and Eukaryotes
Author Name: Shrikant S. Bhute, Mangesh V. Suryavanshi, Suyog M. Joshi , Chittaranjan S. Yajnik et al. , Publication Year: 2017 , Journal Name: Frontiers in Microbiology
Abstract: Diabetes in India has distinct genetic, nutritional, developmental and socio-economic
aspects; owing to the fact that changes in gut microbiota are associated
with diabetes, we employed semiconductor-based sequencing to characterize gut
microbiota of diabetic subjects from this region. We suggest consolidated dysbiosis
of eubacterial, archaeal and eukaryotic components in the gut microbiota of
newly diagnosed (New-DMs) and long-standing diabetic subjects (Known-DMs)
compared to healthy subjects (NGTs). Increased abundance of phylum Firmicutes
(p = 0.010) and Operational Taxonomic Units (OTUs) of Lactobacillus (p < 0.01)
were observed in Known-DMs subjects along with the concomitant graded decrease
in butyrate-producing bacterial families like Ruminococcaceae and Lachnospiraceae.
Eukaryotes and fungi were the least affected components in these subjects but archaea,
except Methanobrevibacter were significantly decreased in them. The two dominant
archaea viz. Methanobrevibacater and Methanosphaera followed opposite trends in
abundance from NGTs to Known-DMs subjects. There was a substantial reduction in
eubacteria, with a noticeable decrease in Bacteroidetes phylum (p = 0.098) and an
increased abundance of fungi in New-DMs subjects. Likewise, opportunistic fungal
pathogens such as Aspergillus, Candida were found to be enriched in New-DMs
subjects. Analysis of eubacterial interaction network revealed disease-state specific
patterns of ecological interactions, suggesting the distinct behavior of individual
components of eubacteria in response to the disease. PERMANOVA test indicated
that the eubacterial component was associated with diabetes-related risk factors like
high triglyceride (p = 0.05), low HDL (p = 0.03), and waist-to-hip ratio (p = 0.02).
Metagenomic imputation of eubacteria depict deficiencies of various essential functions
such as carbohydrate metabolism, amino acid metabolism etc. in New-DMs subjects.
Results presented here shows that in diabetes, microbial dysbiosis may not be just
limited to eubacteria. Due to the inter-linkedmetabolic interactions among the eubacteria,
archaea and eukarya in the gut, it may extend into other two domains leading to
trans-domain dysbiosis in microbiota. Our results thus contribute to and expand the
identification of biomarkers in diabetes.
GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians
Author Name: Suraj S. Nongmaithem, Charudatta V. Joglekar, Ghattu V. Krishnaveni, Sirazul A. Sahariah et al. , Publication Year: 2017 , Journal Name: Human Molecular Genetics
Abstract: Vitamin B12 is an important cofactor in one-carbon metabolismwhose dysregulation is associated with various clinical conditions.
Indians have a high prevalence of B12 deficiency but little is known about the genetic determinants of circulating B12
concentrations in Indians. We performed a genome-wide association study in 1001 healthy participants in the Pune Maternal
Nutrition Study (PMNS), replication studies in 3418 individuals from other Indian cohorts and by meta-analysis identified
new variants, rs3760775 (P¼1.21023) and rs78060698 (P¼8.31017) in FUT6 to be associated with circulating B12 concentrations.
Although in-silico analysis replicated both variants in Europeans, differences in the effect allele frequency, effect size
and the linkage disequilibrium structure of credible set variants with the reported variants suggest population-specific characteristics
in this region. We replicated previously reported variants rs602662, rs601338 in FUT2, rs3760776, rs708686 in FUT6,
rs34324219 in TCN1 (all P<5108), rs1131603 in TCN2 (P¼3.4105), rs12780845 in CUBN (P¼3.0103) and rs2270655 in
MMAA (P¼2.0103). Circulating B12 concentrations in the PMNS and Parthenon study showed a significant decline with
increasing age (P<0.001), however, the genetic contribution to B12 concentrations remained constant. Luciferase reporter
and electrophoretic-mobility shift assay for the FUT6 variant rs78060698 using HepG2 cell line demonstrated strong allele-specific
promoter and enhancer activity and differential binding of HNF4a, a key regulator of expression of various
Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease
Author Name: Ci Song, Stephen Burgess, John D. Eicher, Christopher J. O’Donnell et al. , Publication Year: 2017 , Journal Name: Journal of the American Heart Association
Abstract: Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis.
Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD).
However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk.
To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated
the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1
and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach
using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on
cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the
highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95%
CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model
(odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on
CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal
effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol.
Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose
dysfunction.
Abstract: Background 18% of the world’s population lives in India, and many states of India have populations similar to those of
large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive
state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available
so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state
of India as part of the Global Burden of Disease (GBD) Study 2016.
Methods Using all available data sources, the India State-Level Disease Burden Initiative estimated burden (metrics were
deaths, disability-adjusted life-years [DALYs], prevalence, incidence, and life expectancy) from 333 disease conditions and
injuries and 84 risk factors for each state of India from 1990 to 2016 as part of GBD 2016. We divided the states of India
into four epidemiological transition level (ETL) groups on the basis of the ratio of DALYs from communicable, maternal,
neonatal, and nutritional diseases (CMNNDs) to those from non-communicable diseases (NCDs) and injuries combined
in 2016. We assessed variations in the burden of diseases and risk factors between ETL state groups and between states
to inform a more specific health-system response in the states and for India as a whole.
Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes
Author Name: G. Fulcher, D. R. Matthews, V. Perkovic, D. de Zeeuw et al. , Publication Year: 2016 , Journal Name: Diabetes Obes Metab
Abstract: To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in
the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like
peptide-1 (GLP-1) receptor agonist]. CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine
therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients
from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18. Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18weeks, canagliflozin
100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [−0.56% (95%
confidence interval [CI]: −0.77, −0.35), and −0.75% (95% CI: −0.95, −0.54), respectively] and GLP-1 receptor agonists [−1.00% (95% CI: −1.35, −0.65),
and −1.06% (95% CI: −1.43, −0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both
subsets. Higher incidences of genital mycotic infections and osmotic diuresis–related adverse events (AEs) were seen with canagliflozin compared with
placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background
insulin or insulin secretagogues. In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs
related to SGLT2 inhibition.
Lack of replication of association of THSD7A with obesity
Author Name: M Ahmad, S S Nongmaithem, G V Krishnaveni, C H D Fall , Publication Year: 2016 , Journal Name: International Journal of Obesity
Abstract: This is a PDF file of an unedited peer-reviewed manuscript that has been accepted
for publication. NPG are providing this early version of the manuscript as a service
to our customers. The manuscript will undergo copyediting, typesetting and a proof
review before it is published in its final form. Please note that during the production
process errors may be discovered which could affect the content, and all legal
disclaimers apply. We read with interest the recently published article by Nizamuddin et al that reported
a novel locus THSD7A to be associated with body mass index (BMI) in the Indian
population (1). The discovery is important for two reasons; one because obesity as an
intermediate trait is a shared risk factor for many disease conditions including type 2
diabetes and cardiovascular disorders and second, THSD7A is proposed to be a
population-specific and male-specific locus, although the latter is not highlighted in
the observations. Several obesity-associated loci such as FTO, MC4R, TMEM18, etc.
have been identified in European populations and we and others have reported similar
association for them in the Indian population (2-4). However, Nizamuddin et al failed
to replicate them in their study samples and hence, the results need to interpreted with
caution (1).
Association between Ambient Temperature and Blood Biomarker of Systemic Inflammationin (C-reactive protien) in Diabetes Patients
Author Name: Morteza A Khafaie, Chittaranjan S Yajnik, Mehdi Mojadam, Behzad Khafaie et al. , Publication Year: 2016 , Journal Name: iMedPub Journals
Abstract: Climatic conditions, especially changes in temperature are associated
with cardiovascular (CV) events but underlying mechanisms are not well
understood. We investigated association between air temperature and C-reactive
protein (CRP), in type 2 diabetes patients. The subjects were resident of Pune city and suburbs (n=1700). The
relationships between air temperature at lag 0-5 and different averaging time
periods (3 and 7 days) and CRP concentration were analyzed using robust regression
models. Sensitivity of our result to possible influence of additional adjustments for
season, and air pollutants variable including PM10, NOx, and SO2 were investigated.
Mean daily air temperature during study period varied between 15°C
to 34°C. A 5°C decrease in the air temperature was associated with significant
increase of 15.26% (95% CI=4.42 to 24.88) in geometric mean of CRP concentration
with a lag of 1-day. This study suggests that decrease in temperature is associated
with change in CRP which is important risk factor for CV. We need to investigate
physiological and environmental mediators of this association to help improve CV
risk.
Prevalence of vitamin B-12 insufficiency during pregnancy and its effect on offspring birth weight: a systematic review and meta-analysis
Author Name: Nithya Sukumar, Snorri B Rafnsson, Ngianga-Bakwin Kandala, Raj Bhopal et al. , Publication Year: 2016 , Journal Name: American Society for Nutrition
Abstract: Vitamin B-12 and folate are micronutrients essential
for normal embryogenesis. Vitamin B-12 insufficiency in pregnancy
is high in certain parts of the world, such as India, and although this
has been linked to low birth weight (LBW) in these populations, the
relation between vitamin B-12 and birth weight (BW) elsewhere is
unknown. We performed a systematic review to assess 1) the
worldwide prevalence of vitamin B-12 insufficiency in pregnancy
and 2) its association with BW. A search of 5 electronic databases was performed to identify
eligible articles. Random-effects meta-analysis was conducted
according to geographic regions and pregnancy trimesters for the
prevalence sub review and by categorical measures of BW. A total of 57 and 23 articles were included for the prevalence
and BW subreviews, respectively. The pooled estimates of
vitamin B-12 insufficiency were 21%, 19%, and 29% in the first,
second, and third trimesters, respectively, with high rates for the
Indian subcontinent and the Eastern Mediterranean. The large heterogeneity
between studies was partially addressed by creating
a standardized score for each study (mean vitamin B-12 insufficiency
O cutoff value), which internally corrected for geographic
region, trimester, and assay type. Twelve of the 13 longitudinal
studies included showed a decrease in mean or median vitamin
B-12 across trimesters. Pooled analysis showed nonsignificantly
lower maternal vitamin B-12 concentrations in LBW than in
normal-BW infants and higher odds of LBW with lower vitamin
B-12 values (adjusted OR: 1.70; 95% CI: 1.16, 2.50), but studies
from India largely contributed to the latter. Our review indicates that vitamin B-12 insufficiency
during pregnancy is common even in nonvegetarian populations and
that concentrations of vitamin B-12 decrease from the first to the third
trimester. There is no consistent association between vitamin B-12
insufficiency and LBW. However, given the long-term risks of LBW,
this observation warrants further cohort studies and randomized controlled
trials.
CRITICAL REVIEW OF AIR POLLUTION HEALTH EFFECTS WITH SPECIAL CONCERN ON RESPIRATORY HEALTH
Author Name: Morteza Abdullatif Khafaie, Chittaranjan S. Yajnik, Sundeep S. Salvi, Ajay Ojha. , Publication Year: 2016 , Journal Name: Journal of Air Pollution and Health
Abstract: Searching, PubMed (accessed Nov. 10, 2015) for “Air pollution” and
“Health” resulted in 26,156 citations. Since the 1930 Meuse Valley
episode in Belgium, Donora 1948 and the London fog of December
1952, the number of studies showing adverse health effects of short
and long term exposure to outdoor air pollution has grown. This review
looks at historical air pollution studies to get a general overview
of the overall health effects that can be attributed to bad air quality.
Then we specifically reviewed the important respiratory effects, the
plausible mechanism and population at greater risk. Further research is
central concern of researcher and policy maker to assess the plausible
biological mechanisms of air pollution effects and identifying specific
air pollutant that would be more dangerous
High prevalence of cardiometabolic risk factors in young employees of Information Technology industry
Author Name: Tejas Y. Limaye, Ravindra L. Kulkarni, Manisha R. Deokar, Kalyanaraman Kumaran , Publication Year: 2016 , Journal Name: Indian Journal of Occupational and Environmental Medicine
Abstract: We assessed the burden of
cardiometabolic risk factors in Information Technology (IT)
employees as they are exposed to adverse lifestyle.
In this cross‑sectional study,
health records were obtained from two IT industries in Pune.
Prevalence of cardiometabolic risk factors [hyperglycemia,
high blood pressure (BP), hypertriglyceridemia, high
low‑density lipoprotein (LDL)‑cholesterol, low high‑density
lipoprotein (HDL)‑cholesterol, and overweight/obesity]
was determined using standard cutoffs. We also
examined clustering of risk factors (≥two risk factors). Data were available on 1,350 of 5,800
employees (mean age: 33 ± 6 years, 78% men).
Prevalence of diabetes and hypertension was 2.5% and
13.5%, respectively. Prevalence of prediabetes, borderline
high BP, hypertriglyceridemia, high LDL‑cholesterol, low
HDL‑cholesterol, and overweight/obesity was 6.5%,
20.3%, 21%, 22.1%, 70.1%, and 51.4%, respectively.
Risk factor clustering was observed in 63.5% that
increased with age (P < 0.001). Given
the high burden of risk factors at relatively young age,
spreading awareness and promoting healthy lifestyle
through workplace interventions are warranted.
Abstract: The main objective of this report is to measure to what extent folate or vitamin B12
given daily for 6 months to young North Indian Children improves hemoglobin (Hb) concentration. In a randomized placebo controlled trial in low-to-middle income neighborhoods in New
Delhi, India, children were randomized into four groups in a 1:1:1:1 ratio and supplemented daily for 6
months with 2 RDAs of vitamin B12, folic acid, both, or placebo. All children with anemia at baseline were
given iron supplementation daily for 2 months. We measured the plasma concentrations of soluble
transferrin receptor (sTfR), folate, vitamin B12, total homocysteine (tHcy) and Hb in 262 children.
Results: Mean Hb concentration decreased in all four study groups during the six months of follow up
and supplementation of either or both of the vitamins did not improve the Hb concentration. Iron
supplements for the initial 2 mo had limited effect on anemia at 6 mo as almost 90% were still anemic at
study end. Supplementation of folic acid and/or vitamin B12 for 6 months does not improve Hb concentration
in young children. Our findings do not argue for widespread vitamin B12 or folic acid supplementation
to combat anemia. Our results also call for alternative strategies to improve iron status and
treat iron deficiency anemia.
METHODOLOGICAL APPROACH IN AIR POLLUTION HEALTH EFFECTS STUDIES
Author Name: Morteza A. Khafaie, Ajay Ojha, Sundeep S. Salvi, Chittaranjan S. Yajnik. , Publication Year: 2016 , Journal Name: Journal of Air Pollution and Health
Abstract: Number of scientific studies linking possible effects of air pollution on health
are increasing. However, the disparity in the effect estimated from different
studies and recognizing important determinants of these diversity are essential
. We have explained the types and sources of air pollution, and the common
terms in epidemiological studies of air pollution. Then we reviewed the
study design and critically evaluated methodological approach to estimate
association between air pollution and health with deep insight into dispersion
model. The quality of exposure measurement is critical determinant in an
environmental epidemiology study. However, the available exposure data and
feasible methods for its collection are often the determinant of the design to
be used. Beside vast development in this field, epidemiological approaches to
find out the risks of exposure to air pollutants is still challenging.
Efficacy of a virtual assistance-based lifestyle intervention in reducing risk factors for Type 2 diabetes in young employees in the information technology industry in India: LIMIT, a randomized controlled trial
Author Name: T. Limaye, K. Kumaran, C. Joglekar, D. Bhat et al. , Publication Year: 2016 , Journal Name: Diabetic Medicine
Abstract: To investigate a virtual assistance-based lifestyle intervention to reduce risk factors for Type 2 diabetes in young
employees in the information technology industry in India. LIMIT (Lifestyle Modification in Information Technology) was a parallel-group, partially blinded,
randomized controlled trial. Employees in the information technology industry with ≥3 risk factors (family history of
cardiometabolic disease, overweight/obesity, high blood pressure, impaired fasting glucose, hypertriglyceridaemia, high
LDL cholesterol and low HDL cholesterol) from two industries were randomized to a control or an intervention (1:1)
group. After initial lifestyle advice, the intervention group additionally received reinforcement through mobile phone
messages (three per week) and e-mails (two per week) for 1 year. The primary outcome was change in prevalence of
overweight/obesity, analysed by intention to treat. Results Of 437 employees screened (mean age 36.2 9.3 years; 74.8% men), 265 (61.0%) were eligible and
randomized into control (n=132) or intervention (n=133) group. After 1 year, the prevalence of overweight/obesity
reduced by 6.0% in the intervention group and increased by 6.8% in the control group (risk difference 11.2%; 95% CI
1.2–21.1; P=0.042). There were also significant improvements in lifestyle measurements, waist circumference, and total
and LDL cholesterol in the intervention group.The number-needed-to-treat to prevent one case of overweight/obesity in
1 year was 9 (95% CI 5–82), with an incremental cost of INR10665 (£112.30) per case treated/prevented. A total of
98% of participants found the intervention acceptable. A virtual assistance-based lifestyle intervention was effective, cost-effective and acceptable in reducing risk
factors for diabetes in young employees in the information technology industry, and is potentially scalable.
Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data
Author Name: Tormod Rogne, Myrte J. Tielemans, Mary Foong-Fong Chong, Chittaranjan S. Yajnik et al. , Publication Year: 2016 , Journal Name: American Journal of Epidemiology
Abstract: Vitamin B12 (hereafter referred to as B12) deficiency in pregnancy is prevalent and has been associated with
both lower birth weight (birth weight <2,500 g) and preterm birth (length of gestation <37 weeks). Nevertheless,
current evidence is contradictory. We performed a systematic review and a meta-analysis of individual participant
data to evaluate the associations of maternal serum or plasma B12 concentrations in pregnancy with offspring
birth weight and length of gestation. Twenty-two eligible studies were identified (11,993 observations).
Eighteen studies were included in the meta-analysis (11,216 observations). No linear association was observed
between maternal B12 levels in pregnancy and birth weight, but B12 deficiency (<148 pmol/L) was associated
with a higher risk of low birth weight in newborns (adjusted risk ratio = 1.15, 95% confidence interval (CI): 1.01,
1.31). There was a linear association between maternal levels of B12 and preterm birth (per each 1-standarddeviation
increase in B12, adjusted risk ratio = 0.89, 95% CI: 0.82, 0.97). Accordingly, B12 deficiency was associated
with a higher risk of preterm birth (adjusted risk ratio = 1.21, 95% CI: 0.99, 1.49). This finding supports
the need for randomized controlled trials of vitamin B12 supplementation in pregnancy.
Molecular Characterization and Meta-Analysis of Gut Microbial Communities Illustrate Enrichment of Prevotella and Megasphaera in Indian Subjects
Author Name: Shrikant Bhute, Pranav Pande, Sudarshan A. Shetty, Rahul Shelar et al. , Publication Year: 2016 , Journal Name: Frontiers in Microbiology
Abstract: The gut microbiome has varied impact on the wellbeing of humans. It is influenced by
different factors such as age, dietary habits, socio-economic status, geographic location,
and genetic makeup of individuals. For devising microbiome-based therapies, it is crucial
to identify population specific features of the gut microbiome. Indian population is one
of the most ethnically, culturally, and geographically diverse, but the gut microbiome
features remain largely unknown. The present study describes gut microbial communities
of healthy Indian subjects and compares it with the microbiota from other populations.
Based on large differences in alpha diversity indices, abundance of 11 bacterial phyla
and individual specific OTUs, we report inter-individual variations in gut microbial
communities of these subjects. While the gut microbiome of Indians is different from that
of Americans, it shared high similarity to individuals from the Indian subcontinent i.e.,
Bangladeshi. Distinctive feature of Indian gut microbiota is the predominance of genus
Prevotella and Megasphaera. Further, when compared with other non-human primates,
it appears that Indians share more OTUs with omnivorous mammals. Our metagenomic
imputation indicates higher potential for glycan biosynthesis and xenobiotic metabolism
in these subjects. Our study indicates urgent need of the identification of population-specific
microbiome biomarkers of Indian subpopulations to have a more holistic view of the Indian
gut microbiome and its health implications.
The Elevated Susceptibility to Diabetes in India: An Evolutionary Perspective
Author Name: Jonathan C. K. Wells, Emma Pomeroy, Subhash R. Walimbe, Barry M. Popkin et al. , Publication Year: 2016 , Journal Name: Frontiers in public health
Abstract: India has rapidly become a “diabetes capital” of the world, despite maintaining high
rates of under-nutrition. Indians develop diabetes at younger age and at lower body
weights than other populations. Here, we interpret these characteristics in terms of a
“capacity–load” model of glucose homeostasis. Specifically, we assume that glycemic
control depends on whether the body’s “metabolic capacity,” referring to traits, such
as pancreatic insulin production and muscle glucose clearance, is able to resolve the
“metabolic load” generated by high levels of body fat, high dietary glycemic load, and
sedentary behavior. We employ data from modern cohorts to support the model and the
interpretation that elevated diabetic risk among Indian populations results from the high
metabolic load imposed by westernized lifestyles acting on a baseline of low metabolic
capacity. We attribute this low metabolic capacity to the low birth weight characteristic of
Indian populations, which is associated with short stature and low lean mass in adult life.
Using stature as a marker of metabolic capacity, we review archeological and historical
evidence to highlight long-term declines in Indian stature associated with adaptation
to several ecological stresses. Underlying causes may include increasing population
density following the emergence of agriculture, the spread of vegetarian diets, regular
famines induced by monsoon failure, and the undermining of agricultural security during
the colonial period. The reduced growth and thin physique that characterize Indian populations
elevate susceptibility to truncal obesity, and increase the metabolic penalties
arising from sedentary behavior and high glycemic diets. Improving metabolic capacity
may require multiple generations; in the meantime, efforts to reduce the metabolic load
will help ameliorate the situation.
Developmental Origins of Non-Communicable Diseases
Author Name: CHITTARANJAN YAJNIK, ANJALI GANPULE-RAO, TEJAS LIMAYE, FATEMA RAJGARA , Publication Year: 2016 , Journal Name: Proceedings of the Indian National Science Academy
Abstract: The burden of chronic non-communicable diseases (NCDs) such as diabetes, obesity, and cardiovascular diseases is rising
rapidly in low- and middle-income countries (LMICs). LMICs also have a high occurrence of undernutrition and infectious
diseases which together form the ‘double burden of diseases. The connection between undernutrition and NCDs is
puzzling but explained by David Barker’s idea of intrauterine programming. This idea [now expanded into ‘Developmental
Origins of Health and Disease’ (DOHaD)] focuses on maternal health and nutrition as major determinants of the offspring’s
health. India offers a unique opportunity to study these links. Studies in India have shown that Indian babies are thin but
fat (more adipose tissue) compared to European babies, and maternal nutrition during pregnancy is a determinant of
offspring’s size and body composition. Both, maternal-fetal undernutrition and overnutrition are associated with increased
adiposity and insulin resistance in children. Micronutrients like vitamin B12, folate and vitamin D may be particularly
important. Improving the nutritional status of the young generation (especially that of young women of reproductive age)
offers potential for intergenerational prevention of NCDs.
Genetic studies of body mass index yield new insights for obesity biology
Author Name: Chittaranjan S. Yajnik , Publication Year: 2015 , Journal Name: HHS Public Access
Abstract: Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis. To expand the catalogue of BMI susceptibility loci and gain a better understanding of the genes and biological pathways influencing obesity, we performed the largest GWAS meta-analysis for BMI so far. This work doubles the number of individuals contributing GWAS results, incorporates results from >100,000 individuals genotyped with Metabochip7, and nearly doubles the number of BMI-associated loci. Comprehensive assessment of meta-analysis results provides several lines of evidence supporting candidate genes at many loci and highlights pathways that reinforce and expand our understanding of biological processes underlying obesity.
Lack of knowledge about diabetes in Pune - the city of knowledge!
Author Name: Tejas Y. Limaye, Sonali S. Wagle, Kalyanaraman Kumaran, Charudatta V. Joglekar et al. , Publication Year: 2015 , Journal Name: International Journal of Diabetes in Developing Countries - Springer
Abstract: India is experiencing an escalating epidemic of diabetes for which the most cost-effective solution is prevention. Awareness is the first step towards prevention. We undertook a questionnaire-based study to evaluate gaps in awareness of different implications of diabetes among various sections of the urban population of Pune. Individuals aged ≥13 years (378 diabetic, 1122 non-diabetic) from different socio-economic backgrounds were interviewed using a structured questionnaire. Awareness regarding causes, symptoms, complications, treatment and preventive measures, curability of diabetes and long-term implications of diabetes in pregnancy was evaluated. An awareness score was calculated based on the percent of total questions correctly answered. Of those surveyed, 78 % scored less than 50 %, 44 % did not know the meaning of diabetes, 30 % could not name any of the risk factors, symptoms, complications and preventive measures for diabetes, and 70 % were unaware of the long-term risks of diabetes in pregnancy. As a group, diabetic participants scored marginally better than non-diabetic participants (mean score 39 vs. 31 %; P<0.001). Participants at high risk of diabetes (sedentary workers, non-diabetic participants with first-degree family history of diabetes and non-diabetic hypertensive participants) had poor knowledge about the condition (mean scores <40 %). Lower age, lower education and male gender were independently associated with poor awareness; education was the strongest predictor. Awareness regarding different implications of diabetes is poor in the population of Pune. There is a need for widespread and extensive public education campaigns to raise awareness and contribute to the national diabetes prevention initiatives.
Abstract: Objective: Vitamin B12 and folate are critical micronutrients needed to support the increased metabolic demands of pregnancy. Recent studies from India have suggested that low vitamin B12 and folate concentrations in pregnancy are associated with increased obesity; however differences in diet, antenatal vitamin supplementation, and socioeconomic status may limit the generalisability of these findings. We aimed to explore the cross-sectional relationship of circulating serum vitamin B12 and folate at 28 weeks’ gestation with maternal adiposity and related biochemical markers in a white non diabetic UK obstetric cohort. Methods: Anthropometry and biochemistry data was available on 995 women recruited at 28 weeks gestation to the Exeter Family Study of Childhood Health. Associations between B12 and folate with maternal BMI and other obesity-related biochemical factors (HOMA-R, fasting glucose, triglycerides, HDL and AST) were explored using regression analysis, adjusting for potential confounders (socioeconomic status, vegetarian diet, vitamin supplementation, parity, haemodilution (haematocrit)). Results: Higher 28 week BMI was associated with lower circulating vitamin B12 (r = -0.25; P<0.001) and folate (r = -0.15; P<0.001). In multiple regression analysis higher 28 week BMI remained an independent predictor of lower circulating B12 (β (95% CI) = -0.59 (-0.74, -0.44) i.e. for every 1% increase in BMI there was a 0.6% decrease in circulating B12). Other markers of adiposity/body fat metabolism (HOMA-R, triglycerides and AST) were also independently associated with circulating B12. In a similar multiple regression AST was the only independent obesity-related marker associated with serum folate (β (95% CI) = 0.16 (0.21, 0.51)) Conclusion: In conclusion, our study has replicated the previous Indian findings of associations between lower serum B12 and higher obesity and insulin resistance during pregnancy in a non-diabetic White British population. These findings may have important implications for fetal and maternal health in obese pregnancies.
New genetic loci link adipose and insulin biology to body fat distribution
Author Name: C. S. Yajnik et al. , Publication Year: 2015 , Journal Name: Europe PMC Funders Group
Abstract: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
To further elucidate the genetic architecture of fat distribution and to increase our understanding of molecular connections with cardiometabolic traits, we performed a meta-analysis of WHRadjBMI associations in 142,762 individuals with GWAS data and 81,697 individuals genotyped with the Metabochip11, all from the Genetic Investigation of ANthropometric Traits (GIANT) Consortium. Given the marked sexual dimorphism previously observed among established WHRadjBMI loci7,8, we performed analyses in men and women separately, the results of which were subsequently combined. To more fully characterize the genetic determinants of specific aspects of body fat distribution, we performed secondary GWAS meta-analyses for five additional traits: unadjusted WHR, BMI-adjusted and unadjusted waist (WCadjBMI and WC), and hip circumferences (HIPadjBMI and HIP). We evaluated the associated loci to understand their contributions to variation in fat distribution and adipose tissue biology, and their molecular links to cardiometabolic traits.
Vitamin B12 and Folic Acid Improve Gross Motor and Problem-Solving Skills in Young North Indian Children: A Randomized Placebo-Controlled Trial
Author Name: Ingrid Kvestad, Sunita Taneja, Tivendra Kumar, Mari Hysing et al. , Publication Year: 2015 , Journal Name: PLOS ONE
Abstract: Deficiencies of vitamin B12 and folate are associated with delayed development and neurological
manifestations. The objective of this study was to measure the effect of daily supplementation
of vitamin B12 and/or folic acid on development in young North Indian children.
In a randomized, double blind trial, children aged six to 30 months, received supplement
with placebo or vitamin B12 and/or folic acid for six months. Children were allocated in a
1:1:1:1 ratio in a factorial design and in blocks of 16. We measured development in 422 children
by the Ages and Stages Questionnaire 3rd ed. at the end of the intervention.Compared to placebo, children who received both vitamin B12 and folic acid had 0.45 (95%
CI 0.19, 0.73) and 0.28 (95% CI 0.02, 0.54) higher SD-units in the domains of gross motor
and problem-solving functioning, respectively. The effect was highest in susceptible subgroups
consisting of stunted children, those with high plasma homocysteine (> 10 μmol/L)
or in those who were younger than 24 at end study. With the exception of a significant
improvement on gross motor scores by vitamin B12 alone, supplementation of either vitamin
alone had no effect on any of the outcomes. Our findings suggest that supplementation of vitamin B12 and folic acid benefits development in North Indian Children.
Influence of early life environment on risk of non-nommunicable diseases (NCDs) in Indians
Author Name: Prachi Katre, Chittaranjan S Yajnik , Publication Year: 2015 , Journal Name: PUNE EXPERIENCE
Abstract: India is one of the capitals of the world for diabetes and coronary
artery disease.1 At the KEM Hospital Diabetes Unit in Pune,
India, we have been actively involved in studying the susceptibility
of Indians to these disorders. Our early research described
the characteristics of Indian type 2 diabetic patients: younger
age and lower BMI but higher waist-hip ratio and higher insulin
resistance compared with European patients.2,3,4 This was
the beginning of the ‘thin-fat’ Indian concept which provided
an explanation for higher susceptibility of Indians to diabetes
compared to Europeans despite a lower BMI.5
Over the past 25 years, we have progressed to define lifecourse
evolution of the Indian phenotype through a number
of prospective studies and tested the contribution of genetics,
epigenetics, nutrition and other environmental factors to this
phenotype
Author Name: Urmila Deshmukh Nick Brown Chittaranjan Yajnik , Publication Year: 2015 , Journal Name: PAEDIATRICS AND CHILD HEALTH
Abstract: After long periods of vast child health disparities between industrialized
countries and Resource-limited Settings (RLS) a wave of research
has started to address and reduce the gap. Major global collaborations
have been mutually rewarding and have established funding
and career structures unthinkable even 25 years ago. Despite this
progress, work remains to ensure academic and funding equity and
ethical parity. This paper outlines the background to and history of
research in RLS, illustrates the current situation and points to potential
future developments.
Keywords Millennium Development Goals (MDGs); research ethics;
Resource-limited Settings (RLS); United Nations Children’s Fund
(UNICEF); World Health Organisation (WHO)
Association of Maternal Vitamin C Status with Gestational Diabetes Mellitus
Author Name: Hedyeh Masoodi, Trupti Vilas Kamat, Kurus Jhangir Coyaji, Dattatray Shivram Bhat et al. , Publication Year: 2015 , Journal Name: Journal of Krishna Institute of Medical Sciences University
Abstract: Background: The role of antioxidants in the etiology of
gestational diabetes mellitus (GDM) has been given
limited attention. Vitamin C is a nutrient with radical
quenching property and has been claimed to influence
glucose tolerance. Aim: To study the association
between vitamin C status (dietary intake and plasma
concentrations) and GDM. Material and Methods:
Using a case-control design with 1:3 ratio we examined
42 pregnant women with GDM and 158 normal glucose
tolerant (NGT) gestational age-matched healthy
pregnant women at an average of 26 weeks of gestation.
Maternal vitamin C intake was determined using
detailed semi food frequency questionnaire (SFFQ) and
24 hour diet recall. Plasma vitamin C was determined
using a spectrophotometric method in non-fasting
samples. GDM was diagnosed by 75 gm oral glucose
tolerance test (OGTT) using International Association
for Diabetes in Pregnancy Study Group (IADPSG)
criteria (fasting ≥92mg%, 1hour ≥180mg%, 2 hour
≥153mg %). Results: GDM women had lower median
intake of vitamin C (35.0 mg/day vs. 66.7; p<0.001)
and lower median plasma vitamin C concentration
(45.9 μmol/L vs. 95.2; p<0.001) compared to NGT
women. Plasma vitamin C concentration was inversely
related to fasting, 1 hour and 2 hour post glucose plasma
glucose concentrations (p<0.001). The associations
remained significant after adjustment for age, income,
pre-pregnancy BMI, and stress. Conclusion: Our
findings suggest that low vitamin C intake as well as
low plasma vitamin C concentration is associated with
GDM. This association needs to be tested in a large
prospective study and subsequently in a clinical trial.
Keywords: GDM, Vitamin C, Antioxidant.
Low Maternal Vitamin B12 Status Is Associated with Lower Cord Blood HDL Cholesterol in White Caucasians Living in the UK
Author Name: Antonysunil Adaikalakoteswari, Manu Vatish, Alexander Lawson, Catherine Wood et al. , Publication Year: 2015 , Journal Name: Nutrients
Abstract: Background and Aims: Studies in South Asian population show that low maternal vitamin B12 associates with insulin resistance and small for gestational age in the offspring. Low vitamin B12 status is attributed to vegetarianism in these populations. It is not known whether low B12 status is associated with metabolic risk of the offspring in whites, where the childhood metabolic disorders are increasing rapidly. Here, we studied whether maternal B12 levels associate with metabolic risk of the offspring at birth. Methods: This is a cross-sectional study of 91 mother-infant pairs (n = 182), of white Caucasian origin living in the UK. Blood samples were collected from white pregnant women at delivery and their newborns (cord blood). Serum vitamin B12, folate, homocysteine as well as the relevant metabolic risk factors were measured. Results: The prevalence of low serum vitamin B12 (<191 ng/L) and folate (<4.6 μg/L) were 40% and 11%, respectively. Maternal B12 was inversely associated with offspring’s Homeostasis Model Assessment 2-Insulin Resistance (HOMA-IR), triglycerides, homocysteine and positively with HDL-cholesterol after adjusting for age and BMI. In regression analysis, after adjusting for likely confounders, maternal B12 is independently associated with neonatal HDL-cholesterol and homocysteine but not triglycerides or HOMA-IR. Conclusions: Our study shows that low B12 status is common in white women and is independently associated with adverse cord blood cholesterol. vitamin B12; maternal; offspring; metabolic risk; lipids.
Higher glucose, insulin and insulin resistance (HOMA-IR) in childhood predict adverse cardiovascular risk in early adulthood: the Pune Children’s Study
Author Name: Chittaranjan S. Yajnik, Prachi A. Katre, Suyog M. Joshi, Kalyanaraman Kumaran et al. , Publication Year: 2015 , Journal Name: Diabetologia
Abstract: Aims/hypothesis The Pune Children’s Study aimed to test
whether glucose and insulin measurements in childhood predict
cardiovascular risk factors in young adulthood.
Methods We followed up 357 participants (75%follow-up) at
21 years of age who had undergone detailed measurements at
8 years of age (glucose, insulin, HOMA-IR and other indices).
Oral glucose tolerance, anthropometry, plasma lipids, BP, carotid
intima–media thickness (IMT) and arterial pulse wave
velocity (PWV) were measured at 21 years.
Results Higher fasting glucose, insulin and HOMA-IR at
8 years predicted higher glucose, insulin, HOMA-IR, BP,
lipids and IMT at 21 years. A 1 SD change in 8 year variables
was associated with a 0.10–0.27 SD change at 21 years independently
of obesity/adiposity at 8 years of age. A greater rise
in glucose–insulin variables between 8 and 21 years was associated
with higher cardiovascular risk factors, including PWV.
Participants whose HOMA-IR measurement remained in the
highest quartile (n=31) had a more adverse cardiovascular risk
profile compared with those whose HOMA-IR measurement
remained in the lowest quartile (n=28).
Conclusions/interpretation Prepubertal glucose–insulin metabolism
is associated with adult cardiovascular risk and
markers of atherosclerosis. Our results support interventions
to improve glucose–insulin metabolism in childhood to reduce
cardiovascular risk in later life.
Keywords Cardiovascular risk . Childhood insulin
resistance . Diabetes . Indians . Young adults
Abstract: The prevalence of diabetes and adiposity has increased
at an alarming rate and together they contribute to
the rise in morbidity and mortality worldwide. Genetic studies
till date have succeeded in explaining only a proportion of
heritability, while a major component remains unexplained.
Early life determinants of future risk of these diseases are
likely contributors to the missing heritability and thus have a
significant potential in disease prevention. Epidemiological
and animal studies show the importance of intrauterine and
early postnatal environment in programming of the fetus to
adverse metabolic outcomes and support the notion of Developmental
Origins of Health and Disease (DOHaD). Emerging
evidence highlights the role of epigenetic mechanisms in mediating
effects of environmental exposures, which in certain
instances may exhibit intergenerational transmission even in
the absence of exposure. In this article, we will discuss the
complexity of diabetes and increased adiposity and mechanisms
of programming of these adverse metabolic conditions.
Keywords Diabesity . Intermediate traits . Fetal
programming . Fuel- and nutrient-mediated teratogenesis .
Mendelian randomization . Thrifty epigenotype
Body size and body composition: a comparison of children in India and the UK through infancy and early childhood
Author Name: S D’Angelo, C S Yajnik, K Kumaran, C Joglekar et al. , Publication Year: 2015 , Journal Name: J Epidemiol Community Health
Abstract: Indian babies are characterised by the
‘thin-fat phenotype’ which comprises a ‘muscle-thin but
adipose’ body composition compared with European
babies. This body phenotype is of concern because it is
associated with an increased risk of diabetes and
cardiovascular disease. We examined whether the ‘thinfat
phenotype’ persists through early childhood,
comparing Indian children with white Caucasians in the
UK at birth, infancy and childhood, using comparable
measurement protocols. We used data from two cohorts, the Pune
Maternal Nutrition Study (N=631) and the Southampton
Women’s Survey (N=2643). Measurements of weight,
head circumference, mid-upper arm circumference,
height, triceps and subscapular skinfold thickness were
compared at birth, 1, 2, 3 and 6 years of age. SD scores
were generated for the Pune children, using the
Southampton children as a reference. Generalised
estimating equations were used to examine the changes
in SD scores across the children’s ages. The Indian children were smaller at birth in all
body measurements than the Southampton children and
became relatively even smaller from birth to 2 years,
before ‘catching up’ to some extent at 3 years, and more
so by 6 years. The deficit for both skinfolds was
markedly less than for other measurements at all ages;
triceps skinfold showed the least difference between the
two cohorts at birth, and subscapular skinfold at all
ages after birth. The ‘thin-fat phenotype’ previously found
in Indian newborns, remains through infancy and early
childhood. Despite being shorter and lighter than UK
children, Indian children are relatively adipose.
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with
cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide
association studies for estimated glomerular filtration rate (eGFR), combining data across
133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and
confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals
with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are
enriched for expression in kidney tissues and in pathways relevant for kidney development
and transmembrane transporter activity, kidney structure, and regulation of glucose
metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult
tissues demonstrate preferential mapping of associated variants to regulatory regions in
kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR
are mediated largely through direct effects within the kidney and highlight important cell
types and biological pathways.
Cord IGF-I concentrations in Indian newborns: associations with neonatal body composition and maternal determinants
Author Name: A. S. Wiley, H. G. Lubree, S. M. Joshi, D. S. Bhat et al. , Publication Year: 2015 , Journal Name: Original Research
Abstract: Indian newborns have been described as ‘thin-fat’ compared with
European babies, but little is known about how this phenotype relates to the foetal
growth factor IGF-I (insulin-like growth factor I) or its binding protein IGFBP-3.
To assess cord IGF-I and IGFBP-3 concentrations in a sample of
Indian newborns and evaluate their associations with neonatal adiposity and
maternal factors. A prospective cohort study of 146 pregnant mothers with dietary,
anthropometric and biochemical measurements at 28 and 34 weeks gestation.
Neonatal weight, length, skin-folds, circumferences, and cord blood IGF-I and
IGFBP-3 concentrations were measured at birth. Average cord IGF-I and IGFBP-3 concentrations were 46.6 (2.2) and
1269.4 (41) ng mL−1, respectively. Girls had higher mean IGF-I than boys
(51.4 ng mL−1 vs. 42.9 ng mL−1; P < 0.03), but IGFBP-3 did not differ. Cord IGF-I
was positively correlated with all birth size measures except length, and most
strongly with neonatal sum-of-skin-folds (r = 0.50, P < 0.001). IGFBP-3 was positively
correlated with ponderal index, sum-of-skin-folds and placenta weight
(r = 0.21, 0.19, 0.16, respectively; P < 0.05). Of maternal demographic and
anthropometric characteristics, only parity was correlated with cord IGF-I (r = 0.27,
P < 0.001). Among dietary behaviours, maternal daily milk intake at 34 weeks
gestation predicted higher cord IGF-I compared to no-milk intake (51.8 ng mL−1 vs.
36.5 ng mL−1, P < 0.01) after controlling for maternal characteristics, placental
weight, and newborn gestational age, sex, weight and sum-of-skin-folds. Sumof-
skin-folds were positively associated with cord IGF-I in this multivariate model
(57.3 ng mL−1 vs. 35.1 ng mL−1 for highest and lowest sum-of skin-fold quartile,
P < 0.001). IGFBP-3 did not show significant relationships with these covariates.
Conclusion: In this Indian study, cord IGF-I concentration was associated with
greater adiposity among newborns. Maternal milk intake may play a role in this
relationship.
Directional dominance on stature and cognition in diverse human populations
Author Name: Joshi et al. , Publication Year: 2015 , Journal Name: Europe PMC Funders Group
Abstract: Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
Multigenerational Undernutrition Increases Susceptibility to Obesity and Diabetes that Is Not Reversed after Dietary Recuperation
Author Name: Anandwardhan A. Hardikar, Sarang N. Satoor, Mahesh S. Karandikar, Anthony C. Keech et al. , Publication Year: 2015 , Journal Name: cell metabolism
Abstract: People in developing countries have faced multigenerational
undernutrition and are currently undergoing
major lifestyle changes, contributing to an epidemic
of metabolic diseases, though the underlying mechanisms
remain unclear. Using a Wistar rat model of
undernutrition over 50 generations, we show that
Undernourished rats exhibit low birth-weight, high
visceral adiposity (DXA/MRI), and insulin resistance
(hyperinsulinemic-euglycemic clamps), compared
to age-/gender-matched control rats. Undernourished
rats also have higher circulating insulin, homocysteine,
endotoxin and leptin levels, lower adiponectin,
vitamin B12 and folate levels, and an 8-fold
increased susceptibility to Streptozotocin-induced
diabetes compared to control rats. Importantly,
these metabolic abnormalities are not reversed after
two generations of unrestricted access to commercial
chow (nutrient recuperation). Altered epigenetic
signatures in insulin-2 gene promoter region of
Undernourished rats are not reversed by nutrient
recuperation, and may contribute to the persistent
detrimental metabolic profiles in similar multigenerational
undernourished human populations.
The FIGO recommendations on adolescent, preconception, and maternal nutrition “Think Nutrition First”
Author Name: Mark A. Hanson, Anne Bardsley, Luz Maria De-Regil, Sophie E. Moore et al. , Publication Year: 2015 , Journal Name: International Journal of Gynecology and Obstetrics
Abstract: Adolescent, preconception, and maternal nutrition represent
a major public health issue that affects not only the health of
adolescents and women, but also that of future generations.
FIGO recommends that maternal nutrition should be part of
a life course approach that views perinatal health within the
context of women’s overall health. This approach emphasizes
the importance of the adolescent and young adult periods for
lifelong health, and the potential benefits to health and human
capital in the next generation gained by achieving healthy
lifestyles prior to conception.
Iodine status during pregnancy in India and related neonatal and infant outcomes
Author Name: Chittaranjan Yajnik , Publication Year: 2014 , Journal Name: Public Health Nutrition
Abstract: Objective: To document iodine status in Indian pregnancies, associations with maternal diet and demographics, and offspring developmental measures. Design: Longitudinal study following mothers through pregnancy and offspring up to 24 months. Setting: Rural health-care centre (Vadu) and urban antenatal clinic (Pune) in the Maharashtra region of India. Subjects: Pregnant mothers at 17 (n 132) and 34 weeks’ (n 151) gestation and their infants from birth to the age of 24 months. Results: Median urinary iodine concentration (UIC) was 203 and 211mg/l at 17 and 34 weeks of pregnancy, respectively (range 26–800mg/l). Using the UIC distribution adjusted for within-person variation, extreme UIC quartiles were compared for predictors and outcomes. There was no correlation between UIC at 17 and 34 weeks, but 24% of those with UIC in the lowest quartile at 17 weeks had UIC in the same lowest quartile at 34 weeks. Maternal educational, socioeconomic status and milk products consumption (frequency) were different between the lowest and highest quartile of UIC at 34 weeks. Selected offspring developmental outcomes differed between the lowest and highest UIC quartiles (abdominal circumference at 24 months, subscapular and triceps skinfolds at 12 and 24 months). However, UIC was only a weak predictor of subscapular skinfold at 12 months and of triceps skinfold at 24 months. Conclusions: Median UIC in this pregnant population suggested adequate dietary provision at both gestational stages studied. Occasional high results found in spot samples may indicate intermittent consumption of iodine-rich foods. Maternal UIC had limited influence on offspring developmental outcomes.
Anguli Parimana in Ayurveda and its association with adiposity and diabetes
Author Name: Chittaranjan Yajnik , Publication Year: 2014 , Journal Name: Journal of Ayurveda and Integrative Medicine - Elsevier
Abstract: Background: Recent studies have shown the association of disproportionate body size measurements with noncommunicable diseases like diabetes. This concept is described in Ayurveda (1500 BC), which uses Anguli Parimana (the breadth of one’s own finger as 1 unit) to measure the body proportions. Excessive tallness or shortness (deviation from the reference value of Anguli Parimana) indicated deranged meda dhaatu (mainly adipose tissue). Deranged meda dhatu was associated with Prameha (diabetes). Objectives: To find association of Anguli Parimana with modern parameters of adiposity and diabetes. Materials and Methods: We studied 192 village residents representing the whole population (94 men and 98 women) to measure height, arm span, facial structures and limbs and expressed them in Anguli pariman (ratio of each measure as: Length or height of the body part [cm]/anguli, i.e. average finger breadth [cm]). The Anguli measurements were associated with body mass index, body fat percentage by DEXA, glucose and fasting insulin levels. Results: The volunteers were adults between 20 and 40 years age. Their mean fasting and 2 h plasma glucose concentrations were 91.6 mg% and 102.8 mg%, respectively. Of all, only 6 subjects had impaired glucose tolerance, while 3 were diabetic (WHO 1999). When compared with reference Anguli measurements mentioned by Charaka Samhita and Sushruta Samhita, the participants had smaller height, facial structures, and lower limbs. Those, who had proportionately smaller facial, neck and limb structures, had higher obesity, adiposity, plasma glucose, insulin and insulin resistance (homeostatic model assessment [HOMA]‑R) indicating higher metabolic risk. In contrast, those who had proportionately larger forehead and face had higher beta cell function measured as HOMA‑B indicating lower risk for diabetes (r = 0.20 both P < 0.05 all, adjusted for age and gender). Conclusion: Compared with ancient Indian Anguli reference, our subjects were proportionately smaller in most of the measurements except fingers and upper arm. Relative smallness of body parts was predictive of increased risk of type 2 diabetes.
Tracking of cardiovascular risk factors from childhood to young adulthood - the Pune Children_s Study
Author Name: Chittaranjan Yajnik , Publication Year: 2014 , Journal Name: International Journal of Cardiology
Abstract: To target preventive measures appropriately in early life, it is important to know what childhood cardiovascular (CVD) risk profiles mean in terms of predicting adult risk. Studies from high-income countries have reported tracking of individual risk factors from childhood to adulthood; there are no reports of child–adult tracking in low- and middle-income countries (LMICs). The Pune Children's Study is a cohort of 477 individuals born in the KEM Hospital, Pune, India in 1987–1989. We measured a range of CVD risk factors at 8 (1996–7) and 21 (2009–11) years of age, using similar methods, providing the first opportunity to assess child–adult tracking in a LMIC. Ethical permission was obtained from the KEM Hospital Ethics Committee and informed consent was obtained from all the participants. Plasma insulin and leptin were measured using an immunoenzymometric assay and RIA respectively at 8 years, and a Delfia technique and ELISA at 21 years. Insulin resistance (HOMA-IR) was calculated at both ages using the online Oxford model. Our findings are consistent with studies from high-income countries. Tracking may occur due to persistence of environmental factors through childhood and into adulthood. A metaanalysis showed that dietary behavior and physical activity tracks from childhood into adulthood. As both are modifiable factors, it suggests intervening earlier in the lifecourse may be beneficial. Tracking may also be due to genetic factors. Another possible reason could be ‘programming’ of risk factors during early life, and may suggest stability of epigenetic changes established earlier. Our previous finding linking birthweight to insulin resistance at four years supports this possibility adding weight to interventions before and during pregnancy to improve fetal growth. Despite significant correlations of child and adult risk factors, predictive values do not support their use as screening tools. This suggests that measures to reduce risk factors in children should be public health interventions, such as encouraging regular physical activity and healthier diets, rather than individually targeted interventions.
Maternal homocysteine in pregnancy and offspring birthweight epidemiological associations and Mendelian randomization analysis
Author Name: Chittaranjan Yajnik , Publication Year: 2014 , Journal Name: International Journal of Epidemiology
Abstract: Background: Disturbed one-carbon (1-C) metabolism in the mother is associated with poor fetal growth but causality of this relationship has not been established. Methods: We studied the association between maternal total homocysteine and offspring birthweight in the Pune Maternal Nutrition Study (PMNS, Pune, India) and Parthenon Cohort Study (Mysore, India). We tested for evidence of causality within a Mendelian randomization framework, using a methylenetetrahydrofolatereductase (MTHFR) gene variant rs1801133 (earlier known as 677C!T) by instrumental variable
and triangulation analysis, separately and using meta-analysis. Results: Median (IQR) homocysteine concentration and mean (SD) birthweight were 8.6 mmol/l (6.7,10.8) and 2642 g (379) in the PMNS and 6.0 mmol/l (5.1,7.1) and 2871 g
(443) in the Parthenon study. Offspring birthweight was inversely related to maternal homocysteine concentration—PMNS: –22 g/SD [95% confidence interval (CI): (–50, 5), adjusted for gestational age and offspring gender]; Parthenon: –57 g (–92, –21); meta-analysis: –40 g (–62, –17)]. Maternal risk genotype at rs1801133 predicted higher homocysteine
concentration [PMNS: 0.30 SD/allele (0.14, 0.46); Parthenon: 0.21 SD (0.02, 0.40); meta-analysis: 0.26 SD (0.14, 0.39)]; and lower birthweight [PMNS: –46 g (–102, 11, adjusted for gestational age, offspring gender and rs1801133 genotype); Parthenon: –78 g (–170, 15); meta-analysis: –61 g (–111, –10)]. Instrumental variable and triangulation analysis
supported a causal association between maternal homocysteine concentration and offspring birthweight. Conclusions: Our findings suggest a causal role for maternal homocysteine (1-C metabolism) in fetal growth. Reducing maternal homocysteine concentrations may improve fetal growth.
Transmission of Obesity-Adiposity and Related Disorders from the Mother to the Baby
Author Name: Chittaranjan S. Yajnik , Publication Year: 2014 , Journal Name: Ann Nutrition and Metabolosm.
Abstract: The conventional aetiological model of obesity and diabetes
proposes a genetic predisposition and a precipitation by an
unhealthy adult lifestyle. This hypothesis was challenged
by David Barker who proposed that the intrauterine environment influences the risk of non-communicable disease (NCDs). The original idea was based on fetal undernutrition
because lower birth weight was associated with a higher risk
of diabetes and heart disease. However, soon it was clear that
the association was U shaped, and that the increased risk in
large babies was driven by maternal obesity and diabetes. A
number of human and animal studies have refined our ideas
of ‘fetal programming’, which is now thought to be related
to acquired chemical changes in DNA (methylation), histones (acetylation and other) and the role of non-coding
miRNAs. Maternal nutritional disturbances are the major
programming stimulus, in addition to a deranged metabolism, infections, maternal stress, extreme atmospheric temperature, etc. The first demonstration of a link between fetal
‘starvation’ and future ill-health was in the Dutch Hunger
Winter studies. In the prospective Pune Maternal Nutrition
Study, we found that small and thin Indian babies were more
adipose compared to larger English babies, and their higher
risk of future diabetes was reflected in higher insulin and
leptin and lower adiponectin concentrations in the cord
blood. This phenotype was partly related to a deranged
1-carbon metabolism due to an imbalance in vitamin B 12
(low) and folate (high) nutrition, which was also related to
insulin resistance in the offspring. Maternal obesity and diabetes have made an increasing contribution to childhood
obesity and diabetes at a young age. This was prominently
shown in Pima Indians but is now obvious in all other populations. The best window of opportunity to prevent fetal programming of NCDs is in the periconceptional period. This is the period when gametogenesis, fertilisation, implantation,
embryogenesis and placentation occur. Improving the nutrition and the health of young girls could make a substantial
contribution to reducing the rapidly rising epidemic of NCDs
in the world. This is referred to as ‘primordial’ prevention.
Abstract: Studies in the West have shown lower cardiovascular disease (CVD) risk among people taking a vegetarian
diet, but these findings may be confounded and only a minority selects these diets. We evaluated the association between
vegetarian diets (chosen by 35%) and CVD risk factors across four regions of India.
Study participants included urban migrants, their rural siblings and urban residents, of the Indian Migration Study
from Lucknow, Nagpur, Hyderabad and Bangalore (n = 6555, mean age-40.9 yrs). Information on diet (validated intervieweradministered semi-quantitative food frequency questionnaire), tobacco, alcohol, physical history, medical history, as well as
blood pressure, fasting blood and anthropometric measurements were collected. Vegetarians ate no eggs, fish, poultry or
meat. Using robust standard error multivariate linear regression models, we investigated the association of vegetarian diets
with blood cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides, fasting blood glucose
(FBG), systolic (SBP) and diastolic blood pressure (DBP).
Vegetarians (32.8% of the study population) did not differ from non-vegetarians with respect to age, use of
smokeless tobacco, body mass index, and prevalence of diabetes or hypertension. Vegetarians had a higher standard of
living and were less likely to smoke, drink alcohol (p,0.0001) and were less physically active (p = 0.04). In multivariate
analysis, vegetarians had lower levels of total cholesterol (b = 20.1 mmol/L (95% CI: 20.03 to 20.2), p = 0.006), triglycerides
(b = 20.05 mmol/L (95% CI: 20.007 to 20.01), p = 0.02), LDL (b = 20.06 mmol/L (95% CI: 20.005 to 20.1), p = 0.03) and
lower DBP (b = 20.7 mmHg (95% CI: 21.2 to 20.07), p = 0.02). Vegetarians also had decreases in SBP (b = 20.9 mmHg (95%
CI: 21.9 to 0.08), p = 0.07) and FBG level (b = 20.07 mmol/L (95% CI: 20.2 to 0.01), p = 0.09) when compared to nonvegetarians.
: We found beneficial association of vegetarian diet with cardiovascular risk factors compared to non-vegetarian
diet.
Treatment of hyperglycemia in newly diagnosed diabetic patients is associated with a reduction in oxidative stress and improvement in β-cell function
Author Name: Jhankar D. Acharya, Amol J. Pande, Suyog M. Joshi, Chittaranjan S. Yajnik, et al. , Publication Year: 2014 , Journal Name: DIABETES/METABOLISM RESEARCH AND REVIEWS
Abstract: The burden of chronic noncommunicable diseases (NCDs) such as diabetes, obesity and cardiovascular disease is shifting rapidly to low- and middle-income countries. It calls for a review of the classic ‘dogma’ of genetic predisposition, precipitated by adult lifestyle. The paradigm of early life origins of chronic disease has focused attention on maternal health
and nutrition as major determinants of the health of the offspring. India has high burden of maternal ill health and also of diabetes and cardiovascular disease, offering unique opportunities to study the links between the two. Pune studies showed that the Indian babies were thin but fat (more adipose) compared to European babies, and that maternal micronutrient status during pregnancy was a determinant of offspring size and body composition. Two thirds of the mothers had low vitamin B 12 concentrations, while folate deficiency was rare. Higher circulating concentrations of homocysteine predicted smaller baby size. Follow-up studies revealed that higher maternal folate in pregnancy predicted higher adiposity and insulin resistance in the child at 6 years of age, and that low maternal vitamin B 12 exaggerated the risk of insulin resistance. Low maternal vitamin B 12 status is also associated with increased risk of neural tube defects and poor offspring cognitive functions. Our results suggest an important role for maternal one-carbon metabolism in offspring growth and programming of NCD risk. These ideas are supported by animal studies. Improvement of adolescent nutrition could effect inter-generational prevention of chronic diseases.
Abstract: Background: Neonates from low and middle income countries (LAMIC) tend to have lower birth weight compared with
Western European (WE) neonates. Parental height, BMI and maternal parity, age and educational level often differ according
to ethnic background, and are associated with offspring birth weight. Less is known about how these factors affect ethnic
differences in neonatal body composition.
Objectives: To explore differences in neonatal body composition in a multi-ethnic population, and the impact of key
parental factors on these differences.
Methods: A population-based cohort study of pregnant mothers, fathers and their offspring, living in Oslo, Norway. Genderand gestational-specific z-scores were calculated for several anthropometric measurements, with the neonates of WE ethnic origin as reference. Mean z-scores for neonates with LAMIC origin, and their parents, are presented as outcome variables. Results: 537 singleton, term neonates and their parents were included. All anthropometric measurements were smaller in neonates with LAMIC origin. Abdominal circumference and ponderal index differed the most from WE (mean z-score: 20.57 (95% CI:20.69 to 20.44) and 20.54 (20.66 to 20.44), and remained so after adjusting for parental size. Head circumference and skin folds differed less, and length the least (20.21 (20.35 to 20.07)). These measures became comparable to WEs when adjusted for parental factors.
Conclusions: LAMIC origin neonates were relatively ‘‘thin-fat’’, as indicated by reduced AC and ponderal index and relatively
preserved length and skin folds, compared with neonates with WE origin. This phenotype may predispose to type 2
diabetes.
Maternal Lipids Are as Important as Glucose for Fetal Growth
Author Name: SMITA R. KULKARNI, KALYANARAMAN KUMARAN, SHOBHA R. RAO, SURESH D. CHOUGULE et al. , Publication Year: 2013 , Journal Name: DIABETES CARE
Abstract: To study the relationship between maternal circulating fuels and neonatal size and compare the relative effects of glucose and lipids.
The Pune Maternal Nutrition Study (1993–1996) investigated the influence of maternal nutrition on fetal growth. We measured maternal body size and glucose and lipid concentrations during pregnancy and examined their relationship with birth size in full-term babies using correlation and regression techniques.
The mothers (n = 631) were young (mean age 21 years), short (mean height 151.9
cm), and thin (BMI 18.0 kg/m2) but were relatively more adipose (body fat 21.1%). Their diet was
mostly vegetarian. Between 18 and 28 weeks gestation, fasting glucose concentrations remained
stable, whereas total cholesterol and triglyceride concentrations increased and HDL-cholesterol
concentrations decreased. The mean birth weight of the offspring was 2666 g. Total cholesterol
and triglycerides at both 18 and 28 weeks and plasma glucose only at 28 weeks were associated
directly with birth size. One SD higher maternal fasting glucose, cholesterol, and triglyceride
concentrations at 28 weeks were associated with 37, 54, and 36 g higher birth weights, respectively (P, 0.05 for all). HDL-cholesterol concentrations were unrelated to newborn measurements. The results were similar if preterm deliveries also were included in the analysis (total n =
700.
Our results suggest an influence of maternal lipids on neonatal size in
addition to the well-established effect of glucose. Further research should be directed at defining
the clinical relevance of these findings.
Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease
Author Name: EC Rush, P Katre, CS Yajnik , Publication Year: 2013 , Journal Name: European Journal of Clinical Nutrition
Abstract: This review brings together human and animal studies and reviews that examine the possible role of maternal vitamin B12 (B12)
on fetal growth and its programming for susceptibility to chronic disease. A selective literature review was undertaken to identify
studies and reviews that investigate these issues, particularly in the context of a vegetarian diet that may be low in B12 and protein
and high in carbohydrate. Evidence is accumulating that maternal B12 status influences fetal growth and development. Low
maternal vitamin B12 status and protein intake are associated with increased risk of neural tube defect, low lean mass and excess
adiposity, increased insulin resistance, impaired neurodevelopment and altered risk of cancer in the offspring. Vitamin B12 is a key
nutrient associated with one carbon metabolic pathways related to substrate metabolism, synthesis and stability of nucleic acids
and methylation of DNA which regulates gene expression. Understanding of factors regulating maternal–fetal one carbon
metabolism and its role in fetal programming of non communicable diseases could help design effective interventions, starting
with maternal nutrition before conception
Across the life course, the dietary supply of the methyl donors:
folate, vitamin B12, betaine, methionine and choline, is essential
for normal growth, development and physiological functions. One
carbon metabolism refers to a network of interrelated biochemical
pathways that donate and regenerate one–carbon units, including
the methyl group (Figure 1). Maternal diet is the primary source of
nutrient availability to the conceptus,1,2 and the placenta has a
vital regulatory role.3 The developmental pathway of the child
defines it’s phenotype and the balance between future health and
disease.4 Critical periods of cell division and differentiation occur
in utero.
5 Optimal organogenesis, growth and development of the
foetus is dependent on the maternal diet and supply of nutrients,
including the methyl donors.
Folate, the key methyl donor, has been extensively studied and
world-wide there is recommendation for supplementation of
women who plan to become pregnant. In more than 50 countries
fortification of the food supply with folate is mandated but the
extent of implementation and effectiveness vary.6 On the other
hand, vitamin B12 is often deficient in pregnant women who are
ovo-lacto vegetarians or eat little or no meat,7 and this continues
to be a major nutritional problem in parts of the world where the
population is predominantly vegetarian. Even in countries, such as
Canada, where fortification has been effective there remains a
residual problem with B12 deficiency.
We performed a selective literature review and identified studies and
reviews that investigated the association of maternal B12 status with
metabolic pathways and future health of offspring. Over 250 articles were identified, and we selected those that focussed on Vitamin B12, one
carbon metabolism, fetal growth and programming for chronic disease
and, where possible, were published in the last 10 years.
vitamin B12; methyl donor; one-carbon metabolism; fetal growth; programming; chronic disease
Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children
Author Name: Ghattu V. Krishnaveni, Sargoor R. Veena, Samuel C. Karat, Chittaranjan S. Yajnik et al. , Publication Year: 2013 , Journal Name: Diabetologia
Abstract: Aims/hypothesis In an Indian birth cohort, higher maternal
homocysteine concentration in pregnancy was associated with
lower birthweight of the offspring. Lower maternal vitamin
B12 and higher folate concentrations were associated with
higher offspring insulin resistance. Disordered one-carbon
metabolism during early development may increase later metabolic risk. We explored these associations in another birth
cohort in India at three age points.
Methods We measured plasma vitamin B12, folate and homocysteine concentrations at 30±2 weeks’ gestation in 654
women who delivered at one hospital. Neonatal anthropometry was recorded, and the children’s glucose and insulin concentrations were measured at 5, 9.5 and 13.5 years of age.
Insulin resistance was estimated using HOMA of insulin
resistance (HOMA-IR).
Results Maternal homocysteine concentrations were inversely associated with all neonatal anthropometric measurements
(p <0.05), and positively associated with glucose concentrations in the children at 5 (30 min; p =0.007) and 9.5 years of
age (120 min; p =0.02). Higher maternal folate concentrations
were associated with higher HOMA-IR in the children at 9.5
(p =0.03) and 13.5 years of age (p =0.03). Maternal vitamin
B12 concentrations were unrelated to offspring outcomes.
Conclusions/interpretation Maternal vitamin B12 status did
not predict insulin resistance in our cohort. However, associations of maternal homocysteine and folate concentrations
with birth size, and with childhood insulin resistance and
glycaemia in the offspring, suggest a role for nutritionally
driven disturbances in one-carbon metabolism in fetal programming of diabetes.
Keywords Child . Folate . Homocysteine . Insulin
resistance . Pregnancy . Programming . Vitamin B12.
Abstract: Until recently, a successful pregnancy was equated
with the delivery of a live baby, together with an additional
minor concern about the baby’s weight. There was little
appreciation that the health of the baby in utero is intricately
linked to its overall childhood and adult health. David
Barker and colleagues changed this paradigm when they
demonstrated that maternal nutrition influences the future risk
of noncommunicable diseases (NCDs) in the baby (1). There is
increasing understanding that these influences may span more
than a single generation, and that non Mendelian, modifiable
epigenetic mechanisms contribute to the heritability. Against
this background, we are investigating the influence of maternal
nutrition on fetal growth and its risk for future NCDs like
diabetes, hypertension, and cardiovascular disease (CVD).
Around the globe, a major concern is maternal
undernutrition and its effects on pregnancy outcomes and
neonatal health. In the last three decades, an estimated 15% of
reproductive age women (20 to 49 years) have been reported
to be chronically undernourished (BMI <18.5 kg/m2), with the
highest proportion in Asian countries (~18%) (2). Survey data
from India found that 36% of women aged 15 to 49 years
had a BMI <18.5 kg/m2 (3).The aggregate effect of maternal
undernutrition (through fetal growth restriction, stunting,
wasting, specific nutritional deficiencies, and suboptimal
breastfeeding) contributed to an estimated 3.1 million child
deaths in 2011, accounting for 45% of all child deaths.
The role of the one-carbon cycle in the developmental origins of Type 2 diabetes and obesity
Author Name: S. Finer, P. Saravanan, G. Hitman, C. Yajnik , Publication Year: 2013 , Journal Name: Diabetic Medicine
Abstract: Vitamin B12 deficiency is common in certain populations, such as in India, where there is also a rising prevalence of
Type 2 diabetes, obesity and their complications. Human cohorts and animal models provide compelling data suggesting
the role of the one-carbon cycle in modulating the risk of diabetes and adiposity via developmental programming. Early
mechanistic studies in animals suggest that alterations to the cellular provision of methyl groups (via the one-carbon
cycle) in early developmental life may disrupt DNA methylation and induce future adverse phenotypic changes.
Furthermore, replacement of micronutrient deficits at suitable developmental stages may modulate this risk. Current
human studies are limited by a range of factors, including the accuracy and availability of methods to measure
nutritional components in the one-carbon cycle, and whether its disruptions exert tissue-specific effects. A greater
understanding of the causal and mechanistic role of the one-carbon cycle is hoped to generate substantial insights into its
role in the developmental origins of complex metabolic diseases and the potential of targeted and population-wide
prevention strategies.
Abstract: : Anemia is an important health concern worldwide, particularly in poor populations such
as in India. The objective of this study was to determine the prevalence and predictors of anemia
and iron status.
Methods: One thousand children ages 6 to 30 mo were included in a study undertaken in low- to
middle-income neighborhoods in New Delhi, India. Children of Tigri and Dakshinpuri were identified through a community survey. Plasma concentrations of hemoglobin (Hb), soluble transferrin
receptor (sTfR), folate, vitamin B12, and total homocysteine (tHcy) were measured. Predictors for
plasma Hb concentration were identified in multiple linear regression models and considered
significant if P-value <0.05.
Results: The prevalence of anemia (Hb concentration <11 g/dL) was 69.6% (n ¼ 696) whereas the
prevalence of iron deficiency (elevated sTfR i.e., >4.7 nmol/L) was 31% (n ¼ 309). The main predictors for Hb concentration were plasma concentrations of sTfR (standardized beta coefficient [b],
0.49; P < 0.001), folate (b, 0.15; P < 0.001), vitamin B12 (b, 0.10; P < 0.001), tHcy (b, 0.11; P <
0.001) among the biomarkers. Length-for-age Z score (b, 0.08; P ¼ 0.002) and family income (b,
0.06; P ¼ 0.027) also predicted Hb concentration.
Conclusion: Anemia was common in this population. Iron, folate, and vitamin B12 status were
important predictors for plasma Hb concentration. Improving the status of these nutrients might
reduce the burden of childhood anemia in India
Abstract: Objective: Central (truncal) adiposity is associated strongly with insulin resistance and diabetes. There are very few reports
comparing methods of trunk fat measurement in their ability to predict glycaemia and insulin resistance. We report a
comparative analysis of different trunk fat measurements in predicting glycaemia and insulin resistance in middle aged
Indian men.
Materials and Methods: Trunk fat measurements were performed using anthropometry, magnetic resonance imaging
(MRI), dual-energy X-ray absorptiometry (DXA) and computed tomography (CT) on 128 men. Additional measurements
were taken to characterise insulin resistance (Matsuda index) and beta cell function (Insulinogenic Index), glycaemia (fasting
and 120 min glucose concentrations). Using residual approach we compared the ability of different trunk fat measurement
techniques to predict insulin resistance, beta cell function and glycaemia.
Results: There was a strong association between trunk fat measures from each technique with glycaemia and insulin
resistance indices but not with the Insulinogenic Index. Insulin resistance and glycaemia, were best predicted using
anthropometric measurements, notably by waist circumference and subscapular skinfold thickness. Neither MRI measures
of trunk or visceral fat nor DXA trunk fat added significantly. CT liver density contributed to some extent to predict insulin
resistance and 120 min glucose after anthropometric measurements.
Conclusions: Our results suggest that, in Indian men, anthropometric measurements are good predictors of glycaemia and
insulin resistance. Other complex measurements such as MRI, DXA and CT make only a small addition to the prediction. This
finding supports the application of anthropometry for determining trunk fat in clinical and epidemiological settings.
Maternal vitamin B12 and folate status during pregnancy and insulin resistance and body composition in the offspring at 12 years in a rural Indian birth cohort: data from the Pune Maternal Nutrition Study
Author Name: T. A. Bond, C. V. Joglekar, E. Marley-Zagar, H. G. Lubree et al. , Publication Year: 2013 , Journal Name: Proceedings of the Nutrition Society
Abstract: Maternal nutrition during pregnancy may influence offspring risk of developing type 2 diabetes mellitus and cardiovascular disease in
later life(1). Previous studies have shown that low maternal vitamin B12 and high folate concentrations during pregnancy were associated
with higher insulin resistance in the offspring at 6 years(2). As both B12 and folate are regulators of 1-carbon (1-C) metabolism, this
suggested a role for 1-C metabolism in the development of type 2 diabetes mellitus. The current study aimed to test the hypothesis that
low maternal vitamin B12 concentration and high maternal folate concentration during pregnancy are associated with higher insulin
resistance and adiposity in the offspring at 12 years.
Data was from the Pune Maternal Nutrition Study, a community based prospective study of a rural Indian birth cohort. Plasma vitamin
B12 and erythrocyte folate (exposures) were measured at 18 and 28 weeks gestation in 638 women in six villages near Pune, India, along
with anthropometry and dietary assessment (24h intake and food frequency questionnaire). Outcomes measured in the children at 12 years
included fasting plasma glucose and insulin, vitamin B12, total homocysteine (tHcy), serum folate and lipid concentrations, blood pressure
and body composition (anthropometry and dual X-ray absorptiometry scans (DXA)). Insulin resistance was estimated using the HOMA
model. Relationships were analysed using multiple linear regression, adjusting for important covariates and potential confounders.
Maternal erythrocyte folate concentration at 18 and 28 weeks gestation was positively related to offspring weight, BMI, fat and lean
mass and triceps skinfold (p<0.05 for all), but not to insulin resistance. Maternal vitamin B12 concentration was not related to offspring
insulin resistance or adiposity measures. Higher maternal vitamin B12 concentration was related to higher offspring B12 concentration
and lower offspring tHcy concentration (p<0.01 for both). All reported associations were adjusted for offspring age, sex, socioeconomic
status and serum folate concentration at 12 years. Associations with maternal folate as the exposure were also adjusted for offspring serum
vitamin B12 concentration at 12 years.
Response to Comment on: Hardikar et al. Spuriously High Prevalence of Prediabetes Diagnosed by HbA1c in Young Indians
Author Name: PALLAVI S. HARDIKAR, SUYOG M. JOSHI, DATTATRAY S. BHAT, DEEPA A. RAUT et al. , Publication Year: 2013 , Journal Name: DIABETES CARE
Abstract: We are grateful to Schindhelm et al.
(1) for their interest in our article.
WemeasuredHbA1c during followup
of a birth cohort in the hope of substituting
it for an oral glucose tolerance test.We
found a discrepancy between the results of
the oral glucose tolerance test (World
Health Organization, 1999) and HbA1c
(American Diabetes Association, 2009): A
large number of individuals were classified
as having “prediabetes” by HbA1c when
considered normal glucose tolerant by oral
glucose tolerance test (2). This prompted
us to investigate possible causes of this
discrepancy. We found that a number of
hematological parameters (lower hemoglobin
concentration, lower mean corpuscular
volume, lowermean corpuscular hemoglobin,
and higher red cell distribution width)
predicted higher HbA1c. These hematological
parameters were indicative of iron deficiency,
so we measured serum ferritin
concentrations. We found that lower ferritin
concentrations also predicted higher
HbA1c, supporting an association with
iron deficiency.We did not find an association
of HbA1c with another nutritional
problem, i.e., vitamin B12 deficiency,
which is quite common in this population.
We searched the literature and found supportive
data that HbA1c is elevated in iron
deficiency.We admit that our interpretation
of previous studies (3,4) about prolonged
erythrocyte survival in iron deficiency was
not accurate.
The cost-effectiveness of gestational diabetes screening including prevention of type 2 diabetes: application of a new model in India and Israel
Author Name: Elliot Marseille, Nicolai Lohse, Aliya Jiwani, Moshe Hod et al. , Publication Year: 2013 , Journal Name: The journal of maternal fetal and neonatal medicine
Abstract: Objective: Gestational diabetes mellitus (GDM) is associated with elevated risks of perinatal
complications and type 2 diabetes mellitus, and screening and intervention can reduce these
risks. We quantified the cost, health impact and cost-effectiveness of GDM screening and
intervention in India and Israel, settings with contrasting epidemiologic and cost environments.
Methods: We developed a decision-analysis tool (the GeDiForCE) to assess cost-effectiveness.
Using both local data and published estimates, we applied the model for a general medical
facility in Chennai, India and for the largest HMO in Israel. We computed costs (discounted
international dollars), averted disability-adjusted life years (DALYs) and net cost per DALY
averted, compared with no GDM screening.
Results: The programme costs per 1000 pregnant women are $259 139 in India and $259 929 in
Israel. Net costs, adjusted for averted disease, are $194 358 and $76 102, respectively. The cost
per DALY averted is $1626 in India and $1830 in Israel. Sensitivity analysis findings range from
$628 to $3681 per DALY averted in India and net savings of $72 420–8432 per DALY averted
in Israel.
Conclusion: GDM interventions are highly cost-effective in both Indian and Israeli settings, by
World Health Organization standards. Noting large differences between these countries in GDM
prevalence and costs, GDM intervention may be cost-effective in diverse settings.
An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy
Author Name: Michael N Weedon, Sian Ellard, Marc J Prindle, Richard Caswell et al. , Publication Year: 2013 , Journal Name: Nature Genetics
Abstract: DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication1 . It carries out this synthesis with high fidelity owing to its intrinsic 3′- to 5′-exonuclease activity, which confers proofreading ability. Missense mutations affecting the exonuclease domain of POLD have recently been shown to predispose to colorectal and endometrial cancers2. Here we report a recurring heterozygous single-codon deletion in POLD1 affecting the polymerase active site that abolishes DNA polymerase activity but only mildly impairs 3′- to 5′-exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This discovery suggests that perturbing the function of the ubiquitously expressed POLD polymerase has unexpectedly tissue-specific effects in humans and argues for an important role for POLD function in adipose tissue homeostasis.
Progressive loss of subcutaneous adipose tissue, or lipodystrophy, with concomitant severe insulin resistance is a major feature of the recently described mandibular hypoplasia, deafness and progeroid features (MDP) syndrome3. Defining the genetic basis of this newly described form of progressive partial lipodystrophy would pro
vide insights into the regulation of adipose tissue. Several genetic causes of partial lipodystrophy have previously been described4. Some of these affect genes with established roles in adipocyte dif
ferentiation or function, including PPARG, PLIN1 and CIDEC. However, for other commonly implicated genes, including LMNA and ZMPSTE24, the link between the cellular defect and the adipose phenotype is poorly understood4. The mechanism underlying selec
tive loss of only some adipose depots across all these conditions is also
currently unclear.
Folic acid and vitamin B-12 supplementation and common infections in 6230-mo-old children in India: a randomized placebo-controlled trial1–3
Author Name: Sunita Taneja, Tor A Strand, Tivendra Kumar, Madhu Mahesh et al. , Publication Year: 2013 , Journal Name: The American Journal of Clinical Nutrition
Abstract: Young children in low- and middle-income countries
frequently have inadequate vitamin B-12 (cobalamin) status. Poor
folate status is also common and is associated with increased diarrheal
and respiratory morbidity.
Objective: The objective was to measure the effect of folic acid
and/or vitamin B-12 administration on the incidence of diarrhea and
acute lower respiratory tract infections.
Design: One thousand North Indian children (6230 mo of age)
were enrolled in a randomized, double-blind, placebo-controlled
trial to receive 2 times the Recommended Dietary Allowance of
folic acid and/or vitamin B-12 or placebo daily for 6 mo. Children
were individually randomly assigned in a 1:1:1:1 ratio in blocks of
16. Primary outcomes were the number of episodes of acute lower
respiratory infections, diarrhea, and prolonged diarrhea.
Results: Folic acid and vitamin B-12 supplementation significantly
improved vitamin B-12 and folate status, respectively. Neither folic
acid nor vitamin B-12 administration reduced the incidence of diarrhea
or lower respiratory infections. In comparison with placebo,
children treated with folic acid alone or in combination with vitamin
B-12 had a significantly higher risk of persistent diarrhea (OR: 2.1;
95% CI: 1.1, 3.8).
Conclusions: Folic acid or vitamin B-12 supplementation did not
reduce the burden of common childhood infections. In view of the
increased risk of diarrhea, the safety of folic acid supplements in
young children should be further assessed.
Quick and Simple Evaluation of Sudomotor Function for Screening of Diabetic Neuropathy
Author Name: Chittaranjan Yajnik , Publication Year: 2012 , Journal Name: International Scholarly Research Notices (ISRN) Endocrinology
Abstract: Objective. The aim of this study was to compare SUDOSCAN, a new device to evaluate sweat function (reflecting peripheral small C-fiber status), with conventional measures of peripheral and cardiac neuropathy in patients with type 2 diabetes. Methods. 265 diabetic patients were tested for symptoms and clinical signs of neuropathy using Michigan Neuropathy Screening Instrument (MNSI), vibration perception threshold (VPT) using biothesiometer, and cardiac autonomic neuropathy (CAN) using Ewing’s protocol. Sudomotor function was investigated with SUDOSCAN through measurement of electrochemical skin conductance (ESC) of hands and feet. Lower ESC is suggestive of sudomotor dysfunction. Results. Lower ESC at feet was significantly associated both with increasing symptoms (MNSI A) and increasing score on physical abnormalities (MNSI B). Lower ESC at feet was also significantly associated with increasing VPT by biothesiometry (P < 0.01), and with higher number of abnormal CAN results (P < 0.05). ESC was associated with postural fall in blood pressure (sympathetic abnormality) (P < 0.05), but not with heart rate variability (HRV) tests (parasympathetic abnormalities). Conclusions. Sudomotor dysfunction testing may be a simple test to alert physicians to peripheral nerve and cardiac sympathetic dysfunction. Ease of performance could make it useful in a busy diabetic clinic. Further studies with hard clinical outcomes are indicated.
Abstract: Objectives: REGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2
diabetes mellitus (DM) patients.
Methods: Double-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA1c. Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status.
Results: At baseline, patients were 59.1610.5 years old with HbA1c 8.360.8%, and DM duration 7.166.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.3060.80 to 7.7761.31 versus pioglitazone: from 8.3060.80 to 7.4561.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p,0.001)
and non-inferiority of benfluorex was not confirmed (p = 0.19). Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Emergent morphological abnormalities occurred in 8 patients with benfluorex versus 4 with pioglitazone (OR 1.99), 95% CI (0.59 to 6.69). Emergent regurgitation (new or increased by one grade or more) occurred more frequently with benfluorex (82 patients, 27%) than with pioglitazone (33
patients, 11%) (OR 2.97), 95% CI (1.91 to 4.63) and were mainly rated grade 1; grade 2 (mild) was detected in 2 patients with benfluorex and 3 with pioglitazone. There was no moderate or severe regurgitation.
Conclusion: After 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug.
Abstract: Aims Recent genome-wide association studies have identified several Type 2 diabetes-related loci. We investigated the effect of susceptibility genetic variants, individually, together and in combination with conventional risk factors, on Type 2 diabetes and diabetes-related traits in Indians. Methods We genotyped 33 variants in 1808 Indian patients and 1549 control subjects and performed association analyses with Type 2 diabetes and related traits using an additive model for individual variant and for genetic risk score based on 32 polymorphisms. The discriminatory value of genetic risk over conventional risk factors was analysed using receiver-operating characteristics curve analysis. Results The allelic odds ratio ranged from 1.01 (95% CI 0.85–1.19) to 1.66 (95% CI 1.32–2.01) for single-variant analyses. Although, only 16 variants had significant odds ratios, the direction of association for others was similar to earlier reports. The odds ratio for Type 2 diabetes at each genetic risk score point was 1.11 (95% CI 1.09–1.14; P = 5.6 · 10)17) and individuals with extremes of genetic risk score (‡ 29.0 and £ 17.0) had a 7.5-fold difference in risk of Type 2 diabetes. The discrimination rate between control subjects and patients improved marginally on addition of genetic risk score to conventional risk factors (area under curve = 0.959 and 0.963, respectively; P = 0.001). Of all the quantitative traits analysed, MC4R variants showed strong association with BMI (P = 4.1 · 10)4), fat mass per cent (P = 2.4 · 10)4) and other obesity-related traits, including waist circumference and hip circumference (P = 2.0 · 10)3 for both), as well as insulin resistance (P = 0.02). Conclusions We replicated the association of well-established common variants with Type 2 diabetes in Indians and observed a similar association as reported in Western populations. Combined analysis of 32 variants aids identification of subgroups at increased risk of Type 2 diabetes, but adds only a minor advantage over conventional risk factors.
Abstract: After long periods of vast child health disparities between industrialized countries and Resource-limited Settings (RLS) research has started to address and reduce the gap. It is well established worldwide, has yielded mutually rewarding collaborations and has a funding and career structure unthinkable even 25 years ago. Despite this progress, work remains to
ensure academic and funding equity and ethical parity. This paper outlines the background to and history of research in RLS, illustrates the current situation and points to potential future developments.
Abstract: There has been a complete turnaround in scientific thinking about malnutrition as a protective factor to that of a major determinant of diabetes. Development of Type 2 diabetes is attributed to a combination of genetic susceptibility and precipitation factors in adult or early adult life. Current trials and preventive interventions are based on this gene-obesity model causing glucose intolerance necessitating food restriction for management. However when we compare the burden of low birth weight and intrauterine growth restriction with that of type 2 diabetes it can be hypothesised that good nutrition during intrauterine development and early childhood is more important. Foetal programming due to under nutrition can result in inter-generational transfer of long latency disorders. This hypothesis led to the establishment of the Pune maternal nutrition study and Pune children study involving cohorts. Low vitamin B12 levels, folate levels and high homocysteine levels are shown to be associated with low birth weight and insulin resistance in offspring. This demonstrates that maternal micro nutrient status influences risk of diabetes in the offspring and birth weight is a marker of intrauterine environment. Policy implications include ensuring the health of the young girl and addition of vitamin B12 along with folate for pregnant women. The biochemical estimation was made possible by storage of samples in biobanks which is a most useful resource for subsequent measurements, but there are ethical concerns and issues of subject approval.
Child’s homocysteine concentration at 2 years is influenced by pregnancy vitamin B12 and folate status
Author Name: Chittaranjan Yajnik , Publication Year: 2012 , Journal Name: Journal of Developmental Origins of Health and Disease
Abstract: Longitudinal studies investigating vitamin B12 and folate status of mothers and their offspring will provide a better understanding of inter-generational nutrition. During pregnancy and 2 years (2y) after delivery, we measured plasma vitamin B12 and folate concentrations in 118 women [aged (mean±S.D.) 22.9±3.9y] who attended a rural (n=68) or an urban (n=50) antenatal clinic in Pune, India. Cord blood vitamin B12 and folate were measured, and when the child was 2y total homocysteine (tHcy) was also measured. Demographic and diet measurements were recorded using standard methods. Pregnancy plasma vitamin B12 concentration at 34 weeks was low [median (25th, 75th), 115 (95, 147) pM]; 75% had low status (<150 pM). Plasma folate was high (mean ±S.D., 33±21 nM); one had a folate concentration <7pM. Cord plasma vitamin B12 and folate concentrations were higher than and positively associated with maternal concentrations. In stepwise regression, higher child vitamin B12 at 2y was predicted (total R2 15.7%) by pregnancy vitamin B12 (std β 0.201, R2 7.7%), current consumption of cow’s milk (std β 0.194, R2 3.3%) and whether breast feeding was stopped before 2y (std β -0.234 R2 7.2%). Child’s 2y tHcy concentration was high (11.4±3.6µM) and predicted by lower pregnancy vitamin B12 (std β -0.206, R2 4.1%), lack of vitamin supplementation (std β -0.256, R2 5.6%) in pregnancy and whether currently breastfed (std β 0.268, R2 8.4%). Low maternal vitamin B12 status in pregnancy and prolonged breast-feeding results in disturbed one-carbon metabolism in offspring at 2y. Supplementation of women of child-bearing age, particularly during pregnancy and lactation, may improve the homocysteine status of these children.
Abstract: OBJECTIVE: To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily.
RESULTS: Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA1c 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA1c reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were -1.53 vs. -1.48 (P = 0.620), -1.63 (P = 0.328), and -1.15 (P < 0.001), respectively.Weight changes (kg) were -2.0 vs. -2.0 (P = 0.892), +1.5 (P < 0.001), and -0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred. CONCLUSIONS: EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA1c reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.
Impact of ethnicity on gestational diabetes identified with the WHO and the modified International Association of Diabetes and Pregnancy Study
Author Name: Chittaranjan Yajnik , Publication Year: 2012 , Journal Name: European Journal of Endocrinology
Abstract: Objective: The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recently proposed new criteria for diagnosing gestational diabetes mellitus (GDM). We compared prevalence rates, risk factors, and the effect of ethnicity using the World Health Organization (WHO) and modified IADPSG criteria.
Methods: This was a population-based cohort study of 823 (74% of eligible) healthy pregnant women, of whom 59% were from ethnic minorities. Universal screening was performed at 28±2 weeks of gestation with the 75 g oral glucose tolerance test (OGTT). Venous plasma glucose (PG) was measured on site. GDM was diagnosed as per the definition of WHO criteria as fasting PG (FPG) ≥ 7.0 or 2-h PG ≥ 7.8 mmol/l; and as per the modified IADPSG criteria as FPG ≥ 5.1 or 2-h PG ≥ 8.5 mmol/l. Results: OGTT was performed in 759 women. Crude GDM prevalence was 13.0% with WHO (Western Europeans 11%, ethnic minorities 15%, P=0.14) and 31.5% with modified IADPSG criteria (Western Europeans 24%, ethnic minorities 37%, P<0.001). Using the WHO criteria, ethnic minority origin was an independent predictor (South Asians, odds ratio (OR) 2.24 (95% confidence interval (CI) 1.26–3.97); Middle Easterners, OR 2.13 (1.12–4.08)) after adjustments for age, parity, and prepregnant body mass index (BMI). This increased OR was unapparent after further adjustments for body height (proxy for early life socioeconomic status), education and family history of diabetes. Using the modified IADPSG criteria, prepregnant BMI (1.09 (1.05–1.13)) and ethnic minority origin (South Asians, 2.54 (1.56–4.13)) were independent predictors, while education, body height and family history had little impact.
Conclusion: GDM prevalence was overall 2.4-times higher with the modified IADPSG criteria compared with the WHO criteria. The new criteria identified many subjects with a relatively mild increase in FPG, strongly associated with South Asian origin and prepregnant overweight.
Abstract: Aims/hypothesis Evaluation of the association of 31 common single nucleotide polymorphisms (SNPs)with fasting glucose, fasting insulin, HOMA-beta cell function (HOMA-β), HOMA-insulin resistance (HOMA-IR) and type 2 diabetes in the Indian population. Methods We genotyped 3,089 sib pairs recruited in the Indian Migration Study from four cities in India (Lucknow, Nagpur, Hyderabad and Bangalore) for 31 SNPs in 24 genes previously associated with type 2 diabetes in European populations. We conducted within-sib-pair analysis for type 2 diabetes and its related quantitative traits. Conclusions/interpretation We validated the association of seven established loci with intermediate traits related to type 2 diabetes in an Indian population using a design resistant to population stratification.
Vitamin B12 and folate during pregnancy and offspring motor, mental and social development at 2 years of age
Author Name: Chittaranjan Yajnik , Publication Year: 2012 , Journal Name: Journal of Developmental Origins of Health and Disease
Abstract: Insufficiency of vitamin B12 (B12) and folate during pregnancy can result in low concentrations in the fetus and have adverse effects on brain development. We investigated the relationship between maternal B12 and folate nutrition during pregnancy and offspring motor, mental and social development at two years of age (2 y). Mothers (n=123) and their offspring (62 girls, 61 boys) from rural and middle-class urban communities in and around Pune city were followed through pregnancy up to 2 y. Maternal B12 and folate concentrations were measured at 28 and 34 weeks of gestation. At 2 y, the Developmental Assessment Scale for Indian Infants was used to determine motor and mental developmental quotients and the Vineland Social Maturity Scale for the social developmental quotient. Overall, 62% of the mothers had low B12 levels (<150 pmol/l) and one mother was folate deficient during pregnancy. Maternal B12 at 28 and 34 weeks of gestation was associated with offspring B12 at 2 y (r=0.29, r=0.32, P,0.001), but folate was not associated with offspring folate. At 2 y, motor development was associated with maternal folate at 28 and 34 weeks of gestation. Mental and social development quotients were associated positively with head circumference and negatively with birth weight. In addition, pregnancy B12 and folate were positively associated with mental and social development quotients. Maternal B12 and folate during intrauterine life may favorably influence brain development and function. Pregnancy provides a window of opportunity to enhance fetal psychomotor (motor and mental) development.
Abstract: OBJECTIVE: To examine the influence of glycemic and nonglycemic parameters on HbA1c concentrations in young adults, the majority of whom had normal glucose tolerance.
RESEARCH DESIGN AND METHODS: We compared the diagnosis of normal glucose tolerance, prediabetes, and diabetes between a standard oral glucose tolerance test (OGTT; World Health Organization 2006 criteria) and HbA1c concentrations (American Diabetes Association [ADA] 2009 criteria) in 116 young adults (average age 21.6 years) from the Pune Children’s Study. We also studied the contribution of glycemic and nonglycemic determinants to HbA1c concentrations.
RESULTS: The OGTT showed that 7.8% of participants were prediabetic and 2.6% were diabetic. By ADA HbA1c criteria, 23.3% were prediabetic and 2.6% were diabetic. The negative predictive value of HbA1c was 93% and the positive predictive value was 20% (only 20% had prediabetes or diabetes according to the OGTT; this figure was 7% in anemic participants). Of participants, 34%were anemic, 37%were iron deficient (ferritin,15 ng/mL), 40% were vitamin B12 deficient (<150 pmol/L), and 22% were folate deficient (<7 nmol/L). On multiple linear
regression analysis, HbA1c was predicted by higher 2-h glucose (R2 = 25.6%) and lower hemoglobin (R2 = 7.7%). When hematological parameters were replaced by ferritin, vitamin B12, and folate, HbA1c was predicted by higher glycemia (R2 = 25.6%) and lower ferritin (R2 = 4.3%).
CONCLUSIONS: The use of HbA1c to diagnose prediabetes and diabetes in iron-deficient populations may lead to a spuriously exaggerated prevalence. Further investigation is required before using HbA1c as a screening tool in nutritionally compromised populations.
Abstract: Aims/hypothesis FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is
growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently
of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2
diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
Methods All studies published on the association between FTO-rs9939609 (or proxy [r2>0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
Results The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p=9.0×10-19), overweight by 1.13-fold/allele (p=1.0×10−11) and type 2 diabetes by 1.15- fold/allele (p=5.5×10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10- fold/allele, p=6.6×10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p=2.8×10−17), WHR by 0.003/allele (p=1.2×10−6), and body fat percentage by 0.31%/allele (p=0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
Conclusions/interpretation FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Fetal programming Maternal nutrition and role of one-carbon metabolism
Author Name: Chittaranjan Yajnik , Publication Year: 2012 , Journal Name: Reviews in Endocrine and Metabolic Disorders- Springer
Abstract: India is world’s capital for low birth weight (LBW), which is ascribed to intrauterine growth restriction (IUGR) rather than prematurity. An average Indian mother is short and thin and gives birth to a light and thin baby. Maternal undernutrition is thought to be a major factor in the aetiology of IUGR, and the undernutrition is usually thought to be a low macronutrient intake. The Pune Maternal Nutrition Study (PMNS) showed that the Indian babies were thin but fat (more adipose) compared to European babies, and that maternal intake of micronutrient-rich foods was a strong determinant of fetal size. Two thirds of the mothers had low vitamin B12 concentrations, folate deficiency was rare, and high circulating concentrations of homocysteine predicted IUGR. Follow up of these children revealed that higher maternal folate in pregnancy predicted higher adiposity and insulin resistance at 6 years of age. The most insulin resistant children were born to mothers who were vitamin B12 deficient and had high folate concentrations. Thus, PMNS suggests an important role for maternal onecarbon (1C) metabolism in fetal growth and programming of diabetes risk. This could be due to the role of 1C metabolism in synthesis of nucleic acids, genomic stability and the epigenetic regulation of gene function. In addition, methionine has important role in protein synthesis. These ideas are supported by animal studies. The next logical step in India will be to improve 1C metabolism in adolescents to effect intergenerational prevention of adiposity, diabetes and other related conditions.
Abstract: Background/Aims: The concept of the ‘thin–fat’ Indian baby is well established, but there is little comparative data in older children, and none that examines the metabolic correlates. Accordingly, we investigated the impact of body composition on the metabolic profiles of Asian Indian and white UK children. Methods: Body mass index (BMI), waist circumference, sum of four skin-folds, % body fat (by dualenergy X-ray absorptiometry), glucose, insulin, insulin resistance (Homeostasis Model Assessment), trigylcerides, cholesterol [total, low-density lipoprotein, high-density lipoprotein {HDL}, total/HDL ratio] and blood pressure (systolic, diastolic and mean arterial) were measured in 262 white Caucasian children from Plymouth, UK (aged 6.9 ± 0.2 years, 57% male), and 626 Indian children from rural villages around Pune, India (aged 6.2 ± 0.1 years, 53% male). Results: Indian children had a significantly lower BMI (boys: -2.1 kg m-2, girls: -3.2 kg m-2, both P < 0.001), waist circumference (P < 0.001) and skin-fold thickness (P < 0.001) than white UK children, yet their % body fat was higher (boys +4.5%, P < 0.001, girls: +0.5%, P = 0.61). Independently of the differences in age and % body fat, the Indian children had higher fasting glucose (boys +0.52 mmol L-1, girls +0.39 mmol L-1, both P < 0.001), higher insulin (boys +1.69, girls +1.87 mU L-1, both P < 0.01) and were more insulin resistant (boys +0.25, girls +0.28 HOMA-IR units, both P < 0.001). Conclusions: The ‘thin–fat’ phenotype observed in Indian babies is also apparent in pre-pubertal Indian children who have greater adiposity than white UK children despite significantly lower BMIs. Indian children are more insulin resistant than white UK children, even after adjustment for adiposity.
Iron fortification of whole wheat flour reduces iron deficiency and iron deficiency anemia and increases body iron stores in Indian school-aged children
Abstract: Wheat is the primary staple food for nearly one-third of the worlds population. NaFeEDTA is the only iron (Fe) compound suitable for fortifying high extraction flours. We tested the hypothesis that NaFeEDTA-fortified, whole wheat flour reduces Fe deficiency (ID) and improves body Fe stores (BIS) and cognitive performance in Indian children. In a randomized, double-blind, controlled, school feeding trial, 6- to 15-y-old, Fe-depleted children (n = 401) were randomly assigned to either a daily wheat-based lunch meal fortified with 6 mg of Fe as NaFeEDTA or an otherwise identical unfortified control meal. Hemoglobin (Hb) and Fe status were measured at baseline, 3.5 mo, and 7 mo. Cognitive performance was evaluated at baseline and 7 mo in children (n = 170) at one of the study sites. After 7 mo, the prevalence of ID and ID anemia in the treatment group significantly decreased from 62 to 21% and 18 to 9%, respectively. There was a time x treatment interaction for Hb, serum ferritin, transferrin receptor, zinc protoporphyrin, and BIS (all P < 0.0001). Changes in BIS differed between the groups; it increased in the treatment group (0.04 ± 0.04 mmol/kg body weight) and decreased in the control group (20.02 ± 0.04 mmol/kg body weight) (P < 0.0001). In sensory tests, NaFeEDTA-fortified flour could not be
differentiated from unfortified flour. There were no significant differences in cognitive performance tests between the groups. NaFeEDTA-fortified wheat flour markedly improved BIS and reduced ID in Fe-depleted children. It may be recommended for wider use in national school feeding programs.
Evaluation of seven common lipid associated loci in a large Indian sib pair study
Author Name: Chittaranjan Yajnik , Publication Year: 2012 , Journal Name: Lipids in Health and Disease
Abstract: Background: Genome wide association studies (GWAS), mostly in Europeans have identified several common
variants as associated with key lipid traits. Replication of these genetic effects in South Asian populations is important since it would suggest wider relevance for these findings. Given the rising prevalence of metabolic disorders and heart disease in the Indian sub-continent, these studies could be of future clinical relevance. Methods: We studied seven common variants associated with a variety of lipid traits in previous GWASs. The study sample comprised of 3178 sib-pairs recruited as participants for the Indian Migration Study (IMS). Associations with various lipid parameters and quantitative traits were analyzed using the Fulker genetic association model. Results: We replicated five of the 7 main effect associations with p-values ranging from 0.03 to 1.97x10-7. We identified particularly strong association signals at rs662799 in APOA5 (beta=0.18 s.d, p=1.97 x 10-7), rs10503669 in LPL (beta =−0.18 s.d, p=1.0 x 10-4) and rs780094 in GCKR (beta=0.11 s.d, p=0.001) loci in relation to triglycerides. In addition, the GCKR variant was also associated with total cholesterol (beta=0.11 s.d, p=3.9x10-4). We also replicated the association of rs562338 in APOB (p=0.03) and rs4775041 in LIPC (p=0.007) with LDL-cholesterol and HDL-cholesterol respectively. Conclusions: We report associations of five loci with various lipid traits with the effect size consistent with the same reported in Europeans. These results indicate an overlap of genetic effects pertaining to lipid traits across the European and Indian populations.
Cardiorenal end points in a trial of aliskiren for type 2 diabetes
Author Name: Chittaranjan Yajnik , Publication Year: 2012 , Journal Name: The New England Journal of Medicine
Abstract: Background: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. Methods: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting–enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or
initiated; or doubling of the baseline serum creatinine level. Results: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P = 0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). Conclusions: The addition of aliskiren to standard therapy with renin–angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful.
Systemic Inflammation (C-Reactive Protein) in Type 2 Diabetic Patients Is Associated With Ambient Air Pollution in Pune City, India
Author Name: MORTEZA A. KHAFAIE, BEHZAD KHAFAIE, SUNDEEP S. SALVI, AJAY OJHA , Publication Year: 2012 , Journal Name: Original Article
Abstract: To study the association between ambient air pollutants and serum C-reactive
protein (CRP) concentration in 1,392 type 2 diabetic patients in Pune, India.
METHODSdA cross-sectional study was conducted that
linked daily time series of ambient air pollution data (obtained fromcentral monitoring sites) and
plasma CRP concentration in type 2 diabetic patients from the Wellcome Trust Genetic (Well-
Gen) Study, recruited between March 2005 and May 2007. Air pollution effects on CRP concentration
were investigated with delays (lags) of 0–7 days and multiday averaging spans of 7, 14,
and 30 days before blood collection adjusted for age, sex, BMI, hemoglobin, fasting plasma
glucose, treatment with agents with anti-inflammatory action, season, air temperature, and
relative humidity.
RESULTSdMedian CRP concentration was 3.49 mg/L. For 1 SD increase in SO2 and oxides of
nitrogen (NOx) concentrations in ambient air, a day before blood collection (lag1), we observed a
significant increase in CRP (9.34 and 7.77%, respectively). The effect was higher with lag2
(12.42% for SO2 and 11.60% for NOx) and wore off progressively thereafter. We also found a
significant association with multiday averaging times of up to 30 and 7 days for SO2 and NOx,
respectively. No significant associations were found between particulate matter with an aerodynamic
profile#10 mm (PM10) and CRP concentration except in summer. The association was
significantly higher among patients with a shorter duration of diabetes, and in those not on statin
and thiazolidinedione treatment.
We demonstrate, for the first time, a possible contribution of ambient air
pollution to systemic inflammation in Indian type 2 diabetic patients. This may have implications
for vascular complications of diabetes.
Screening of cardiovascular autonomic neuropathy in patients with diabetes using non-invasive quick and simple assessment of sudomotor function
Author Name: C.S. Yajnik a, V. Kantikar a, A. Pande a, J.P. Deslypere et al. , Publication Year: 2012 , Journal Name: Elsevier
Abstract: Aim. – Cardiovascular autonomic neuropathy (CAN) is a common but often overlooked complication of diabetes. Sympathetic C-fibers innervating
sweat glands can be impaired early on in patients with diabetes. In this study, SUDOSCAN, a new non-invasive device that assesses sudomotor
function was compared to methods generally used for the investigation of CAN.
Patients. – A total of 232 patients with diabetes were measured for heart rate variability (HRV) at rest and during moderate activity. Time and
frequency domain analysis techniques, including measurement of the low-frequency (LF) domain component, were assessed during HRV testing.
Ewing tests, as recommended by the French Health Authority, were also done. Electrochemical sweat conductance (ESC) was measured on the
hands and feet, and a risk-score was calculated.
Results. – Using two abnormal Ewing tests as a reference for the area under the curve (AUC) of the receiver operating characteristics (ROC)
curve for SUDOSCAN, the risk-score was 0.74, with a sensitivity of 92% and specificity of 49% for a risk-score cut-off value of 35%. For the ROC
curve analysis using the LF power component during moderate activity at a threshold of 90 ms2 (first quartile) as reference, the AUC was higher
for the SUDOSCAN risk-score (0.77) compared with the standard Ewing tests [E:I ratio (0.62), 30:15 ratio (0.76) and blood pressure change on
standing (0.55)]. Using a cut-off value of 35%, risk-score sensitivity and specificity were 88 and 54%, respectively.
Conclusion. – SUDOSCAN, which allows quick quantitative assessment of sudomotor function, may be used for early screening of CAN in
everyday clinical practice before resorting to the more sophisticated and specific, but ultimately more time-consuming, Ewing tests.
Abstract: Visceral adiposity is a risk factor for cardiovascular disorders, type 2 diabetes mellitus (T2D) and associated metabolic diseases. Sub-cutaneous fat is believed to be intrinsically different from visceral fat. To understand molecular mechanisms involved in metabolic advantages of fat transplantation, we studied a rat model of diet-induced adiposity. Adipokine genes (Adiponectin, Leptin, Resistin and Visfatin) were expressed at 10,000 to a million-fold lower in visceral fat depot as compared to peripheral (thigh/chest) fat depots. Interestingly, autologous transplantation of visceral fat to subcutaneous sites resulted in increased gene transcript abundance in the grafts by 3 weeks post-transplantation, indicating the impact of local (residence) factors influencing epigenetic memory. We show here that active transcriptional state of adipokine genes is linked with glucose mediated recruitment of enzymes that regulate histone methylation. Adipose depots have ‘‘residence memory’’ and autologous transplantation of visceral fat to sub-cutaneous sites offers metabolic advantage.
Abstract: The worldwide explosion of diabetes during the last three decades is generally recognized as a phenomenon of increasing numbers of affected persons. Little attention has been paid to qualitative changes, to the expansion or emergence of forms that do not fit traditional categories defined by the American Diabetes Association (ADA) or the World Health Organization (WHO). This is unfortunate, as the standard classification of diabetes into “type 1” and “type 2”—with a passing nod to “atypical” diabetes—suffers from imprecise definitions that do little justice to the complexities of heterogeneous phenotypes and impede the progress of research into novel disease mechanisms and rational treatment. Modifications of the classification scheme have been proposed, but generally not in a manner helpful to translational researchers. It is beyond the scope of this review to define and assess the specificity of all these variant forms. Hence, we have limited the
discussion to two striking phenotypes that appear to be widespread and increasing in prevalence, and have a background of significant clinical investigation into etiology and pathophysiology. Finally, the application of broad-scale “-omics” approaches to such well-characterized phenotypes—especially through integration of genomics, transcriptomics and metabolomics, as validated in an animal model (83)—is likely to yield a richer harvest of mechanistic data on the athophysiology of diabetes than we currently possess.
Early life origins of diabetes and obesity General aspects and the thin – fat baby paradigm
Author Name: Chittaranjan Yajnik , Publication Year: 2011 , Journal Name: Perinatal Programming: The State of the Art
Abstract: The increasing realization that obesity and type 2 diabetes are best prevented has focused researchers’ attention on the influence of early life factors. The environment in utero has been shown to program the body composition and metabolic-endocrine axes, which determine the individual’s adaptability to later-life exposures. Accumulating evidence suggests that epigenetic mechanisms contribute to this programming. Thus, maternal factors (nutrition and metabolism) that influence the in utero milieu have a large role to play in the primordial prevention of chronic diseases. Optimizing adolescent health rather than focusing only on adult lifestyle modifications would be much more beneficial and cost effective in preventing
obesity and diabetes.
Abstract: Aims/hypothesis The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial reported that 3 years of therapy with rosiglitazone reduced the primary outcome of diabetes or death by 60%. Here we investigated whether an effect on diabetes prevention persists more than 1.5 years after therapy has been discontinued.
Methods The DREAM On passive follow-up study was conducted at 49 of the 191 DREAM sites. Consenting participants were invited to have a repeat OGTT 1–2 years after active therapy ended. A diagnosis of diabetes at that time was based on either a fasting or 2 h plasma glucose level of ≥7.0 mmol/l or ≥11.1 mmol/l, respectively, or a confirmed diagnosis by a non-study physician. Regression to normoglycaemia was defined as a fasting and 2 h plasma glucose level of <6.1 mmol/l and <7.8 mmol/l, respectively. Results After a median of 1.6 years after the end of the trial and 4.3 years after randomisation, rosiglitazone participants had a 39% lower incidence of the primary outcome (hazard ratio [HR] 0.61, 95% CI 0.53–0.70; p<0.0001) and 17% more regression to normoglycaemia (95% CI 1.01–1.34; p=0.034). When the analysis was restricted to the passive follow-up period, a similar incidence of both the primary outcome and regression was observed in people from both treatment groups (HR 1.00, 95% CI 0.81–1.24 and HR 1.14, 95% CI 0.97–1.32, respectively). Similar effects were noted when new diabetes was analysed separately from death. Ramipril did not have any significant long-term effect.
Conclusions/interpretation Time-limited exposure to rosiglitazone reduces the longer term incidence of diabetes by delaying but not reversing the underlying disease process.
Is a low blood level of vitamin B12 a cardiovascular and diabetes risk factor A systematic review of cohort studies
Author Name: Chittaranjan Yajnik , Publication Year: 2011 , Journal Name: European Journal of Nutrition - Springer
Abstract: Purpose To assess the prior hypothesis that low blood vitamin B12, partly through hyperhomocysteinemia and partly through direct effects, increases the risk of cardiovascular diseases and diabetes. As background, we also extracted all-cause mortality from the studies that met our criteria. Methods A systematic review of prospective cohort studies identified through searching six electronic databases, screening of reference lists, and citation search. Included studies reported data on the association between vitamin B12 blood levels, or other appropriate surrogate biological markers e.g. holotranscobalamin or serum/urine methylmalonic acid, and fatal or non-fatal incident diabetes and cardiovascular events. Results Seven studies were included. Studies differed regarding the population studied, length of follow-up, study outcomes, and data analysis—a narrative synthesis approach was performed to examine the results. Most studies met few of the quality assessment criteria which were adapted from the Scottish Intercollegiate Guidelines Network (SIGN). Only one high-quality study reported that low B12 increased the risk of incident cerebral ischaemia (RR = 1.76; 95% CI = 1.16–2.68). After controlling for homocysteine, the association persisted although weakened (RR = 1.57; 95% CI = 1.02–2.43), suggesting that the effects of low B12 were only partly mediated by homocysteine. In two studies, higher B12 levels were associated with a greater risk of total mortality (RR = 1.00; 95% CI = 1.00–1.00 and HR = 1.15; 95% CI = 1.08–1.22, respectively) and combined fatal and non-fatal coronary events (RR = 1.00; 95% CI = 1.00–1.00). No association between study outcomes and vitamin B12 levels was found in four other studies. Conclusions Surprisingly, there is only very limited evidence that vitamin B12 deficiency predisposes to the risk of mortality and morbidity from either cardiovascular diseases
or diabetes in adults. Current data do not support vitamin B12 supplementation to reduce the risk of cardiovascular diseases or diabetes.
Maternal C-reactive Protein Is A Predictor Of Neonatal Size At Birth PMNS
Author Name: Chittaranjan Yajnik , Publication Year: 2011 , Journal Name: 7th World Congress on Developmental Origins of Health and Disease
Abstract: Aims: There is increasing interest in the role of maternal sub-clinical inflammation in fetal growth restriction. We studied the association between maternal high sensitive C-reactive protein (CRP) and offspring size at birth in Pune Maternal Nutrition Study (PMNS).
Methods: In PMNS we have information on prepregnant body size, adiposity, and socioeconomic status. Pregnancy measurements at 28 weeks gestation include anthropometry, physical activity, nutritional intake, circulating nutrients (vitamin B12, folate, total homocysteine, vitamin C and vitamin D), biochemical measurements (CRP, oral glucose tolerance, hematology and lipids) and blood pressure (BP). Baby's anthropometry was measured within 72 hours of birth.
Results: Results are available in 558 mother-offspring pairs. Before conception women were (median) 21y (19, 23), height 152 cm (149, 156), body mass index of 17.8 kg/m2 (16.7, 19.1) and body fat 20.4% (17.8, 23.4). At 28 weeks, plasma CRP concentrations were 1.55 (0.68-3.44) mg/L and 28% had >3.0 mg/L. Gestation at delivery was 39.3 weeks (38.3, 40.3) and birth weight 2600 gm (2368, 2900). CRP was inversely related to age and parity and directly related to body fat percent (p< 0.05, all), but not with body mass index and socioeconomic status. Pregnancy weight gain, physical activity, macronutrient (total calories, carbohydrate, proteins and fat) intake, circulating micronutrient (vitamin B12, folate, vitamin C, vitamin D) concentrations, glucose tolerance, and lipids were not associated with CRP concentration. CRP was inversely associated with total homocysteine (p=0.05) and directly associated with systolic BP (p=0.05). Mothers in highest quartile of CRP concentrations were 4.20 times (CI 1.64, 10.80) more likely to deliver preterm, and 1.68 times (CI 1.02, 2.76) more likely to deliver a low birth weight baby compared to those in lowest quartile. Association of maternal CRP and fetal growth restriction was independent of her age, adiposity, and parity. Maternal total leucocyte count (TLC) not associated with preterm delivery and size at birth. Conclusions: Maternal inflammation is a risk factor for early delivery and small size at birth in India.
Abstract: The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide singlenucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P 5 3.6 3 1028) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P 5 4.7 3 1028). The top IBC association for SBP was rs2012318 (P 5 6.4 3 1026) near SLC25A42 and for DBP was rs2523586 (P 5 1.3 3 1026) near HLA-B. None of the top variants replicated in additional AA (n 5 11 882) or European-American (n 5 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P 5 0.009; TBX3-TBX5, P 5 0.03; and CSK-ULK3, P 5 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
Marked Gender Difference in Plasma Total Homocysteine Concentrations in Indian Adults with low Vitamin B12
Author Name: Chittaranjan Yajnik , Publication Year: 2011 , Journal Name: International Journal for Vitamin and Nutrition Research
Abstract: Context: Plasma total homocysteine (tHcy) is higher in men than women. Objective: To explore the gender differences in tHcy in relation to determinants of one-carbon metabolism in Indian people with low B 12 and adequate folate. Setting: The study took place in rural and urban areas of Pune, India. Design and participants: Participants were 441 men from the cross-sectional Coronary Risk of Insulin Sensitivity in Indian Subjects study (CRISIS) and premenopausal wives of 146 men (median ages 38 and 34 years, respectively). Main outcome measures: Gender difference in fasting tHcy in relation to plasma albumin and creatinine concentrations, lifestyle factors, diet and lean mass, plasma B12 and red cell folate (RCF) was assessed. Results: Prevalence of high tHcy ( > 15 μmol/L, median 14.4 μM) was 40 %, low B12 ( < 150 pmol/L, 114 pmol/L) 66 %, and low RCF ( < 283 nmol/L, 525 nmol/L) 8 %. Men had higher (1.8x) plasma tHcy concentrations (16.2 μmol/L) than women (9.5 μmol/L). Only 50 % of the gender difference was explained by age, lean mass, B12, and RCF. The difference remained after controlling for other explanatory variables. Women with a tHcy of 9.3 μM had the same B12 concentration (129 pmol/L) as men with a tHcy of 15 μM; and for a tHcy of 10.0 μmol/L women had the same RCF concentration (533 nmol/L) as men with a tHcy of 15 μ mol/L. Conclusions: Adult Indian women have markedly lower tHcy concentrations compared to men. This suggests a lower threshold for supplementation to improve reproductive and cardiovascular outcomes.
Maternal one-carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India
Author Name: Chittaranjan Yajnik , Publication Year: 2011 , Journal Name: Birth Defects Research Part A: Clinical and Molecular Teratology
Abstract: BACKGROUND: Neural tube defects (NTDs) are among the most common severe congenital malformations, representing a long-term public health burden in India. A deranged one-carbon metabolism and genes regulating this metabolism have been linked to NTDs. Vitamin B12 deficiency is reported to be more prevalent than folate deficiency in the Indian population. We investigated the role of maternal nutritional and genetic markers related to one-carbon metabolism in the etiology of NTDs. METHODS: We conducted a multicenter case-control study to compare plasma folate, vitamin B12, homocysteine and holo-transcobalamin levels, and polymorphisms in methylenetetrahydrofolate reductase (MTHFR, 677C>T, 1298A>C, 1781G>A and 2361724A>G) and transcobalamin (TCN2, 776C>G) genes, in 318 women with NTD-affected offspring (cases) and 702 women with apparently healthy offspring (controls). The samples were collected at diagnosis in cases and at delivery in controls. RESULTS: We observed a significant association of high maternal plasma homocysteine concentrations with NTDs in the offspring (p 5 0.026). There was no association of maternal folate or B12 levels with NTDs (p > 0.05) but low maternal holo-transcobalamin predicted strong risk of NTDs in the offspring (p 5 0.003). The commonly associated maternal polymorphism 677C>T in the MTHFR gene did not predict risk of NTDs in the offspring (p > 0.05) and 1298A>C and 1781G>A polymorphisms in MTHFR were protective (p 5 0.024 and 0.0004 respectively). Maternal 776C>G polymorphism in TCN2 was strongly predictive of NTD in the offspring (p 5 0.006). CONCLUSION: Our study has demonstrated a possible role for maternal B12 deficiency in the etiology of NTDs in India over and above the well-established role of folate deficiency.
Abstract: Blood pressure is a heritable trait1 influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension ($140mmHg systolic blood pressure or$90mmHg diastolic blood pressure)2. Even small increments in blood pressure are associated with an increased risk of cardiovascular events3. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3–GUCY1B3, NPR3–C5orf23, ADM, FURIN–FES, GOSR2, GNAS–EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genomewide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Aims/hypothesis This study reports the results of the first phase of a national study to determine the prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in India. Methods A total of 363 primary sampling units (188 urban, 175 rural), in three states (Tamilnadu, Maharashtra and Jharkhand) and one union territory (Chandigarh) of India were sampled using a stratified multistage sampling design to survey individuals aged ≥20 years. The prevalence rates of diabetes and prediabetes were assessed by measurement of fasting and 2 h post glucose load capillary blood glucose. Results Of the 16,607 individuals selected for the study, 14,277 (86%) participated, of whom 13,055 gave blood samples. The weighted prevalence of diabetes (both known and newly diagnosed) was 10.4% in Tamilnadu, 8.4% in Maharashtra, 5.3% in Jharkhand, and 13.6% in Chandigarh. The prevalences of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were 8.3%, 12.8%, 8.1% and 14.6% respectively. Multiple logistic regression analysis showed that age, male sex, family history of diabetes, urban residence, abdominal obesity, generalised obesity, hypertension and income status were significantly associated with diabetes. Significant risk factors for prediabetes were age, family history of diabetes, abdominal obesity, hypertension and income status. Conclusions/interpretations We estimate that, in 2011, Maharashtra will have 6 million individuals with diabetes and 9.2 million with prediabetes, Tamilnadu will have 4.8 million with diabetes and 3.9 million with prediabetes, Jharkhand will have 0.96 million with diabetes and 1.5 million with prediabetes, and Chandigarh will have 0.12 million with diabetes and 0.13 million with prediabetes. Projections for the whole of India would be 62.4 million people with diabetes and 77.2 million people with prediabetes.
Prediction of body-fat percentage from skinfold and bio-impedance measurements in Indian school children
Author Name: Chittaranjan Yajnik , Publication Year: 2011 , Journal Name: European Journal of Clinical Nutrition - Nature
Abstract: Background/Objectives: Few equations for calculating body-fat percentage (BF%) from field methods have been developed in South-Asian children. The objective of this study was to assess agreement between BF% derived from primary reference methods and that from skinfold equations and bio-impedance analysis (BIA) in Indian children. Subjects/Methods: We measured BF% in two groups of Indian children. In Pune, 570 rural children aged 6–8 years underwent dual-energy X-ray absorptiometry (DXA) scans. In Mysore 18O in doubly labeled water was administered to 59 urban children aged 7–9 years. We conducted BIA at 50 kHz and anthropometry, including sub-scapular and triceps skinfold thicknesses. We used the published equations of Wickramasinghe, Shaikh, Slaughter and Dezenburg to calculate BF% from anthropometric data and the manufacturer’s equation for BIA measurements. We assessed agreement with values derived from DXA and doubly labeled water using Bland–Altman analysis. Results: Children were light and thin on average compared with international standards. There was poor agreement between the reference BF% values and those from all equations. Assumptions for Bland–Altman analysis were not met for Wickramasinghe, Shaikh and Slaughter equations. The Dezenberg equations under-predicted BF% for most children (mean difference in Pune -13.4, LOA -22.7, -4.0 and in Mysore -7.9, LOA (-13.7 and -2.2). The mean bias for the BIA equation in Pune was +5.0% and in Mysore +1.95%, and the limits of agreement were wide; -5.0, 15.0 and –7.8, 11.7 respectively. Conclusions: Currently available skinfold equations do not accurately predict BF% in Indian children. We recommend development of BIA equations in this population using a four-compartment model.
Conventional and novel cardiovascular risk factors and markers of vascular damage in rural and urban Indian men
Author Name: Chittaranjan S. Yajnik, Charudatta V. Joglekar , Manoj C. Chinchwadkar , Mehmood G. Sayyad et al. , Publication Year: 2011 , Journal Name: Elsevier
Abstract: Background: India is undergoing rapid epidemiological and nutritional transition largely as a consequence of
rapid urbanisation. We investigated conventional and novel cardiovascular risk factors in rural and urban Indian
men and studied their association with markers of vascular damage.
Methods: We randomly selected and studied 149 rural, 142 urban slum residents and 150 urban middle class
middle aged Indian men. We measured conventional (obesity, blood pressure, lipids, smoking habits) and
novel (proinflammatory and prothrombotic factors) cardiovascular risk factors and markers of vascular damage
(carotid intima media thickness (IMT), von Willebrand Factor (vWF), e-selectin).
Results: There was a progressive increase in most of the conventional cardiovascular (CV) risk factors from
rural to slum to urban middle class men. Plasminogen activator inhibitor-1 (PAI-1), platelet count, total homocysteine
and C-reactive protein showed similar patterns. Carotid IMT was similar in the three groups; vWF
was highest in rural and e-selectin in slum men. Adjusting for location, age explained 17%, obesity 3% and
conventional risk factors 1% of the variance in carotid IMT, whilst novel cardiovascular risk factors were without
any significant impact.
Conclusions: Urbanization increases obesity-related as well as prothrombotic and proinflammatory CV risk
factors in Indian men, but appears not to impact on IMT.
Vitamin B12 and folic acid supplementation and plasma total homocysteine concentrations in pregnant Indian women with low B12 and high folate status
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: Asia Pacific Journal of Clinical Nutrition
Abstract: Maternal vitamin B12 deficiency and hyperhomocysteinemia predict poor pregnancy outcome, foetal adiposity and insulin resistance. In India amongst practicing clinicians and policy makers there is little appreciation of widespread vitamin B12 deficiency. We investigated 163 (86 rural, 77 urban) pregnant women attending antenatal clinics in a rural health centre and a referral hospital in the city of Pune, at 17, 28, and 34 weeks gestation for vitamin supplements, and circulating concentrations of vitamin B12, folate, and total homocysteine. At enrolment 80% rural and 65% urban women had low vitamin B12 but only two rural women had low folate concentrations. During pregnancy 85% rural and 95% of urban women received folic acid; 12% rural and 84% urban women also received vitamin B12. In women receiving no supplementation (n=17) plasma vitamin B12 and folate did not change from 17 to 34 weeks gestation, but homocysteine increased (p<0.05). Homocysteine concentrations at 34 weeks gestation in women receiving only folic acid (n=71, mean 8.4 (95% CI 7.8, 9.1) μmol/L) were comparable to the unsupplemented group (9.7 (7.3, 12.7), p=0.15), but women who received a total dose of > 1000 μg of vitamin B12 up to 34 weeks (n=42, all with folic acid) had lower concentrations (6.7 (6.0, 7.4), p<0.001). Increasing dose of vitamin B12 (rs=-0.31, p=0.006) but not folic acid (rs=-0.19, p=0.11) was associated with lower plasma total homocysteine concentration. In vitamin B12 insufficient, folate replete pregnant women, vitamin B12 supplementation is associated with a reduction of plasma total homocysteine concentration in late pregnancy.
The Kathmandu Declaration Life Circle approach to prevention and care of diabetes mellitus
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: Diabetes Research and Clinical Practice
Abstract: Objectives: To formulate strategies and action plans for the prevention and care of diabetes
mellitus as part of the implementation of the International Diabetes Federation (IDF) United
Nations Resolution (UNR) 61/225 through a unique concept of a ‘‘Life Circle’’ approach.
Method: Consensus following review of evidence available and presented at a meeting
convened to achieve the objective co-chaired by the IDF President and President elect
and diabetologists from several countries in the IDF regions.
Conclusions: The Kathmandu Declaration presents the concept of a ‘‘Life Circle’’ approach to
prevention and care of diabetes—a continuum beginning from preconception, pregnancy,
infancy and childhood to adult life in an integrated manner. Emphasis is on the benefits on
entering the circle at any point and formulates guidelines that could be incorporated in any
national diabetes prevention and care programme, indicating the interactive role of all
known aetiological factors.
Assessment of physical activity using accelerometry, an activity diary, the heart rate method and the Indian Migration Study
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: Public Health Nutrition
Abstract: Objective: To validate questionnaire-based physical activity level (PAL) against accelerometry and a 24 h physical activity diary (24 h AD) as reference methods (Protocol 2), after validating these reference methods against the heart rate–oxygen consumption (HRVO2) method (Protocol 1).
Design: Cross-sectional study.
Setting: Two villages in Andhra Pradesh state and Bangalore city, South India.
Subjects: Ninety-four participants (fifty males, forty-four females) for Protocol 2; thirteen males for Protocol 1.
Results: In Protocol 2, mean PAL derived from the questionnaire (1?72 (SD 0?20)) was comparable to that from the 24 h AD (1?78 (SD 0?20)) but significantly higher than the mean PAL derived from accelerometry (1?36 (SD 0?20); P,0?001). Mean bias of PAL from the questionnaire was larger against the accelerometer (0?36) than against the 24 h AD (20?06), but with large limits of agreement against both. Correlations of PAL from the questionnaire with that of the accelerometer (r50?28; P50?01) and the 24 h AD (r50?30; P50?006) were modest. In Protocol 1, mean PAL from the 24 h AD (1?65 (SD 0?18)) was comparable, while that from the accelerometer (1?51 (SD 0?23)) was significantly lower (P,0?001), than mean PAL obtained from the HRVO2 method (1?69 (SD 0?21)).
Conclusions: The questionnaire showed acceptable validity with the reference methods in a group with a wide range of physical activity levels. The accelerometer underestimated PAL in comparison with the HRVO2 method.
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: Journal of Perinatal Medicine
Abstract: The Pune Maternal Nutrition Study demonstrated that the ‘thinfat’ body composition originates in utero, and that it is linked to maternal nutrition, metabolism and other environmental factors. Low vitamin B12 status and high folate status (due to vegetarian food habits and supplementation by obstetricians) predicted higher adiposity and insulin resistance in the child. Urban Indian mothers seem to suffer from a double burden: as yet uncorrected, predominantly micronutrient undernutrition side by side with rapidly increasing prevalence of gestational diabetes, which both cooperate in influencing adverse fetal programming (‘Dual Teratogenesis’). Tackling the epidemic will require a ‘life-cycle’ approach and given the intergenerational influences it may take a few generations to reduce the susceptibility to type 2 diabetes.
Role of maternal vitamin B12 on the metabolic health of the offspring a contributor to the diabetes epidemic
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: The British Journal of Diabetes & Vascular Disease
Abstract: There is increasing evidence, in humans and other mammals, that periconceptional nutritional status influences health in adulthood. This is called ‘foetal programming’ and is likely to be mediated through DNA methylation. Micronutrients, especially B vitamins such as folic acid and vitamin B12 play crucial roles in providing methyl groups for such reactions. This is called epigenetic regulation and may provide some clues to the epidemic of type 2 diabetes and cardiovascular disease. Evidence from mandatory folic acid fortification studies suggests that in the presence of adequate folic acid, neural tube defects due to B12 deficiency have tripled. Such ‘imbalance of high folic acid and low vitamin B12’ in the elderly causes cognitive impairment. A longitudinal study of young women in India showed that children born to those with ‘high folic acid and low B12’ had higher adiposity and insulin resistance. In addition to increased levels of folic acid, B12 deficiency is increasing in countries with mandatory folic acid fortification. Studies on the prevalence of vitamin B12 deficiency during pregnancy and in women of childbearing age, plus the effects of B12 supplementation are therefore urgently needed. This article reviews the role of vitamin B12 during pregnancy on the offspring’s metabolic risk.
Milk or dairy intake has no impact on birth outcome in a rural and urban cohort from Pune, India
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: American Journal of Human Biology
Abstract: Pregnant women are recommended to increase their intake of milk and/or dairy products to provide essential nutrients to meet fetal needs for growth. There has been little research on the effects of milk or dairy intake on neonatal anthropometric indices. In India, milk and dairy product consumption is widespread, but at low per capita intakes, and this study tests the hypothesis that women who consumed moremilk ormore dairy products had larger neonates (assessed through birth weight, length, abdominal circumference, and skinfolds) than those who consumed less. After controlling for maternal height, parity, gestational age, rural/urban residence, SLI, and total calorie intake, milk intake frequency was not related to birth weight, length, sum of skinfolds, ponderal index, or abdominal circumference. A similar pattern was observed for dairy product intake. Neither milk nor dairy product frequency was associated with any measure of birth outcome in a non-energy adjusted model.
Current Status of Diabetes in India and Need for Novel Therapeutic Agents
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: Sight and Life
Abstract: The prevalence of diabetes is rising all over the world due to population growth, ageing, urbanisation and an increase of obesity and physical inactivity. Unlike in the West, where older persons are most affected, diabetes in Asian countries is disproportionately high in young to middle-aged adults. This could have long-lasting adverse effects on a nation’s health and economy, especially for developing countries. The International Diabetes Federation (IDF) estimates the total number of people in India with diabetes to be around 50.8 million in 2010, rising to 87.0 million by 2030. The primary goal in the management of diabetes mellitus is the attainment of near-normal glycaemia. In India, more than half of patients have poor glycaemic control and have vascular complications. Therefore, there is an urgent need to develop novel therapeutic agents of diabetes without the development and progression of complications or compromising on safety. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) are novel agents that show promising results. Exenatide is the first in the incretin mimetic class and liraglutide is a once-daily human GLP-1 analogue. Oncedaily liraglutide was effective and well tolerated when used as monotherapy or in combination with oral antidiabetic drugs (OADs) in patients with type 2 diabetes, and is therefore a promising new treatment option for the management of type 2 diabetes.
Intrauterine Programming of Non-Communicable Disease Role of Maternal Micronutrients
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: Sight and Life
Abstract: Recent developments in the field of DOHaD have thrown an interesting light on the life-course evolution of many of the chronic NCDs. It is becoming increasingly obvious that a substantial proportion of adult health is programmed in utero. The health of young girls in a community is of paramount importance and is a major influence on the health of the next generation. Maternal micronutrient nutrition contributes to the fetal programming of NCDs. Current ideas on preventing NCDs in the middle-aged and the elderly via difficult-to-perform lifestyle adjustments are very ineffective models. Future research should target the more promising option of intervening in the young to influence the intergenerational transmission of health. Balanced micronutrient nutrition of young mothers may be the key.
Patterns of fetal growth in a rural Indian cohort and comparison with a Western European population data from the Pune maternal nutrition study
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: Journal of Ultrasound in Medicine
Abstract: Objective. The purpose of this study was to describe fetal size on sonography in a rural Indian population and compare it with those in European and urban Indian populations. Methods. Participants were from the Pune Maternal Nutrition Study of India. Fetal growth curves were constructed from serial ultrasound scans at approximately 18, 30, and 36 weeks’ gestation in 653 singleton pregnancies. Measurements included femur length (FL), abdominal circumference (AC), biparietal diameter (BPD), and occipitofrontal diameter, from which head circumference (HC) was estimated. Measurements were compared with data from a large population-based study in France and a study of urban mothers in Vellore, south India. Results. Fetal AC and BPD were smaller than the French reference at 18 weeks’ gestation (–1.38 and –1.30 SD, respectively), whereas FL and HC were more comparable (–0.77 and –0.59 SD). The deficit remained similar at 36 weeks for AC (–0.97 SD), FL (–0.43 SD), and HC (–0.52 SD) and increased for BPD (–2.3 SD). Sonography at 18 weeks underestimated gestational age compared with the last menstrual period date by a median of –1.4 (interquartile range, –4.6, 1.8) days. The Pune fetuses were smaller, even at the first scan, than the urban Vellore sample. Conclusions. Fetal size was smaller in a rural Indian population than in European and urban Indian populations, even in mid pregnancy. The deficit varied for different fetal measurements; it was greatest for AC and BPD and least for FL and HC.
Abstract: An upcoming hypothesis about the evolutionary origins of metabolic syndrome is that of a ‘soldier’ to ‘diplomat’ transition in behaviour and the accompanying metabolic adaptations. Theoretical as well as empirical studies have shown that similar to the soldier and diplomat dichotomy, physically aggressive and non-aggressive strategists coexist in animal societies with negative frequency dependent selection. Although dominant individuals have a higher reproductive success obtained through means such as greater access to females, subordinate individuals have alternative means such as sneak-mating for gaining a substantial reproductive success. The alternative behavioural strategies are associated with different neurophysiologic and metabolic states. Subordinate individuals typically have low testosterone, high plasma cholesterol and glucocorticoids and elevated serotonin signalling whereas dominant ones are characterized by high testosterone, low brain serotonin and lower plasma cholesterol. Food and sex are the main natural causes of aggression. However, since aggression increases the risk of injury, aggression control is equally crucial. Therefore chronic satiety in the form of fat should induce aggression control. It is not surprising that the satiety hormone serotonin has a major role in aggression control. Further chronically elevated serotonin signalling in the hypothalamus induces peripheral insulin resistance. Meta-analysis shows that most of the anti-aggression signal molecules are pro-obesity and pro-insulin-resistance. Physical aggression is known to increase secretion of epidermal growth factor (EGF) in anticipation of injuries and EGF is important in pancreatic beta cell regeneration too. In anticipation of
injuries aggression related hormones also facilitate angiogenesis and angiogenesis dysfunction is the root cause of a number of co-morbidities of insulin resistance syndrome. Reduced injury proneness typical of ‘diplomat’ life style would also reorient the immune system resulting into delayed wound healing on the one hand and increased systemic inflammation on the other. Diabetes is negatively associated with physically
aggressive behaviour. We hypothesize that suppression of physical aggression is the major behavioural cue for the development of metabolic syndrome. Preliminary trials of behavioural intervention indicate that games and exercises involving physical aggression reduce systemic inflammation and improve glycemic control.
Abstract: Background: Migration from rural areas of India contributes to urbanisation and may increase the risk of obesity and diabetes. We tested the hypotheses that rural-to-urban migrants have a higher prevalence of obesity and diabetes than rural non-migrants, that migrants would have an intermediate prevalence of obesity and diabetes compared with life-long urban and rural dwellers, and that longer time since migration would be associated with a higher prevalence of obesity and of diabetes. Methods and Findings: The place of origin of people working in factories in north, central, and south India was identified. Migrants of rural origin, their rural dwelling sibs, and those of urban origin together with their urban dwelling sibs were assessed by interview, examination, and fasting blood samples. Obesity, diabetes, and other cardiovascular risk factors were compared. A total of 6,510 participants (42% women) were recruited. Among urban, migrant, and rural men the age- and factory-adjusted percentages classified as obese (body mass index [BMI] .25 kg/m2) were 41.9% (95% confidence interval [CI] 39.1–44.7), 37.8% (95% CI 35.0–40.6), and 19.0% (95% CI 17.0–21.0), respectively, and as diabetic were 13.5% (95% CI 11.6–15.4), 14.3% (95% CI 12.2–16.4), and 6.2% (95% CI 5.0–7.4), respectively. Findings for women showed similar patterns. Rural men had lower blood pressure, lipids, and fasting blood glucose than urban and migrant men, whereas no differences were seen in women. Among migrant men, but not women, there was weak evidence for a lower prevalence of both diabetes and obesity among more recent (#10 y) migrants. Conclusions: Migration into urban areas is associated with increases in obesity, which drive other risk factor changes. Migrants have adopted modes of life that put them at similar risk to the urban population. Gender differences in some risk factors by place of origin are unexpected and require further exploration.
Editorial. Fetal programming of diabetes still so much to learn
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: Editorial. Fetal programming of diabetes still so much to learn
Abstract: In the preinsulin era, pregnancy in a diabetic mother had a bleak outcome for both the mother and the baby. Availability of insulin and modern methods of treatment improved the survival of these babies, but they appear to be at increased risk of obesity and diabetes (1–3). Spread of the diabetes pandemic to the young means there is now a growing epidemic of gestational diabetes mellitus (GDM). This label encompasses all varieties of diabetes that happen to be diagnosed during pregnancy, but the majority of GDM cases have type 2 pathology and metabolic syndrome–like features. There is a tacit assumption that glucose intolerance may have arisen de novo, but this is unlikely. The majority of women have risk factors dating back before pregnancy, sometimes traceable to early life growth and development (4,5), and many continue to be diabetic after delivery or develop diabetes soon after. Prevention of fetal programming of diabetes will need to concentrate on the health of young girls. Definition of critical periods in fetal programming will guide us to the windows of opportunity, which may be pre- and periconceptional, gestational, and even lactational. These issues were highlighted at a meeting in the United Nations (Women, Development and Diabetes) (30) and form the core of the “Kathmandu Declaration” which offers a new interpretation of the blue circle of the International Diabetes Federation by recommending a “life-circle” approach to prevention and treatment of diabetes.
Abstract: Folate and vitamin B-12 are essential for normal brain development. Few studies have examined the relationship of maternal folate and vitamin B-12 status during pregnancy and offspring cognitive function. To test the hypothesis that lower maternal plasma folate and vitamin B-12 concentrations and higher plasma homocysteine concentrations during pregnancy are associated with poorer neurodevelopment, 536 children (aged 9–10 y) from the Mysore Parthenon birth cohort underwent cognitive function assessment during 2007–2008 using 3 core tests from the Kaufman Assessment Battery, and additional tests measuring learning, long-term storage/retrieval, attention and concentration, and visuo-spatial and verbal abilities. Maternal folate, vitamin B-12, and homocysteine concentrations were measured at 3062 wk gestation. During pregnancy, 4% of mothers had low folate concentrations (<7 nmol/L), 42.5% had low vitamin B-12 concentrations (<150 pmol/L), and 3%had hyperhomocysteinemia (>10mmol/L). The children’s cognitive test scores increased by 0.1–0.2 SD per SD increase across the entire range of maternal folate concentrations (P,0.001 for all), with no apparent associations at the deficiency level. The associations with learning, long-term storage/retrieval, visuo-spatial ability, attention, and concentration were independent of the parents’ education, socioeconomic status, religion, and the child’s sex, age, current size, and folate and vitamin B-12 concentrations. There were no consistent associations of maternal vitamin B-12 and homocysteine concentrations with childhood cognitive performance. In this Indian population, higher maternal folate, but not vitamin B-12, concentrations during pregnancy predicted better childhood cognitive ability. It also suggests that, in terms of
neurodevelopment, the concentration used to define folate deficiency may be set too low.
Effect of physiological doses of oral vitamin B12 on plasma homocysteine a randomized, placebo-controlled, double-blind trial in India
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: European Journal of Clinical Nutrition - Nature
Abstract: Background/Objectives: Vitamin B12 (B12) deficiency is common in Indians and a major contributor to hyperhomocysteinemia, which may influence fetal growth, risk of type II diabetes and cardiovascular disease. The purpose of this paper was to study the effect of physiological doses of B12 and folic acid on plasma total homocysteine (tHcy) concentration. Subjects/Methods: A cluster randomized, placebo-controlled, double-blind, 2x3 factorial trial, using the family as the randomization unit. B12 was given as 2 or 10 mg capsules, with or without 200 mg folic acid, forming six groups (B0F0, B2F0,
B10F0, B0F200, B2F200 and B10F200). Plasma tHcy concentration was measured before and after 4 and 12 months of supplementation. Results: From 119 families in the Pune Maternal Nutrition Study, 300 individuals were randomized. There was no interaction between B12 and folic acid (P¼0.14) in relation to tHcy concentration change and their effects were analyzed separately: B0 vs. B2 vs. B10; and F0 vs. F200. At 12 months, tHcy concentration reduced by a mean 5.9 (95% CI: -7.8, -4.1) mmol/l in B2, and by 7.1 (95% CI: -8.9, -5.4) mmol/l in B10, compared to nonsignificant rise of 1.2 (95% CI: -0.5, 2.9) mmol/l in B0. B2 and B10 did not differ significantly. In F200, tHcy concentration decreased by 4.8 (95% CI: -6.3, -3.3) mmol/l compared to 2.8 (95% CI: -4.3, -1.2) mmol/l in F0. Conclusion: Daily oral supplementation with physiological doses of B12 is an effective community intervention to reduce tHcy. Folic acid (200 mg per day) showed no additional benefit, neither had any unfavorable effects.
Abstract: OBJECTIVE—Common variants in PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 genes have been shown to be associated with type 2 diabetes in European populations by genome-wide association studies. We have studied the association of common variants in these eight genes with type 2 diabetes and related traits in Indians by combining the data from two independent case–control studies.
RESEARCH DESIGN AND METHODS—We genotyped eight single nucleotide polymorphisms (PPARG-rs1801282, KCNJ11-rs5219, TCF7L2-rs7903146, SLC30A8-rs13266634, HHEXrs1111875, CDKN2A-rs10811661, IGF2BP2-rs4402960, and CDKAL1-rs10946398) in 5,164 unrelated Indians of Indo-European ethnicity, including 2,486 type 2 diabetic patients and 2,678 ethnically matched control subjects. RESULTS—We confirmed the association of all eight loci with type 2 diabetes with odds ratio (OR) ranging from 1.18 to 1.89 (P = 1.6 x 10-3 to 4.6 x 10-34). The strongest association with the highest effect size was observed for TCF7L2 (OR 1.89 [95% CI 1.71–2.09], P = 4.6 x 10-34). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of β-cell function (P x 6.9 x 10-8 and 3 x 10-4, respectively), which looked consistent with recessive and under-dominant models, respectively. CONCLUSIONS—Our study replicates the association of well-established common variants with type 2 diabetes in Indians and shows larger effect size for most of them than those reported in Europeans.
Abstract: We read with interest the letter by Gupta and Ebrahim complimenting our article published recently in Diabetes. As mentioned rightly by the authors, there have not been many well-powered association studies on type 2 diabetes in the Indian population; hence this collaborative effort, even though as a replication of established genome-wide association study (GWAS) signals, is indeed exemplary. While thanking the authors for acknowledging our contribution, we believe that the issue raised by them of spurious association because of population stratification has limited scientific basis. Above all, Gupta and Ebrahim, even when questioning the validity of the associations reported by us, admit that these are “highly plausible given the high priors for these SNPs from studies in other populations,” and such studies have no problem. We still agree that population stratification
remains an important consideration, but a preliminary ongoing GWAS in a subset of the samples reveals that adjustments for possible stratification based on principal components have yielded results similar to those reported. We hope our joint effort paves the way for more collaboration among South Asian and sub-Saharan researchers themselves, rather than researchers from abroad.
The obesity-diabetes association what is different in Indians
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: The International Journal of Lower Extremity Wounds
Abstract: There is a growing epidemic of obesity and type 2 diabetes in the world, more than 75% of the patients are in the developing countries. India is facing a twin burden of under-nutrition and over-nutrition: it figures prominently both in the hunger map of the world as well as being the world’s capital of diabetes. Indians are susceptible to diabetes at a younger age and at a relatively lower BMI compared to the white Caucasians. This is partly explained by the fact that the thin-looking Indians are quite adipose (higher body fat percent). Intrauterine epigenetic regulation could explain the thin-fat Indian body composition. A combination of maternal one carbon metabolism derangement (influenced by vitamin B12 and Folate nutrition) and hyperglycemia appear to be major drivers. Persistent micronutrient abnormalities and rapid economic development seem to contribute to the inter-generational amplification of the diabetes-adiposity epidemic in Indians. Effective curtailment of the growing epidemic may lie in the realm of maternal and child health and nutrition.
Maternal and paternal height and BMI and patterns of fetal growth The Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: Early Human Development - Elsevier
Abstract: We examined the differential associations of each parent's height and BMI with fetal growth, and examined the pattern of the associations through gestation. Data are from 557 term pregnancies in the Pune Maternal Nutrition Study. Size and conditional growth outcomes from 17 to 29 weeks to birth were derived from ultrasound and birth measures of head circumference, abdominal circumference, femur length and placental volume (at 17 weeks only). Parental height was positively associated with fetal head circumference and femur length. The associations with paternal height were detectible earlier in gestation (17–29 weeks) compared to the associations with maternal height. Fetuses of mothers with a higher BMI had a smaller mean head circumference at 17 weeks, but caught up to have larger head circumference at birth. Maternal but not paternal BMI, and paternal but not maternal height, were positively associated with placental volume. The opposing associations of placenta and fetal head growth with maternal BMI at 17 weeks could indicate prioritisation of early placental development, possibly as a strategy to facilitate growth in late gestation. This study has highlighted how the pattern of parental–fetal associations varies over gestation. Further follow-up will determine whether and how these variations in fetal/placental development relate to health in later life.
A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: The Journal of Clinical Endocrinology & Metabolism
Abstract: Context: Mandibuloacral dysplasia (MAD) is an autosomal recessive progeroid disorder associated with type A (partial) or B (generalized) lipodystrophy and is due to mutations in lamin A/C (LMNA) or zinc metalloproteinase (ZMPSTE24) genes. Objective: The objective of the study was to report a novel syndrome with some overlapping features with MAD. Results: We report seven patients with mandibular hypoplasia, deafness, progeroid features (MDP), and associated lipodystrophy. These patients have similar features toMADpatients such as hypoplastic mandible, beaked nose, stiff joints, and sclerodermatous skin. However, the patients did not harbor any disease causing variants in LMNA or ZMPSTE24 and showed distinct characteristics such as sensorineural hearing loss and absence of clavicular hypoplasia and acroosteolysis. All males withMDPhad undescended testes and were hypogonadal.Oneadult female showed lack of breast development. Skinfold thickness, dual-energy X-ray absorptiometry and whole-body magnetic resonance imaging for body fat distribution revealed a lack of lipodystrophy in a prepubertal female but a progressive loss of sc fat presenting with partial lipodystrophy in young adults and generalized lipodystrophy in older patients. Conclusions: Patients with MDP syndrome have a few overlapping but some distinct clinical features as compared with MAD, suggesting that it is a novel syndrome. The molecular basis of MDP
syndrome remains to be elucidated.
Abstract: Objective: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated. Research Design and Methods: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 noncases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored. Results: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10218). Substantial heterogeneity was present (I2 = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*1024), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10213), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*1025). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference. Conclusions: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.
Insulin Resistance in Children_ Consensus, Perspective, and Future Directions
Author Name: Chittaranjan Yajnik , Publication Year: 2010 , Journal Name: The Journal of Clinical Endocrinology & Metabolism
Abstract: Objective: Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points. Participants: The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants. Evidence: An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children. Consensus Process: The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement. Conclusions: Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases.
Abstract: The world is facing an unprecedented epidemic of type 2 diabetes (T2D) and other chronic non-communicable diseases (NCDs). The rise in the prevalence of T2D in the last few decades has been phenomenal, perhaps unmatched by any other chronic condition. The pattern of affliction is rapidly changing; the poor and the young are increasingly affected. In 2007, there were an estimated 246 million diabetic patients in the world, of which 165 million (80%) were in the developing world [1, 2]. A substantial number are diagnosed before 40 years of age, and it is increasingly common to see T2D in children. Current trials of diabetes prevention have concentrated on modifying lifestyle in middle-aged people with advanced risk factors (obese and impaired glucose tolerant). Such attempts are unlikely to curtail the epidemic, fuelled by the increasing incidence in the young. Over last three decades there has been growing recognition that early life factors have a major influence on the risk of T2D. Studies in Pima Indians showed that maternal hyperglycemia in pregnancy increased the risk of obesity and diabetes in the offspring [3]. On the other hand studies in the UK showed that low birthweight (LBW) was a risk factor for T2D diabetes in the offspring [4]. These studies focused attention on intrauterine environment as an important determinant of subsequent risk of T2D. Subsequent studies demonstrated that rapid childhood growth was also a strong risk factor for obesity and T2D. Thus, factors influencing intrauterine and childhood growth seem to affect the risk of T2D. These new developments have challenged the rather limited idea of controlling the diabetes epidemic by intervening in the middle-aged population with advanced risk factors. Here we will review some of these new ideas and discuss the imperative for a life-course approach to the prevention of chronic NCD, with focus on T2D.
Consensus Statement for Diagnosis of Obesity, Abdominal Obesity and the Metabolic Syndrome for Asian Indians
Author Name: Chittaranjan Yajnik , Publication Year: 2009 , Journal Name: Journal of the Association of Physicians of India
Abstract: Asian Indians exhibit unique features of obesity; excess body fat, abdominal adiposity, increased subcutaneous and intra-abdominal fat, and deposition of fat in ectopic sites (liver, muscle, etc.). Obesity is a major driver for the widely prevalent metabolic syndrome and type 2 diabetes mellitus (T2DM) in Asian Indians in India and those residing in other countries. Based on percentage body fat and morbidity data, limits of normal BMI are narrower and lower in Asian Indians than in white Caucasians. In this consensus statement, we present revised guidelines for diagnosis of obesity, abdominal obesity, the metabolic syndrome, physical activity, and drug therapy and bariatric surgery for obesity in Asian Indians after consultations with experts from various regions of India belonging to the following medical disciplines; internal medicine, metabolic diseases, endocrinology, nutrition, cardiology, exercise physiology, sports medicine and bariatric surgery, and representing reputed medical institutions, hospitals, government funded research institutions, and policy making bodies. It is estimated that by application of these guidelines, additional 10-15% of Indian population would be labeled as overweight/obese and would require appropriate management. Application of these guidelines on countrywide basis is also likely to have a deceleration effect on the escalating problem of T2DM and cardiovascular disease. These guidelines could be revised in future as appropriate, after another large and countrywide consensus process. Till that time, these should be used by clinicians, researchers and policymakers dealing with obesity and related diseases.
Abstract: Aims and hypothesis Variants of the FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes in white Europeans, but these associations are not consistent in Asians. A recent study in Asian Indian Sikhs showed an association with type 2 diabetes that did not seem to be mediated through BMI. We studied the association of FTO variants with type 2 dia-betes and measures of obesity in South Asian Indians in Pune. Methods We genotyped, by sequencing, two single nucleotide polymorphisms, rs9939609 and rs7191344, in the FTO gene in 1,453 type 2 diabetes patients and 1,361 controls from Pune, Western India and a further 961 population-based
individuals from Mysore, South India. Results We observed a strong association of the minor allele A at rs9939609 with type 2 diabetes (OR per allele 1.26; 95% CI 1.13–1.40; p=3×10−5). The variant was also associated with BMI but this association appeared to be weaker (0.06 SDs; 95% CI 0.01–0.10) than the previously reported effect in Europeans (0.10 SDs; 95% CI 0.09–0.12; heterogeneity p=0.06). Unlike in the Europeans, the association with type 2 diabetes remained significant after adjusting for BMI (OR per allele for type 2 diabetes 1.21; 95% CI 1.06–1.37; p=4.0×10−3), and also for waist circumference and other anthropometric variables. Conclusions Our study replicates the strong association of FTO variants with type 2 diabetes and similar to the study in North Indians Sikhs, shows that this association may not be entirely mediated through BMI. This could imply underlying differences between Indians and Europeans in the mechanisms linking body size with type 2 diabetes.
Nutrient-mediated teratogenesis and fuel-mediated teratogenesis two pathways of intrauterine programming of diabetes
Author Name: Chittaranjan Yajnik , Publication Year: 2009 , Journal Name: International Journal of Gynecology & Obstetrics
Abstract: The epidemic of diabetes is spreading quickly to the poor and the deprived. Nutrition during fetal life influences the future risk for diabetes; and both under- and over-nutrition contribute and coexist in rapid transition countries. Nutrient imbalance seems particularly important; for example, low maternal vitamin B12 status coupled with high folate predicted higher adiposity and insulin resistance in Indian children, suggesting a role for 1-C (methyl) group donors in fetal programming. Maternal hyperglycemia worsens the situation. Improving the early-life environment may be more cost-effective for preventing diabetes than controlling lifestyle factors alone in later life.
Abstract: We read with interest the article by Goel et al., titled “Predictive Equations for Body Fat and Abdominal Fat With DXA and MRI as Reference in Asian Indians,” which offers predictive equations for body fat and abdominal fat in Asian Indians as functions of simple anthropometric measures in 171 apparently healthy North Indian respondents to a local advertisement (1). We noticed a possible error in the recommended equation for body fat percent. Correspondence with authors gave us the correct equations which we used for further analysis (%Body Fat = 42.42 + 0.003 × age (years) + 7.04 × gender (M = 1, F = 2) + 0.42 × triceps skinfold (mm) + 0.29 × waist circumference (cm) + 0.22 × weight (kg) − 0.42 × height (cm)). We tested Goel’s recommended equation to calculate body fat percent in subjects of the Pune Maternal Nutrition Study (PMNS), a community-based study in six villages near Pune, Maharashtra, India. The arbitrary nature of statistical models coupled with the large number of predictor variables that are usually used, makes
interpreting the model and its bias(es) difficult. An alternative is to derive population specific equations. Choosing population categories and deciding the number of categories is not always easy and practicality might dictate that we accept a degree of
inaccuracy/error. However, a systematic bias might lead to misleading conclusions; for example it might reduce the adiposity difference between rural and urban subjects. We believe that models based on known physiological or physical relationships between variables will fare better because such relationships should be invariant across populations.
Abstract: Abdominal adiposity and metabolic ill health in Asian Indians are a growing public health concern. Causal pathways are unknown. Preventive measures in adults have had limited success. The aim of this observational case-control study was to compare adipose tissue partitioning in 69 healthy full term Asian Indian and white European newborns born in Pune, India and London, UK, respectively. The main outcome measures were total and regional adipose tissue content measured by whole body magnetic resonance imaging. Although smaller in weight (95% CI for difference 0.757 to 0.385 kg, p 0.001), head circumference (2.15 to 0.9 cm, p 0.001), and length (2.9 to 1.1 cm p 0.001), the Asian Indian neonates had significantly greater absolute adiposity in all three abdominal compartments, internal (visceral) (0.012– 0.023 L, p 0.001), deep s.c. (0.003– 0.017 L, p 0.006) and superficial s.c. (0.006–0.043 L, p 0.011) and a significant reduction in nonabdominal superficial s.c. adipose tissue (0.184 to 0.029 L, p 0.008) in comparison to the white European babies despite similar whole body adipose tissue content (0.175 to 0.034 L, p 0.2). We conclude that differences in adipose tissue partitioning exist at birth. Investigative, screening, and preventive measures must involve maternal health, intrauterine life, and infancy.
Abstract: Context: With increasing globalization and East-West exchanges, the increasing epidemic of type 2 diabetes in Asia has far-reaching public health and socioeconomic implications. Objective: To review recent data in epidemiologic trends, risk factors, and complications of type 2 diabetes in Asia. Evidence Acquisition: Search of MEDLINE using the term diabetes and other relevant keywords to identify meta-analyses, systematic reviews, large surveys, and cohort studies. Separate searches were performed for specific Asian countries. The review was limited to English-language articles published between January 1980 and March 2009; publications on type 1 diabetes were excluded. Evidence Synthesis: The prevalence of diabetes in Asian populations has increased rapidly in recent decades. In 2007, more than 110 million individuals in Asia were living with diabetes, with a disproportionate burden among the young and middle aged. Similarly, rates of overweight and obesity are increasing sharply, driven by economic development, nutrition transition, and increasingly sedentary lifestyles. The “metabolically obese” phenotype (ie, normal body weight with increased abdominal adiposity) is common in Asian populations. The increased risk of gestational diabetes, combined with exposure to poor nutrition in utero and overnutrition in later life in some populations, may contribute to the increasing diabetes epidemic through “diabetes begetting diabetes” in Asia. While young age of onset and long disease duration place Asian patients with diabetes at high risk for cardiorenal complications, cancer is emerging as an important cause of morbidity and mortality. Conclusions: Type 2 diabetes is an increasing epidemic in Asia, characterized by rapid rates of increase over short periods and onset at a relatively young age and low body mass index. Prevention and control of diabetes should be a top public health priority in Asian populations.
Abstract: Neural tube defects (NTDs) are one of the commonest birth defects with a high incidence in India. However, few studies have systematically looked into the etio-pathogeneis of NTDs which mainly includes nutritional deficiencies and genetic predisposition. Efforts are afoot for universal food fortification with folic acid in the hope of preventing NTDs without factual evidence of folate deficiency in the target population. Evidence acquisition: We conducted a review of Indian literature on NTDs focusing on the role of folate and vitamin B12 nutrition and common genetic polymorphisms in 1-carbon metabolism. We performed a literature search of Medline and Indian Medlars (www. indmed.nic.in) for articles using following search terms: Neural tube defect and India, published up to November 2008, on human subjects. We did not include individual case reports and case series describing surgical and medical management, genetic syndromes where NTD was only one of the features or unusual associations of NTDs with other clinical findings. Results: Absence of a nationally representative large study, lack of interventional studies and methodological differences were conspicuous during this review. Larger studies are therefore urgently needed to delineate gene-nutrient interactions in association with NTDs in India. We urge that caution should be exercised before widespread folic acid fortification of food without addressing the issue of concurrent B12 deficiency.
Seasonality in maternal intake and activity influence offspring_s birth size among rural Indian mothers--Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2009 , Journal Name: International Journal of Epidemiology
Abstract: Background: Farming populations from developing countries are exposed to seasonal energy stress due to variations in food availability and energy output related to agricultural activities. This study aims to examine the impact of seasonality in maternal intake and activity on neonatal size. Methods: Maternal anthropometry, dietary intakes (24-h recall and food frequency questionnaire) and activity pattern (questionnaire) at 182 and 282 weeks gestation, and neonatal anthropometry, were measured in a prospective study of 797 rural Indian women. Results: Maternal energy and protein intakes were inadequate (70% of recommended dietary allowance). Both intake and activity showed seasonal variation (P¼0.001), with peak values in winter i.e. during harvest, at 18 weeks (median energy 1863 kcal/day, protein 47.5 g/day) and 28 weeks (median energy 1687 kcal/day, protein 43.7 g/day), coinciding with the maximum maternal activity (median score 86.1 at 18 weeks and 79.5 at 28 weeks). Mean birth weight and length (adjusted for pre-pregnant weight, parity, gestation and sex) of babies was highest in summer (peak at February 2733 g, 48.6 cm, respectively) and lowest in winter (nadir at January 2591 g, 47.1 cm, respectively). Regression analysis showed that maternal intake at 18th week had a positive association (P¼0.05), maternal activity at 28th week had a negative association (P¼0.002) and exposure (in weeks) to winter during gestation had a positive association (P¼0.04) with birth size. Furthermore, higher maternal intakes, coupled with lower maternal activity in late gestation were associated with higher birth weight, especially during winter. Conclusions: If causal, these observations indicate that complete exposure (16 weeks) to the winter season (harvest-time) in late gestation could increase birth weight by 90 g in poor farming communities in rural India, and the benefit would increase further by lowering maternal activity. Our results underscore the importance of considering seasonality in planning targeted intervention strategies in such settings.
Community-specific modifications are essential for objective assessment of maternal dietary intake--Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2009 , Journal Name: Public Health Nutrition
Abstract: Objective: To introduce community-specific modifications in the conventional 24 h recall method for objectively estimating maternal dietary intake and validate it with a reference method. Design: A modified 24 h recall method was developed with the visit of trained local girls at the subject’s home to weigh portion sizes at each mealtime over the 24 h recall period. This was validated with the reference method in which weighed records of the foods consumed were obtained and their laboratory analysis was done to obtain nutrient intakes. Setting: Rural areas located 40–50km from Pune City, India. Subjects: Forty-one pregnant women participated willingly. Results: The estimates of intake obtained from the reference method were comparable to those obtained from the modified 24 h recall method for energy (7795 (SD 1841) kJ (1863 (SD 440) kcal) v. 7615 (SD 1824) kJ (1820 (SD 436) kcal), respectively), protein (48?6 (SD 12?9) g v. 45?3 (SD 12?6) g, respectively) and fat (35?3 (SD 16?6) g v. 36?0 (SD 14?2) g, respectively). Significant correlation was observed between the estimates obtained by the two methods for energy (0?75, P,0?001), protein (0?71, P,0?001) and fat (0?56, P,0?001) and differences in nutrient intake did not reveal any systematic bias. When compared with the reference method, the modified method showed .80% sensitivity and specificity for identifying inadequate maternal energy intakes. Conclusions: Simple modifications to conventional methods backed by understanding of community specifics and nutritional peculiarities are of immense importance in obtaining objective estimates of daily nutritional intakes of individuals in free-living populations. The approach would be adaptable in similar settings in other developing countries.
Abstract: Low plasma concentrations of vitamin B-12 are common in Indians, possibly due to low dietary intakes of animal-source foods. Whether malabsorption of the vitamin contributes to this has not been investigated. A rise in the plasma holotranscobalamin (holo-TC) concentration after a standard dose of oral vitamin B-12 has been proposed as a measure of gastrointestinal absorption in people with normal plasma vitamin B-12 concentrations. We studied 313 individuals (children and parents, 109 families) in the Pune Maternal Nutrition Study. They received 3 doses of 10 mg (n = 191) or 2 mg (n = 122) of cyanocobalamin at 6-h intervals. A rise in plasma holo-TC of $15% and .15 pmol/L above baseline was considered normal vitamin B-12 absorption. The baseline plasma vitamin B- 12 concentration was ,150 pmol/L in 48% of participants; holo-TC was ,35 pmol/L in 98% and total homocysteine was high in 50% of participants (.10 mmol/L in children and .15 mmol/L in adults). In the 10 mg group, the plasma holo-TC concentration increased by 4.8-fold from (mean 6 SD) 9.3 6 7.0 pmol/L to 53.8 6 25.9 pmol/L and in the 2 mg group by 2.2-fold from 11.1 6 8.5 pmol/L to 35.7 6 19.3 pmol/L. Only 10% of the participants, mostly fathers, had an increase less than the suggested cut-points. Our results suggest that an increase in plasma holo-TC may be used to assess vitamin B-12 absorption in individuals with low vitamin B-12 status. Because malabsorption is unlikely to be a major reason for the low plasma vitamin B-12 concentrations in this population, increasing dietary vitamin B-12 should improve their status.
Abstract: Aims/hypothesis: This study was designed to test the hypothesis that low plasma vitamin B12 concentrations combined with high folate concentrations in pregnancy are associated with a higher incidence of gestational diabetes (GDM) and later diabetes. Methods: Women (N=785) attending the antenatal clinics of one hospital in Mysore, India, had their anthropometry, insulin resistance (homeostasis model assessment-2) and glucose tolerance assessed at 30 weeks’ gestation (100 g oral glucose tolerance test; Carpenter–Coustan criteria) and at 5 years after delivery (75 g OGTT; WHO, 1999). Gestational vitamin B12 and folate concentrations were measured in stored plasma samples. Results: Low vitamin B12 concentrations (<150 pmol/l, B12 deficiency) were observed in 43% of women and low folate concentrations (<7 nmol/l) in 4%. B12-deficient women had higher body mass index (p<0.001), sum of skinfold thickness (p<0.001), insulin resistance (p=0.02) and a higher incidence of GDM (8.7% vs 4.6%; OR 2.1, p=0.02; p=0.1 after adjusting for BMI) than non-deficient women. Among B12-deficient women, the incidence of GDM increased with folate concentration (5.4%, 10.5%, 10.9% from lowest to highest tertile, p=0.04; p for interaction= 0.2). Vitamin B12 deficiency during pregnancy was positively associated with skinfold thickness, insulin resistance (p<0.05) and diabetes prevalence at 5 year follow-up (p=0.009; p=0.008 after adjusting for BMI). The association with diabetes became non-significant after excluding women with previous GDM (p=0.06). Conclusions/interpretation: Maternal vitamin B12 deficiency is associated with increased adiposity and, in turn, with insulin resistance and GDM. Vitamin B12 deficiency may be an important factor underlying the high risk of ‘diabesity’ in south Asian Indians.
Neonatal anthropometry thin-fat phenotype in fourth to fifth generation South Asian neonates in Surinam
Author Name: Chittaranjan Yajnik , Publication Year: 2009 , Journal Name: International Journal of Obesity - Nature
Abstract: We assessed whether the earlier described ‘thin–fat phenotype’ is present in Surinam South Asian babies of the fourth to fifth generation after migration from India. In this observational study we collected data from 39 South Asian term neonates and their mothers in Paramaribo, Surinam. We compared the following data with data from an earlier study in Southampton, UK (338 neonates) and in Pune, India (631 neonates): maternal body mass index, neonatal weight, length, head, mid-upper arm and abdominal circumferences and subscapular skinfold thickness. The mothers in Paramaribo were older than the Southampton mothers; their body mass index was comparable. Mean birth weight was 3159 g (Southampton: 3494 g; Pune: 2666 g). Compared with Southampton babies, the Paramaribo babies were smaller in nearly all body measurements, the smallest being abdominal circumference at the umbilicus level (s.d. score: 1.62; 95% confidence interval (CI): 2.07 to 1.16) and mid-upper arm circumference (s.d. score: 1.08; 95% CI: 1.46 to 0.69). In contrast, subscapular skinfold thickness was similar (s.d. score: þ0.08; 95% CI: 0.24 to þ0.55). Except for subscapular skinfold thickness and length, all neonatal measurements were intermediate between those from Southampton and Pune. The thin–fat phenotype is preserved in Surinam South Asian neonates of the fourth to fifth generation after migration from India.
Abstract: Aims/hypothesis The aim of this study was to investigate whether the higher prevalence of insulin resistance and glucose intolerance in urban compared with rural Indian men is related to their higher adiposity (percentage body fat) and the associated inflammatory state. Methods We studied 149 rural, 142 urban slum and 150 urban middle-class male residents (age 30–50 years), who were selected by stratified random sampling. We measured body fat (bioimpedance), waist circumference, glucose tolerance (75 g OGTT), insulin resistance [homeostasis model assessment (HOMA-IR)], beta cell function (insulinogenic index) and inflammatory markers (total leucocyte count, IL-6, TNF-α and C-reactive protein). Results Adiposity, waist circumference, HOMA-IR, insulinogenic index and both fasting and 120 min plasma glucose concentrations increased progressively from rural through to urban slum and urban middle-class men. Inflammatory markers were higher in urban than in rural men. Adiposity was strongly related to HOMA-IR (r=0.57, p<0.001) and to insulinogenic index and glycaemic parameters (r=0.25, p<0.001 for both). Adiposity explained approximately two thirds of the difference in HOMA-IR between the urban middle-class men and the rural and slum residents, but its contribution to the difference in insulinogenic index and 120 min plasma glucose concentration was not significant. Inclusion of C-reactive protein, IL-6 and total leucocyte
count in the models did not further explain these results, nor did the inclusion of waist circumference. There was a significant residual difference after these adjustments. Conclusions/interpretation Adiposity is a major contributor to the difference in insulin resistance between rural and urban Indian men; there was no additional contribution from inflammation or central obesity. Other unmeasured factors also seem to contribute to the metabolic differences between rural and urban men.
Abstract: Aims/hypothesis Raised maternal plasma total homocysteine (tHcy) concentrations predict small size at birth, which is a risk factor for type 2 diabetes mellitus. We studied the association between maternal vitamin B12, folate and tHcy status during pregnancy, and offspring adiposity and insulin resistance at 6 years. Methods In the Pune Maternal Nutrition Study we studied 700 consecutive eligible pregnant women in six villages. We measured maternal nutritional intake and circulating concentrations of folate, vitamin B12, tHcy and methylmalonic acid (MMA) at 18 and 28 weeks of gestation. These were correlated with offspring anthropometry, body composition (dual-energy X-ray absorptiometry scan) and insulin resistance (homeostatic model assessment of insulin resistance [HOMA-R]) at 6 years. Results Two-thirds of mothers had low vitamin B12 (<150 pmol/l), 90% had high MMA (>0.26 μmol/l) and 30% had raised tHcy concentrations (>10 μmol/l); only one had a low erythrocyte folate concentration. Although short and thin (BMI), the 6-year-old children were relatively adipose compared with the UK standards (skinfold thicknesses). Higher maternal erythrocyte folate concentrations at 28 weeks predicted higher offspring adiposity and higher HOMA-R (both p<0.01). Low maternal vitamin B12 (18 weeks; p=0.03) predicted higher HOMA-R in the children. The offspring of mothers with a combination of high folate and low vitamin B12 concentrations were the most insulin resistant. Conclusions/interpretation Low maternal vitamin B12 and high folate status may contribute to the epidemic of adiposity and type 2 diabetes in India.
Abstract: The rapid transition in the developing and emerging societies has manifested as the double burden of disease: the coexistence of as yet unconquered malnutrition and the emerging epidemic of obesity and its related morbidities. A peculiar manifestation of such a double burden in a family is an undernourished child of obese parents, representing two phases of the dual nutritional insult which has led to the current epidemic of chronic non-communicable disease. The interrelationship between these two clinical entities, in spite of a large scientific data, remains to be defined. It perhaps originates in the poor care of pregnant mothers who give rise to a low birthweight baby. Attempts by the parents and the caregivers to feed this baby to ‘normalize’ its growth may lead to a rapid childhood growth and emergence of obesity and associated morbidities at a relatively young age which leads to higher incidence of type 2 diabetes, hypertension, dyslipidemias and coronary heart disease, the so-called metabolic syndrome. The contribution not only of nutritional factors, but also genetic background and epigenetic factors, to these outcomes were addressed. In this context, hypotheses such as the thrifty gene hypothesis were discussed as potential mechanisms to explain the increased susceptibility to obesity in emerging nations. Considerable research still lies ahead in order to address the question of which population segments and at what stage(s) of their lifecycle should be targeted in order to have the most impactful results. The contribution not only of nutritional factors, but also genetic background and epigenetic factors, to these outcomes were addressed. In this context, hypotheses such as the thrifty gene hypothesis were discussed as potential mechanisms to explain the increased susceptibility to obesity in emerging nations. Considerable research still lies ahead in order to address the question of which population segments and at what stage(s) of their lifecycle should be targeted in order to have the most impactful results.
Abstract: OBJECTIVE— Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and rosiglitazone on combined and individual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGNANDMETHODS— total of 5,269 people aged30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up. RESULTS— Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646]; hazard ratio [HR] 0.98 [95% CI 0.84 –1.13]; P0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634]; 0.87 [0.75–1.01]; P 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 [95% CI 1.60 –31.0]; P 0.01) but reduced the risk of the renal component (0.80 [0.68–0.93]; P 0.005); prevention of diabetes was independently associated with prevention of the renal component (P 0.001). CONCLUSIONS— Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.
Abstract: Twin studies have been used to understand the sources of genetic and environmental variation in body height, body weight and other common human quantitative traits. However, it is rather unclear whether these two sources of variation could be really separated in practice. Here, we consider a special study design where phenotype data from married couples and their siblings have been collected. The marital status gives information about the shared environment, while siblings give information about both genetic and environmental variation. To dissect sources of variation and to allow some deviations and pedigree errors in the data, we model such data using a robust polygenic model with finite genome length assumption. As a summary, we provide the estimates for age-dependent proportions of total variation which are due to polygenic and environmental effects. Here, these estimates are provided for body height, weight, systolic blood pressure and total serum cholesterol measured from subjects of the Indian Migration Study.
Maternal nutrition, intrauterine programming and consequential risks in the offspring
Author Name: Chittaranjan Yajnik , Publication Year: 2008 , Journal Name: Reviews in Endocrine and Metabolic Disorders - Springer
Abstract: It is traditionally believed that genetic susceptibility and adult faulty lifestyle lead to type 2 diabetes, a chronic non-communicable disease. The "Developmental Origins of Health and Disease" (DOHaD) model proposes that the susceptibility to type 2 diabetes originates in the intrauterine life by environmental fetal programming, further exaggerated by rapid childhood growth, i.e. a biphasic nutritional insult. Both fetal under nutrition (sometimes manifested as low birth weight) and over nutrition (the baby of a diabetic mother) increase the risk of future diabetes. The common characteristic of these two types of babies is their high adiposity. An imbalance in nutrition seems to play an important role, and micro-nutrients seem particularly important. Normal to high maternal folate status coupled with low vitamin B12 status predicted higher adiposity and insulin resistance in Indian babies. Thus, 1-C (methyl) metabolism seems to play a key role in fetal programming. DOHaD represents a paradigm shift in the model for prevention of the chronic non-communicable diseases.
Abstract: Aim: To assess the addition of sitagliptin to ongoing metformin therapy in patients with type 2 diabetes who were inadequately controlled [haemoglobin A1c (HbA1c) 7–11%] on metformin monotherapy. Methods: Patients (n ¼ 273) on metformin (1500 mg/day) were randomized to receive the addition of once-daily placebo, sitagliptin 100 mg or rosiglitazone 8 mg in a 1 : 1 : 1 ratio for 18 weeks. The efficacy analysis was based on the all-patients-treated population using an analysis of co-variance with change in HbA1c from baseline as the primary endpoint. Results: The mean baseline HbA1c was 7.7% for the entire cohort. After 18 weeks, both active add-on therapies led to greater improvements in HbA1c from baseline: 0.73% for sitagliptin (p < 0.001 vs. placebo) and 0.79% for rosiglitazone compared with 0.22% for placebo. No difference was observed between the sitagliptin and rosiglitazone treatments (0.06% [95% confidence interval (CI): 0.14 to 0.25]). The proportion of patients achieving an HbA1c < 7% was greater with sitagliptin (55%) and rosiglitazone (63%) compared with placebo (38%). Body weight increased from baseline with rosiglitazone (1.5 kg) compared with body weight reduction with sitagliptin (0.4 kg) and placebo (0.8 kg). The difference in body weight between the sitagliptin and rosiglitazone groups was 1.9 kg (95% CI: 1.3–2.5). In a prespecified analysis, the proportion of patients experiencing a greater than 3-kg increase in body weight was 21% in the rosiglitazone group compared with 2% in both the sitagliptin and placebo groups. Both active treatments were generally well tolerated, with no increased risk of hypoglycaemia or gastrointestinal adverse events compared with placebo. Conclusions: In this 18-week study, the addition of sitagliptin was effective and well tolerated in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Treatment with sitagliptin produced similar reductions in HbA1c compared with the addition of rosiglitazone.
Abstract: Background. Recent research has highlighted the influence of maternal factors on the health of the offspring. Intrauterine experiences may program metabolic, cardiovascular, and psychiatric disorders. We have shown that maternal vitamin B12 status affects adiposity and insulin resistance in the child. Vitamin B12 is important for brain development and function. Objective. We investigated the relationship between maternal plasma vitamin B12 status during pregnancy and the child’s cognitive function at 9 years of age. Methods. We studied children born in the Pune Maternal Nutrition Study. Two groups of children were selected on the basis of maternal plasma vitamin B12 concentration at 28 weeks of gestation: group 1 (n = 49) included children of mothers with low plasma vitamin B12 (lowest decile, < 77 pM) and group 2 (n = 59) children of mothers with high plasma vitamin B12 (highest decile, > 224 pM). Results. Children from group 1 performed more slowly than those from group 2 on the Color Trail A test (sustained attention, 182 vs. 159 seconds; p < .05) and the Digit Span Backward test (short-term memory, p <.05), after appropriate adjustment for confounders. There were no differences between group 1 and group 2 on other tests of cognitive function (intelligence, visual agnosia). Conclusions. Maternal vitamin B12 status in pregnancy influences cognitive function in offspring.
Oral vitamin B12 supplementation reduces plasma total homocysteine concentration in women in India
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Asia Pacific Journal of Clinical Nutrition
Abstract: People in India have a high prevalence of low vitamin B12 status and high plasma total homocysteine (tHcy) concentrations. In a proof of principle trial, we studied the effect of oral vitamin B12 (500 μg) and/or 100 g cooked green leafy vegetables (GLV) every alternate day in a 2x2 factorial design over a 6-week period. Forty-two non-pregnant vegetarian women (age 20-50 years) were randomly allocated to four study groups. Clinical measurements were made at the beginning and at the end of the study, and blood samples were collected before, and 2 and 6 weeks after commencement of intervention. Forty women completed the trial. Twenty-six women had low vitamin B12 status (<150 pmol/L) and 24 had hyperhomocysteinemia (>15 μmol/L). GLV supplemen- tation did not alter plasma folate or tHcy. Vitamin B12 supplementation increased plasma vitamin B12 concen-tration (125 to 215pmol/L, p<0.05) and reduced tHcy concentration (18.0 to 13.0 μmol/L, p<0.05) within first 2 weeks, both of which remained stable for the next 4 weeks. Plasma vitamin B12 and tHcy concentrations did not change in those who did not receive vitamin B12, and there was no change in plasma folate concentration in any of the groups. Blood haemoglobin concentration increased marginally within first two weeks in those women who received vitamin B12 (by 3 g/L, p<0.05) and the number of women with macrocytosis decreased from 2 to zero. There was no change in vibration sensory threshold during the period of the study. High-dose per oral vi-tamin B12 supplementation significantly reduced plasma tHcy within 2 weeks but did not achieve normal plasma tHcy concentration even after 6 weeks.
Abstract: Aims and hypothesis India has the greatest number of diabetic subjects in any one country, but the genetic basis of type 2 diabetes mellitus in India is poorly understood. Common non-coding variants in the transcription factor 7-like 2 gene (TCF7L2) have recently been strongly associated with increased risk of type 2 diabetes in European populations. We investigated whether TCF7L2 variants are also associated with type 2 diabetes mellitus in the Indian population. Materials and methods We genotyped type 2 diabetes patients (n=955) and ethnically matched control subjects (n=399) by sequencing three single nucleotide polymorphisms (SNPs) (rs7903146, rs12255372 and rs4506565) in
TCF7L2. Results We observed a strong association with all the polymorphisms, including rs12255372 (odds ratio [OR] 1.50 [95% CI=1.24–1.82], p=4.0×10−5), rs4506565 (OR 1.48 [95% CI=1.24–1.77], p=2.0×10−5) and rs7903146 (OR 1.46 [95% CI=1.22–1.75], p=3.0×10−5). All three variants showed increased relative risk when homozygous rather than heterozygous, with the strongest risk for rs12255372 (OR 2.28 [95% CI=1.40–3.72] vs OR 1.43 [95% CI=1.11–1.83]). We found no association of the TCF7L2 genotypes with age at diagnosis, BMI or WHR, but the risk genotype at rs12255372 was associated with higher fasting plasma glucose (p=0.001), higher 2-h plasma glucose (p=0.0002) and higher homeostasis model assessment of insulin resistance (HOMA-R; p=0.012) in nondiabetic subjects. Conclusions Our study in Indian subjects replicates the strong association of TCF7L2 variants with type 2 diabetes in other populations. It also provides evidence that variations in TCF7L2 may play a crucial role in the pathogenesis of type 2 diabetes by influencing both insulin secretion and insulin resistance. TCF7L2 is an important gene for determining susceptibility to type 2 diabetes mellitus and it transgresses the boundaries of ethnicity.
Abstract: The traditional model of type 2 diabetes encompasses genetic susceptibility and precipitation due to lifestyle factors. The idea of prevention revolves around changing the lifestyle of adults with impaired glucose tolerance, a method supported by many trial results. As the epidemic of diabetes matures, this rather limited idea will prove less and less effective.The risk factors for diabetes (obesity and insulin resistance) are increasingly seen in children and the age at diagnosis of diabetes is falling rapidly.The burden of disease is shifting to a younger population and the focus on prevention must anticipate this changing epidemiology. The concept of the developmental origins of health and disease (DOHaD) makes much sense. Although the medical profession has been slow to embrace this concept, the World Health Organization has endorsed the idea in its life-course model of non-communicable disease. This review article traces the history of the
DOHaD concept and summarizes current thinking. Both fetal undernutrition (low birth weight) and overnutrition (the baby of a diabetic mother) increase the risk of future diabetes. Children who grow rapidly in childhood are also at increased risk of type 2 diabetes, especially if they were born small. Earlier age at adiposity rebound (the age at which BMI starts rising) has been shown to be a particularly powerful risk factor for type 2 diabetes.Thus type 2 diabetes may be regarded as malnutrition-related diabetes, especially when associated with undernutrition in early life. The DOHaD idea thus represents a paradigm shift in the model for prevention of chronic disease. The next challenge is to translate this knowledge into practice.The focus is on the health of young girls.We need to understand the specific aspects of maternal nutrition that influence adiposity in the offspring, as well as the factors that influence a child’s age at adiposity rebound. Special efforts will be needed to change current practice, especially of overfeeding low-birth-weight babies to ‘normalize’ their growth.
P2-35 Circulating maternal lipid concentrations and newborn size Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aims: To study the effect of maternal circulating lipids on offspring birth size.
Conclusions: Our results suggest a strong association between maternal lipid metabolism and neonatal size in addition to the wellestablished role of maternal glycemia during pregnancy. Further research is necessary to understand clinical implications of these findings.
P2-80 Maternal vitamin B12 status in pregnancy and cognitive function in 9-year old Indian children
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aims: Vitamin B12 is important for brain development and function. We investigated the relationship between maternal plasma vitamin B12 concentrations (B12) during pregnancy (28wks) and child’s cognitive performance at 9 y. Study design: A nested case control design in the Pune Maternal Nutrition Study (PMNS). Conclusions: Maternal vitamin B12 status in pregnancy and the child’s head growth are independent predictors of cognitive performance in Indian children.
P2-82 Maternal predictors of fetal size in early pregnancy the Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aims: To examine associations of maternal size, diet and micronutrient status with fetal size at 18 weeks gestation. Study design: The Pune Maternal Nutrition Study is a community-based prospective follow-up study of rural Indian women and their offspring. Conclusion: In these rural Indian mothers, diet and nutritional status were predictors of fetal size in early pregnancy.
P2-83 Maternal B12, folate during pregnancy relationships with gestational diabetes, offspring size and glucose insulin concentrations
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aims: To test the hypothesis that low plasma vitamin B12 and high plasma folate in pregnant mothers is associated with higher offspring adiposity and altered glucose/insulin metabolism. Study design: Prospective observational study.
P2-87 Intergenerational influence of maternal vitamin B12 status
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aim: To investigate the relationship between maternal and offspring vitamin B12 status. Study design: Two population-based longitudinal studies. Subjects: Indian women and their offspring from rural and urban Pune. Ethical approval and consent was obtained. Conclusion: Maternal vitamin B12 status is a significant predictor of the child’s vitamin B12 status at birth and in childhood. Improving maternal vitamin B12 status will contribute to improving the vitamin B12 status of Indians.
6D-4 Associations between maternal nutrition during pregnancy and plasma leptin concentrations in rural Indian children_ Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aim: To study associations between maternal characteristics during pregnancy and plasma leptin concentration in 6-year-old children. Study design: The Pune Maternal Nutrition Study (PMNS) is a prospective study of maternal nutrition and fetal growth. We
recorded maternal pre-pregnancy characteristics, and food intake and physical activity during pregnancy. Circulating levels of nutrients and metabolites were measured twice during pregnancy. Anthropometric measurements on 698 children were carried out at birth and then serially every 6 months. At 6 years body composition and circulating levels of leptin, lipids, and insulin Conclusions: Maternal micronutrient food intake and high
circulating folate concentrations in pregnancy predict plasma leptin concentration (and adiposity) in the offspring, suggesting intrauterine nutritional programming of adiposity.
6E-3 Absorption of oral vitamin B-12 in Indians_ the Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aim: Vitamin B12 deficiency is common among Indian mothers and is associated with an increased risk of delivering a small-for-gestational age baby. Vitamin B12 deficiency in Indians may be due to low dietary intake or poor intestinal absorption. We assessed vitamin B12 absorption by measuring the rise in plasma holotranscobalamin concentration after oral vitamin B12. Study design: Sixty-five families (Group A) received 10 mg×3 doses and 44 families (Group B) received 2mg×3 doses of oral B12 every 6 hours. Fasting blood samples were collected before and after the oral dose. Subjects gave signed consent and the Ethical Committee approved the study protocol. Conclusions: Intestinal malabsorption is unlikely to be a major cause of the high prevalence of vitamin B12 deficiency in Indians.
P1-103 Fetal growth and metabolic risk factors in the children at the age of 6 years_ data from the Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aims: To examine whether body size and metabolic risk factors in children are associated with fetal size and growth at 18 and 28 weeks gestation. Study design: The Pune Maternal Nutrition Study is a population-based prospective study of rural Indian women and their offspring. Conclusion: In this rural Indian population, childhood size is directly associated with fetal growth in the second, but not the first, trimester. There is also evidence that larger fetuses in the second trimester have lower risk factors for cardiovascular disease
in childhood.
4C-5 Maternal nutrition and circulating inflammatory markers in rural Indian children_ Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aims: To study associations between maternal nutrition during pregnancy and inflammatory markers in the children at 6 years. Study design: The Pune Maternal Nutrition Study (PMNS) database has information on maternal pre-pregnancy characteristics and her food intake, physical activity and circulating levels of nutrients and metabolites during pregnancy. Children born in PMNS were measured serially from birth every 6 months. At 6 years body composition and inflammatory markers. Conclusions: This is the first demonstration of an association between maternal nutritional intake in pregnancy and inflammatory markers in the offspring, raising the possibility of nutritional programming of the immune system.
P434 Predictors of Deterioration of Glucose Tolerance in Indian Subjects
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: We have studied progression to impaired glucose tolerance (IGT) and diabetes meUitus (DM) over 10 years in 133 subjects with normal glucose tolerance and without family history of diabetes. There were 76 men (mean age 42 y, BMI 23.5 kg/m 2) and 57 women (39.5 y, 23.5 kg/m2). At 10 year follow-up 22 subjects had progressed to IGT or DM, 73 continued to have normal glucose tolerance and 38 were lost to follow-up. There were no anthropometric and metabolic predictors of deterioration of glucose tolerance in women. Generalised and central obesity and insulin resistance predict deterioration of glucose tolerance in Indian men. Preventive measures should concentrate on controlling obesity and treating insulin resistance.
4B-5 Increased abdominal and visceral adiposity is manifest in Indian babies at birth
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Aim: The determinants of increased abdominal and visceral adiposity in South Asians are unknown. We compared white Caucasian (WC) and Indian neonates to determine if differences in body composition are present at birth. Outcome measures: Total AT: AT depots (visceral, and deep and superficial subcutaneous abdominal). Indian babies had a highly significant increase in all abdominal AT compartments.
Abstract: Background: Insulin resistance, which can lead to a number of diseases including type 2 diabetes and coronary heart disease, is believed to have evolved as an adaptation to periodic starvation. The "thrifty gene" and "thrifty phenotype" hypotheses constitute the dominant paradigm for over four decades. With an increasing understanding of the diverse effects of impairment of the insulin signaling pathway, the existing hypotheses are proving inadequate. Presentation of the hypothesis: We propose a hypothesis that insulin resistance is a socio-ecological adaptation that mediates two phenotypic transitions, (i) a transition in reproductive strategy from "r" (large number of offspring with little investment in each) to "K" (smaller number of offspring with more investment in each) and (ii) a transition from "stronger to smarter" or "soldier to diplomat" i.e. from relatively more muscle dependent to brain dependent lifestyle. A common switch could have evolved for the two transitions since the appropriate environmental conditions for the two transitions are highly overlapping and interacting. Testing the hypothesis: Gestational insulin resistance diverts more energy through the placenta, resulting in increased investment per offspring. On the other hand, insulin resistance is associated with reduced ovulation. The insulin signaling pathway is also related to longevity. Insulin resistance diverts more nutrients to the brain as compared to muscle. Also, hyperinsulinemia has direct positive effects on cognitive functions of the brain. The hypothesis gets support from known patterns in human clinical data and recent research on the molecular interactions in the insulin signaling pathway. Further we state many predictions of the hypothesis that can be tested experimentally or epidemiologically. Implications of the hypothesis: The hypothesis can bring about a significant change in the line of treatment as well as public health policies for the control of metabolic syndrome.
Interleukin-6, tumour necrosis factor-alpha and insulin relationships to body composition, metabolism and resting energy expenditure in a migrant Asian Indian population
Abstract: Objective: Systemic inflammation and insulin resistance may play important roles in the pathogenesis of obesity-related diseases for which migrant Asian Indians are at particularly high risk. We examined relationships between markers of insulin resistance and inflammation, resting energy expenditure (REE), and body composition. Design and methods: Measurements were made of total and regional body composition, including regional fat mass (FM) and appendicular skeletal muscle mass (ASMM) by dual-energy X-ray absorptiometry (DXA), REE by indirect calorimetry and fasting interleukin (IL)-6, tumour necrosis factor (TNF)-α, glucose and insulin, in 79 healthy Asian Indians (38F, 41M; age 30–49 years) from urban Auckland, New Zealand. Beta-cell function (HOMA B%) and insulin sensitivity (HOMA S%) were derived using homeostatic model assessment. Results: Men had a more central distribution of body fat than women. REE was strongly correlated with IL-6 concentrations in men but not in women. In both sexes, IL-6 was associated positively with percentage body fat and HOMA B% and inversely with ASMM
and HOMA S%. Insulin increased and HOMA S% decreased with increasing waist-to-hip ratio and abdominal-to-thigh fat ratio in men but not in women. TNF-α was not significantly associated with any of the variables examined. Conclusion: Relationships between body fat distribution and HOMA S% were strongly sex dependent and may indicate a greater propensity for development of the metabolic syndrome among male
Asian Indians than females in the age group examined.
Abstract: The insulin-deficient mechanism for diabetes, discovered around a century ago, was questioned by observations on the human response to intravenous insulin (1). Later, it was more severely challenged by the raised plasma insulin values usually found by radioimmunoassay in type 2 diabetic subjects (2), then and since rapidly increasing in number, and often with accompanying adiposity (3). At this time, the pathogenesis of type 2 diabetes was unknown, and it seemed crucial to determine whether it was essentially based on increased resistance to the hypoglycemic action of insulin or on failing -cells with secondary gluco- and lipotoxicities. Could this be determined from the glucose and insulin levels of single or duplicate basal blood samples? If so, epidemiological logistics might be transformed, without the need for stimulated tests or tests as sophisticated as measurement of the basal endogenous glucose production rate with tritiated glucose, and the calculation of post-absorptive hepatic insulin resistance to the hypoglycemic effect of insulin as the product of this and the overnight fasting insulin concentration. We are still essentially ignorant as to whether, of 100 type 2 diabetic patients, 90 have the same basic abnormality, whereas 10 each have a different genetic abnormality or whether 10 sets of 10 patients each acquire a different fundamental genetic, epigenetic, or environmental pathogenesis. The answer probably lies in between; certainly, detailed knowledge of proteins and nucleo-proteins reveals increasing plurality. Another unsolved conundrum is whether obesity is an essential part of the type 2 diabetes process(es) or whether it is merely, though importantly, an exacerbating factor.
P1-102 Fetal growth in early pregnancy and weight at birth_ data from the Pune Maternal Nutrition Sub-Study
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: Early Human Development - Elsevier
Abstract: Fetal size measured by ultrasound in the first trimester is used to ‘date’ pregnancies on the assumption that all fetuses have similar early growth. A recent study in IVF pregnancies, with known conception dates, showed that slower first trimester fetal growth predicted lower birth-weight and shorter pregnancy duration. We studied these effects in Indian (non-IVF) mothers, whose last menstrual period (LMP) dates were obtained by monthly home-visits. PMNS fetuses grew slower than expected by a mean 4.0 (SD 4.6) days. For each 1-day increase in DGA, birthweight increased by 9 g (p = 0.3). After adjustment for pregnancy duration, this became 29 g (p < 0.001), and remained after adjustment for other potential confounders. A 1-day increase in DGA was associated with a 1-day decrease in pregnancy duration (p < 0.001). A 1-day increase in DGA reduced the risk of SGA (OR 0.90; 95% CI 0.74 1.08; p = 0.3). PMNS fetuses are smaller than expected from international standards, even at 8 weeks. Variations in birthweight and possibly pregnancy duration are partly determined by first trimester fetal growth.
Abstract: Hales and Barker caused a paradigm shift in our thinking about diabetes prevention when they demonstrated that low birth weight (due to growth retardation) predicted type 2 diabetes (the “thrifty phenotype” or “fetal origins” hypothesis). On the other hand, larger babies of diabetic mothers are also at higher risk of diabetes, apart from their genetic susceptibility (“fuel mediated teratogenesis”) (2,3). A concept evolved that the intrauterine experiences mold the fetal systems (“programming”) and influence future health (4). If the postnatal experiences are at variance with the intrauterine ones, the programmed fetus is
susceptible to disease. Today we have only a preliminary knowledge of mechanisms of epigenetic regulation. Various enzymatic modifications affect gene function, including
methylation of cytosine residues at CpG dinucleotides in DNA molecule and acetylation
of specific lysine residues in the histones that package the DNA, both leading to an alteration in the transcription profile. Shields et al. found that EDTA anticoagulant and refrigeration preserve cord blood insulins for up to 48 h after collection, providing a
useful guideline for researchers. The exciting observation is that girls had 15–25% higher concentrations of cord insulin compared with those in boys, independent of the many confounders (maternal size and glycemia in late pregnancy, length of gestation, mode of delivery, and glucose concentration in the cord blood). They claim that girls are “intrinsically” more insulin resistant than boys. Hyperinsulinemia at birth (unaffected
by lifestyle) may suggest that it’s intrinsic to female sex. This is the basis of the “sex insulin hypothesis”. Most of the recent excitements in genetics of type 2 diabetes are related to -cell function. Investigations into genetics and epigenetics of sex insulin difference could shed more light on the origins of insulin resistance. Future studies should include maternal metabolic, nutritional, and other factors; a standardized protocol to assess fetal growth; and cord blood and placental tissue collection to investigate genetic and epigenetic factors. Analysis of previous datasets by sex difference and parent-of-origin effect are likely to provide valuable information.
Newborn size, infant and childhood growth, and body composition and cardiovascular disease risk factors at the age of 6 years the Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2007 , Journal Name: International Journal of Obesity - Nature
Abstract: Objective: To study associations of size and body proportions at birth, and growth during infancy and childhood, to body composition and cardiovascular disease (CVD) risk factors at the age of 6 years. Design: The Pune Maternal Nutrition Study, a prospective population-based study of maternal nutrition and CVD risk in rural Indian children. Methods: Body composition and CVD risk factors measured in 698 children at 6 years were related to body proportions and growth from birth. Measurements: Anthropometry was performed every 6 months from birth. At 6 years, fat and lean mass (dual X-ray absorptiometry) and CVD risk factors (insulin resistance, blood pressure, glucose tolerance, plasma lipids) were measured. Results: Compared with international references (NCHS, WHO) the children were short, light and thin (mean weight o1.0 s.d. at all ages). Larger size and faster growth in all body measurements from birth to 6 years predicted higher lean and fat mass at 6 years. Weight and height predicted lean mass more strongly than fat mass, mid-upper arm circumference (MUAC) predicted them both approximately equally and skinfolds predicted only fat mass. Neither birthweight nor the ‘thin-fat’ newborn phenotype, was related to CVD risk factors. Smaller MUAC at 6 months predicted higher insulin resistance (P<0.001) but larger MUAC at 1 year predicted higher systolic blood pressure (Po0.001). After infancy, higher weight, height, MUAC and skinfolds, and faster growth of all these parameters were associated with increased CVD risk factors. Conclusions: Slower muscle growth in infancy may increase insulin resistance but reduce blood pressure. After infancy larger size and faster growth of all body measurements are associated with a more adverse childhood CVD risk factor profile. These rural Indian children are growing below international ‘norms’ for body size and studies are required in other populations to determine the generalizability of the findings.
Abstract: OBJECTIVE— To study determinants of incident hyperglycemia in rural Indian mothers 6
years after delivery.
RESEARCH DESIGN AND METHODS— The Pune Maternal Nutrition Study collected information in six villages near Pune on prepregnant characteristics and nutrition, physical
activity, and glucose tolerance during pregnancy. An oral glucose tolerance test (OGTT) was repeated 6 years after delivery.
RESULTS— A total of 597 mothers had an OGTT at 28 weeks’ gestation; 3 had gestational diabetes (by World Health Organization 1999 criteria). Six years later, 42 of 509 originally normal glucose-tolerant mothers were hyperglycemic (8 diabetic, 20 with impaired glucose tolerance, and 14 with impaired fasting glucose). The hyperglycemic women had shorter legs and thicker skinfolds before pregnancy (P 0.01, both), were less active and more hyperglycemic (2-h plasma glucose 4.8 vs. 4.4 mmol/l, P 0.001) during pregnancy, and gained more weight during follow-up (6.0 vs. 2.7 kg, P 0.001). Multivariate analysis revealed that total leukocyte count and blood pressure during pregnancy were additional independent predictors of 2-h glucose concentration at follow-up.
CONCLUSIONS— Our results suggest that compromised linear growth, adiposity, inflammation, and less physical activity predispose to hyperglycemia in young rural Indian women. International cut points of diabetes risk factors are largely irrelevant in these women.
Abstract: Background: Iron, folate, and vitamin B12 deficiencies have adverse effects on pregnancy outcome. In India, data on the concomitant prevalence of these deficiencies among pregnant women are meagre. Objective: We conducted a community-based study to assess the prevalence of deficiencies of iron, folate, and vitamin B12 among pregnant women in a rural block of Haryana State. Methods: The study was approved by the ethics committee of the All India Institute of Medical Sciences, New Delhi. A total of 283 pregnant women were enrolled in the study. After oral informed consent had been obtained from the women, blood was drawn from the antecubital vein for estimation of the levels of serum ferritin by enzyme-linked immunosorbent assay (levels < 12 ng/mL were considered as indicative of poor iron stores); serum folate was determined by radioimmunoassay (levels < 3 ng/mL were considered as indicative of poor folate stores); and serum vitamin B12 was estimated by the microbiologic method (levels < 200 pg/mL were considered as indicative of poor vitamin B12 stores). Results:The results indicated that 67.7%, 26.3%, and 74.1% of the women had poor iron, folate, and vitamin B12 stores, respectively. Concomitant deficiencies of iron, folate, and vitamin B12 occurred in 16.2% of the women. We found that 59.9% of the women were consuming less than 75% of the recommended daily caloric allowance (2,175 kcal), indicating an overall poor food intake. This could be one of the predominant reasons for poor iron, folate, and vitamin B12 stores among the women. Conclusions. Our findings suggest that apart from iron and folate, vitamin B12 deficiencies may play an important role in causing anemia.
Abstract: Background. Recent studies have shown associations between size and body proportions at birth and health outcomes throughout the life cycle, but there are few data on how neonatal phenotype varies in different populations around the world. Methods. Data from the UK, Finland, India, Sri Lanka, China, DR Congo, Nigeria, and Jamaica (n/22,067) were used to characterize geographical differences in phenotype in singleton, live-born newborns. Measurements included birth weight, placental weight, length, head, chest, abdominal and arm circumferences, and skinfolds. Results. Neonates in Europe were the largest, followed by Jamaica, East Asia (China), then Africa and South Asia. Birth weight varied widely (mean values 2,7303,570 g), but in contrast, head circumference was similar in all except China (markedly smaller). The main difference in body proportions between populations was the head to length ratio, with small heads relative to length in China and large heads relative to length in South Asia and Africa. Conclusions. These marked geographical differences in neonatal phenotype need to be considered when investigating determinants of fetal growth, and optimal phenotype for short-term and long-term outcomes.
Abstract: Background. Size and body proportions at birth are partly determined by maternal body composition, but most studies of motherbaby relationships have only considered the effects of maternal height and weight on offspring birth weight, and few have examined the size of effects. Paternal size and body composition also play a role, primarily through the fetal genome, although few studies have investigated relationships with neonatal phenotype. Methods. Data from the UK, Finland, India, Sri Lanka, China, DR Congo, Nigeria and Jamaica were used to investigate the effects of maternal measures (derived at 30 weeks’ gestation, n/16,418), and also paternal size (n/3,733) on neonatal phenotype, for singleton, live-born, term births. Results. After accounting for variation in maternal size and shape across populations, differences in neonatal phenotype were markedly reduced. Motherbaby relationships were similar across populations, although some were stronger in developing countries. Maternal height was generally the strongest predictor of neonatal length, maternal head circumference of neonatal head and maternal skinfold thickness of neonatal skinfolds. Relationships with maternal arm muscle area were generally weak. Effects of paternal height and body mass index were weaker than the equivalent maternal measurements in most studies. Conclusions. Differences in maternal body composition account for a large part of the geographical variation in neonatal phenotype. The size of the effects of all maternal measures on neonatal phenotype suggests that nutrition at every stage of the mother’s life cycle may influence fetal growth. Further research is needed into fatherbaby relationships and the genetic mechanisms that influence fetal growth.
Effect of Ramipril on the Incidence of Diabetes. DREAM trial
Author Name: Chittaranjan Yajnik , Publication Year: 2006 , Journal Name: The New England Journal of Medicine
Abstract: Previous studies have suggested that blockade of the renin–angiotensin system may prevent diabetes in people with cardiovascular disease or hypertension. Methods: In a double-blind, randomized clinical trial with a 2-by-2 factorial design, we randomly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance to receive ramipril (up to 15 mg per day) or placebo (and rosiglitazone or placebo) and followed them for a median of 3 years. We studied the effects of ramipril on the development of diabetes or death, whichever came first (the primary outcome), and on secondary outcomes, including regression to normoglycemia. Results: The incidence of the primary outcome did not differ significantly between the ramipril group (18.1%) and the placebo group (19.5%; hazard ratio for the ramipril group, 0.91; 95% confidence interval [CI], 0.81 to 1.03; P = 0.15). Participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo (hazard ratio, 1.16; 95% CI, 1.07 to 1.27; P = 0.001). At the end of the study, the median fasting plasma glucose level was not significantly lower in the ramipril group (102.7 mg per deciliter [5.70 mmol per liter]) than in the placebo group (103.4 mg per deciliter [5.74 mmol per liter], P = 0.07), though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group (135.1 mg per deciliter [7.50 mmol per liter] vs. 140.5 mg per deciliter [7.80 mmol per liter], P = 0.01). Conclusions: Among persons with impaired fasting glucose levels or impaired glucose tolerance, the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia.
Abstract: Maternal micronutrient nutrition is an important determinant of size and body composition of the fetus. Maternal iron, iodine, calcium, folate, vitamin A, and vitamin C nutrition all influence offspring size. The Pune Maternal Nutrition Study was designed to study the relationship between maternal nutrition and fetal growth, size at birth, and postnatal growth. Maternal circulating folate and vitamin C concentrations predicted larger offspring size, while higher ferritin levels predicted smaller-sized babies. Subclinical vitamin B12 deficiency is common in India, especially in vegetarians, and children born to mothers with the lowest vitamin B12 but the highest folate status were the most adipose and the most insulin resistant. Furthermore, the relationship between maternal nutrition, fetal growth, and risk of type 2 diabetes and coronary heart disease appears to be much more complex than the simplistic postulates of the “fetal origins” hypothesis.
Allelic drop-out may occur with a primer binding site polymorphism for the commonly used RFLP assay for the -1131TC polymorphism of the Apolipoprotein AV gene
Author Name: Chittaranjan Yajnik , Publication Year: 2006 , Journal Name: Lipids in Health and Disease
Abstract: Apolipoprotein AV (ApoAV) gene variant, -1131T>C, is associated with increased triglyceride concentrations in all ethnic groups studied. An MseI based RFLP analysis is the most commonly used method for genotyping this SNP. We genotyped a large cohort comprising 1185 Asian Indians and 173 UK Caucasians for -1131T>C using an ARMS-PCR based tetra-primer method. For quality control, we re-genotyped approximately 10% random samples from this cohort utilizing the MseI RFLP, which showed a 2.9% (3/102) genotyping error rate between the two methods. To investigate further, we sequenced the 900 bp region around the -1131T>C polymorphism in 25 Asian Indians and 15 UK Caucasians and found a number of polymorphisms including the -987C>T polymorphism. Further analysis of the -987C>T SNP showed a higher rare allele frequency of 0.23 in Asian Indians (n = 158) compared to 0.09 in the UK Caucasians (n = 157). This SNP is located 4 bp from the 3' end of the RFLP forward primer and is in weak linkage disequilibrium with -1131T>C variant (r2 = 0.084 and D' = 1). Repeated RFLP analysis of seven subjects heterozygous for -987C>T (seven times), showed discordant results with the sequence at -1131T>C SNP nearly one third (15/ 49) of the time. We conclude that presence of -987C>T polymorphism in the forward primer of the MseI RFLP assay may lead to allelic drop-out and generate unforeseen errors in genotyping the -1131T>C polymorphism. Our results also emphasise the need for careful quality control in all molecular genetic studies, particularly while transferring genotyping methods between various ethnic groups.
Bone mass in Indian children--relationships to maternal nutritional status and diet during pregnancy the Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2006 , Journal Name: The Journal of Clinical Endocrinology & Metabolism
Abstract: Context/Objective: Bone mass is influenced by genetic and environmental factors. Recent studies have highlighted associations between maternal nutritional status during pregnancy and bone mass in the offspring. We hypothesized that maternal calcium intakes and circulating micronutrients during pregnancy are related to bone mass
in Indian children. Design/Setting/Participants/Main Outcome Measures: Nutritional status was measured at 18 and 28 wk gestation in 797 pregnant rural Indian women. Measurements included anthropometry, dietary intakes (24-h recall and food frequency questionnaire), physical workload (questionnaire), and circulating micronutrients (red cell folate and plasma ferritin, vitamin B12, and vitamin C). Six years postnatally, total body and total spine bone mineral content and bone mineral density (BMD) were measured using dual-energy x-ray absorptiometry (DXA) in the children (n 698 of 762 live births) and both parents. Results: Both parents’ DXA measurements were positively correlated with the equivalent measurements in the children (P 0.001 for all). The strength of these correlations was similar for fathers and mothers. Children of mothers who had a higher frequency of intake of calcium-rich foods during pregnancy (milk, milk products, pulses, nonvegetarian foods, green leafy vegetables, fruit) had higher total and spine bone mineral content and BMD, and children of mothers with higher folate status at 28 wk gestation had higher total and spine BMD, independent of parental size and DXA measurements. Conclusions: Modifiable maternal nutritional factors may influence bone health in the offspring. Fathers play a role in determining their child’s bone mass, possibly through genetic mechanisms or through shared environment.
Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose a randomised controlled trial
Abstract: Background Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug’s ability to prevent type 2 diabetes in individuals at high risk of developing the condition. Methods 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. Findings At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11·6%) individuals given rosiglitazone and 686 (26·0%) given placebo developed the composite primary outcome (hazard ratio 0·40, 95% CI 0·35–0·46; p<0·0001); 1330 (50·5%) individuals in the rosiglitazone group and 798 (30·3%) in the placebo group became normoglycaemic (1·71, 1·57–1·87; p<0·0001). Cardiovascular event rates were much the same in both groups, although 14 (0·5%) participants in the rosiglitazone group and two (0·1%) in the placebo group developed heart failure (p=0·01). Interpretation Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.
Vitamin B12 deficiency and hyperhomocysteinemia in rural and urban Indians
Author Name: Chittaranjan Yajnik , Publication Year: 2006 , Journal Name: Journal of the Association of Physicians of India
Abstract: Background : Low vitamin B12 concentration in South Asian Indians is common, but the exact prevalence is not known. Aim : To investigate prevalence and associations of low vitamin B12 concentration and hyperhomocysteinemia in rural and urban Indian men living in and around Pune, Maharashtra. Method : We studied 441 middle-aged men (149 rural, 142 slum and 150 urban middle-class residents, mean age 39 y). Data on lifestyle, socio-economic status, nutrition and medical history were obtained. Circulating concentrations of vitamin B12, folate, ferritin, total homocysteine (tHcy), and haematological indices, and cardiovascular risk variables were measured. Results : Median plasma B12 concentration was low (110 pmol/L): Overall, 67% of men had low vitamin 12
concentration (<150 pmol/L) and 58% had hyperhomocysteinemia (>15 μmol/L). Of the urban middle class, 81% had low vitamin B12 concentration and 79% had hyperhomocysteinemia. Low vitamin B12 concentration contributed 28% to the risk of hyperhomocysteinemia (population attributable risk) while low red cell folate contributed 2%. Vegetarians had 4.4 times (95%CI 2.1, 9.4) higher risk of low vitamin B12 concentrations and 3.0 times (95%CI 1.4, 6.5) higher risk of hyperhomocysteinemia compared to those who ate non-vegetarian foods frequently. Urban middle-class residence was an additional independent risk factor of hyperhomocysteinemia (odds ratio 7.6 (95%CI 2.5, 22.6), compared to rural men). Low vitamin B12 concentration was related to lower blood haemoglobin concentration and higher mean corpuscular volume, but macrocytic anemia was rare. Conclusion : Low vitamin B12 concentration and hyperhomocysteinemia are common in Indian men, particularly in vegetarians and urban middle class residents. Further studies are needed to confirm these findings in other parts of India.
Abstract: Background: The APOA5 gene variants, -1131T>C and S19W, are associated with altered triglyceride concentrations in studies of subjects of Caucasian and East Asian descent. There are few studies of these variants in South Asians. We investigated whether the two APOA5 variants also show similar association with various lipid parameters in Indian population as in the UK white subjects. Methods: We genotyped 557 Indian adults from Pune, India, and 237 UK white adults for -1131T>C and S19W variants in the APOA5 gene, compared their allelic and genotype frequency and determined their association with fasting serum triglycerides, total cholesterol, HDL and LDL cholesterol levels using univariate general linear analysis. APOC3 SstI polymorphism was also analyzed in 175 Pune Indian subjects for analysis of linkage disequilibrium with the APOA5 variants. Results: The APOA5 -1131C allele was more prevalent in Indians from Pune (Pune Indians) compared to UK white subjects (allele frequency 20% vs. 4%, p = 0.00001), whereas the 19W allele was less prevalent (3% vs. 6% p = 0.0015). Patterns of linkage disequilibrium between the two variants were similar between the two populations and confirmed that they occur on two different haplotypes. In Pune Indians, the presence of -1131C allele and the 19W allele was associated with a 19% and 15% increase respectively in triglyceride concentrations although only -1131C was significant (p = 0.0003). This effect size was similar to that seen in the UK white subjects. Analysis of the APOC3 SstI polymorphism in 175 Pune Indian subjects showed that this variant is not in appreciable linkage disequilibrium with the APOA5 -1131T>C variant (r2 = 0.07). Conclusion: This is the first study to look at the role of APOA5 in Asian Indian subjects that reside in India. The -1131C allele is more prevalent and the 19W allele is less prevalent in Pune Indians compared to UK Caucasians. We confirm that the APOA5 variants are associated with triglyceride levels independent of ethnicity and that this association is similar in magnitude in Asian Indians and Caucasians. The -1131C allele is present in 36% of the Pune Indian population making it a powerful marker for looking at the role of elevated triglycerides in important conditions such as pancreatitis, diabetes and coronary heart disease.
Abstract: Aims/hypothesis: Fetal growth is influenced by genetic factors as well as the intra-uterine environment. We hypothesised that some genetic factorsmay alter fetal insulin secretion and insulin action. Subjects, materials and methods: To assess this, we analysed plasma insulin concentration in umbilical cord blood from 644 normal, term,UKCaucasian deliveries from the Exeter Family Study of Childhood Health. We tested for associations between cord insulin and each of parental anthropometry, fasting glucose, insulin and lipids. Results: As expected, cord insulin concentrations correlated with all measures of birth size (weight, length, head and arm circumferences, sum of skinfold thicknesses, ponderal index: r=0.16–0.4, p<0.01 for all) and maternal BMI (r=0.11, p=0.005), maternal glucose (r=0.25, p<0.001) and maternal insulin resistance (r=0.23, p<0.001). Paternal fasting insulin and insulin resistance were correlated with cord insulin (r=0.15, p=0.006; r=0.13, p=0.001, respectively), and this was independent of paternal BMI. Multiple linear regression analysis revealed paternal insulin resistance to be a predictor of cord insulin concentrations, independently of maternal factors. Conclusion: Our results show an independent relationship between paternal insulin resistance and cord insulin concentrations. This is consistent with heritability of insulin resistance from father to offspring and a compensatory increase in fetal insulin secretion, the latter occurring prenatally before the homeostatic feedback loop between glucose and insulin is established.
Size and body composition at birth and risk of type-2 diabetes
Author Name: Chittaranjan Yajnik , Publication Year: 2005 , Journal Name: Nestle Nutr Workshop Ser Pediatr Program
Abstract: It is customary to ascribe diabetes susceptibility to the evolutionary enrichment of thrifty genes. An alternative explanation is the recently proposed thrifty phenotype hypothesis which ascribes it to an unfavorable intrauterine environment. The two explanations are not necessarily exclusive. The fetal insulin hypothesis envisages that the association between birth weight and diabetes could have common genetic determinants but acknowledges the role of intrauterine environment in modifying this relationship. Hales and Barker [4, 5] proposed that undernutrition in utero increased the susceptibility to diabetes in later life. This was based on an inverse association between birth weight and later risk of diabetes in elderly men and women in the UK. It was suggested that an improvement in maternal and therefore fetal nutrition would reduce the risk of diabetes. However, there is growing recognition that the relationship between maternal nutrition, fetal nutrition, neonatal size and later diabetes is more complex. The simplistic assumption that improvement in maternal nutrition will reduce the risk of these disorders is unlikely to be true. Urban Indians havea five times higher risk of diabetes than rural Indians despite the larger size of mothers and their babies (‘better nourished’). Temporally, the epidemic is associated with a rapid epidemiologic and nutritional transition which may be associated with increasing fetal nutrition rather than undernutrition. The Diabetes Unit, King Edward Memorial Hospital, Pune, has contributed a number of observations on the evolution of the insulin resistance syndrome during the life course. Specifically we have studied the relationships between size, body composition and nutrition both in mothers and offspring.
Maternal total homocysteine concentration and neonatal size in India
Author Name: Chittaranjan Yajnik , Publication Year: 2005 , Journal Name: Asia Pacific Journal of Clinical Nutrition
Abstract: The smallness of Indian babies is ascribed to small maternal size and their chronic under nutrition. Micronutrient nutrition of the mother may be particularly important. We investigated the relationship between maternal circulating concentrations of total homocysteine (tHcy), vitamin B12 and folate and offspring size at birth. Mothers of full term small for gestation age babies (SGA, gestation and sex specific birth weight <10th centile, N = 30) and mothers of appropriate for gestational age babies (AGA, >10th centile, N = 50) were compared for their body size, plasma tHcy, vitamin B12 and red cell folate concentration at 28week gestation. Mothers of SGA babies were lighter and shorter than those of AGA babies (P <0.05, both) and had higher plasma tHcy concentration (P<0.01). Total homocysteine concentrations were inversely related to plasma vitamin B12 and red cell folate concentrations (r = ~ -0.5, P <0.01, both). Seventy percent of the women had a low vitamin B12 status (plasma vitamin B12 <150 pmol/L) but none were folate deficient (red cell folate <283 nmol/L). Higher maternal plasma tHcy concentration was significantly associated with lower offspring birth weight (r=-0.28, P<0.05 adjusting for maternal height, weight, gestation at delivery and the baby’s gender), this effect was reduced by adjustment for red cell folate concentration. We conclude that maternal vitamin B12 deficiency reflected in plasma tHcy concentration contributes to small size of Indian babies.
Body fat measurement in Indian men comparison of three methods based on a two-compartment model
Author Name: Chittaranjan Yajnik , Publication Year: 2005 , Journal Name: International Journal of Obesity - Nature
Abstract: Obesity is a major risk factor for diabetes and related disorders. The current classification of obesity is based on body mass index (BMI, kg/m2), which is a surrogate for the total body fat. Since the relationship between BMI and body fat varies in different populations, an independent validation of the BMI–body fat relationship in the population of interest is desirable. Our objectives were to study the validity of field methods of measuring body fat (multiple skinfolds and bioimpedance) against a criterion method (deuterium dilution) and to compare the prevalence of obesity (WHO 2000 criteria for BMI) with adiposity (body fat 425%) in middle-aged Indian men in rural and urban Pune. Community-based multistage stratified random sampling of middle-aged men from rural and urban Pune for study of body composition and cardiovascular risk. A third of these men, selected to represent wide BMI distribution, were studied for body fat measurements by specific methods. Mean total body fat was 14.3 kg (23.0%) by anthropometry, 16.5 kg (26.0%) by BIA and 15.3 kg (24.6%) by D2O method. Although there was a good correlation between fat estimation by three methods (r¼B0.9, Po0.001 all), compared to D2O method anthropometry underestimated body fat by 1.0 kg and BIA overestimated fat by 1.2 kg (Po0.001 both). Using the standard cut-point of 25% body fat for ‘adiposity’ 29.5% rural, 46.0% slum and 75.0% middle class men were adipose. These proportions were considerably higher than the number of men who were ‘preobese’ (BMIZ25–29.9 kg/m2, 9.0% rural, 22.0% urban slums and 27.0% urban middle class) and ‘obese’ (BMI430 kg/m2, 4.0% urban slums, none in rural and urban middle class).We recommend that future studies assessing risk for chronic diseases in Indians should measure adiposity by anthropometry (multiple skinfolds) or BIA (calibrated for Indians) rather than relying only on BMI cut-points.
Rapid assessment of maternal activity among rural Indian mothers (Pune Maternal Nutrition Study)
Author Name: Chittaranjan Yajnik , Publication Year: 2005 , Journal Name: Public Health Nutrition
Abstract: Objective: To develop an activity questionnaire for objective and rapid assessment of maternal habitual physical activity with the aim of describing its relationship with birth size.
Design: Prospective observational study.
Setting: Six villages near Pune, Maharashtra, India.
Subjects: Seven hundred and ninety-seven rural Indian mothers were studied after excluding abortions and termination of pregnancies, foetal anomalies, etc.
Method: Principal components analysis (PCA) was used to identify a few leading questions from an elaborate questionnaire involving 36 questions related to 14 typical maternal activities.
Results: On the basis of high loading (.0.8), PCA identified three activities, i.e. farming, fetching water and washing clothes. Questions and sub-questions related to these activities only were considered for defining an activity score for rapid assessment. Validation of this new activity score, with the score based on the elaborate questionnaire, showed 70% sensitivity as well as specificity. New activity scores showed strong inverse relationships similar to those observed using the elaborate questionnaire, at early as well as late gestation, with neonatal head circumference (P ¼ 0.001 and 0.055) and mid-arm circumference (P ¼ 0.02 and 0.03).
Conclusions: Simple questionnaires, based on leading activities identified by PCA, can be as informative as longer and detailed questionnaires. This method has potential for adaptation, especially in rural communities in developing countries.
Increasing maternal parity predicts neonatal adiposity Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2005 , Journal Name: American Journal of Obstetrics & Gynecology
Abstract: Objective: This study was undertaken to study the effect of parity on maternal and neonatal characteristics.
Study design: Maternal anthropometry, diet, micronutrient status, biochemistry, and physical activity were measured during pregnancy and detailed neonatal size recorded in 770 pregnancies in rural Maharashtra, India.
Results: Increasing parity was associated with larger offspring birth weight, skinfold thicknesses, and abdominal circumference, but not head circumference and length. Compared with primiparous women, multiparous women were older, less adipose, and more physically active but had similar education, socioeconomic status, nutritional intake, and weight gain during pregnancy. They had lower circulating concentrations of hemoglobin, albumin, ferritin, glucose, and insulin and lower total leucocyte counts at 18 and 28 weeks’ gestation. There was no difference in their husbands’ body size. The relationship between maternal parity and neonatal weight and adiposity was significant independent of the difference in maternal characteristics.
Conclusion: Increasing maternal parity predicts increasing adiposity in the newborn infant. This may result from maternal nutritional, cardiovascular, or immunologic factors.
Characteristics of gestational diabetic mothers and their babies in an Indian diabetes clinic
Author Name: Chittaranjan Yajnik , Publication Year: 2005 , Journal Name: Journal of the Association of Physicians of India
Abstract: Aims and Objectives : To compare clinical and metabolic features of mothers with gestational diabetes (GDM) and their offspring with those in non-diabetic pregnancies at the King Edward Memorial Hospital, Pune, India.
Materials and Methods : Antenatal information was obtained from hospital records. GDM was diagnosed by 75 g OGTT (Oral Glucose Tolerance Test) in clinically high-risk women. Anthropometric measurements of mother and the babies were recorded within 24h of delivery and a maternal blood sample collected for hematological and biochemical measurements.
Results : Between the period Jan 1998 to December 2003, 265 women with gestational diabetes were treated in our Unit. Forty nine percent had first-degree relatives with diabetes. Compared to non-diabetic mothers (n=215) GDM mothers were older (29.0 vs. 26.0y, p<0.001), more obese (body mass index- BMI 26.0 vs. 22.0 kg/m2, p<0.001), centrally obese (Waist hip ratio-WHR 0.89 vs 0.86, p<0.001), adipose (sum of 4 skinfolds 98.4 vs. 61.4 mm, p<0.001) and had higher blood pressure (127/80 vs. 122/70 mmHg, p<0.001). GDM mothers had higher concentrations of plasma triglycerides (195.0 vs. 153.0 mg/dl, p<0.01); blood hemoglobin (11.7 vs 10.9 g/dl, p<0.001) and higher platelet count but lower concentration of HDL cholesterol and albumin. Sixty percent GDM mothers and 34% of non-diabetic mothers were delivered by caesarean section, 23% of GDM mothers delivered pre term (<37 wk). Despite the smaller gestation, babies of GDM mothers were heavier (BW 2950.0 vs. 2824.0g, p<0.001, adjusted for gender), longer (48.9 vs. 48.0 cm, p<0.01) and more adipose (sum of 2 skinfolds 10.5 vs. 8.5 mm). Only 5% of babies born to GDM mothers weighed > 4000 g but 30% were >90th centile of birth weight of babies born to non-diabetic mothers. Babies of GDM mothers suffered higher neonatal morbidity.
Conclusions : GDM mothers in urban India are more obese and more adipose than non-diabetic mothers, frequently have a family history of diabetes and show metabolic features of insulin resistance syndrome, suggesting high cardiovascular risk. Neonates of GDM mothers are heavier, longer and more adipose than those born to non-diabetic mothers, and suffer higher neonatal morbidity.
Evidence of genetic regulation of fetal longitudinal growth
Author Name: Chittaranjan Yajnik , Publication Year: 2005 , Journal Name: Early Human Development - Elsevier
Abstract: Background: Genetic as well as environmental factors are important determinants of
fetal growth but there have been few studies of the influence of paternal factors on
fetal growth.
Aim: To study the influence of paternal anthropometry on detailed measurements of
offspring at birth.
Design: A prospective cohort study involving biochemistry, and anthropometry, of mothers and fathers at 28 weeks gestation, and detailed anthropometry of children within 24 h of birth.
Subjects: 567 White Caucasian singleton, non-diabetic, full term pregnancies recruited
from central Exeter, UK.
Results: Paternal height, but not paternal BMI, was correlated with birth weight (r =0.19) and with birth length (r = 0.33). This was independent of potential confounders and maternal height. All measurements of fetal skeletal growth including crown—rump, knee—heel and head circumference were associated with paternal height. Maternal height showed similar correlations with birth weight (r =0.18) and birth length (r =0.26). Maternal BMI was correlated with birth weight (r =0.27) and birth length (r =0.15). In a multifactorial analysis 38% of the variance in fetal height could be explained by gestation, sex, paternal height, maternal height, maternal glucose, maternal BMI, parity and maternal smoking.
Conclusion: Paternal height has an independent influence on size at birth. This predominantly influences length and skeletal growth of the baby. In contrast to maternal obesity the degree of paternal obesity does not influence birth weight. This work suggests that there is genetic regulation of skeletal growth while the maternal environment predominantly alters the adiposity of the fetus.
Abstract: There is a rapidly increasing epidemic of type 2 diabetes in India and other Asian countries. The thrifty genotype and the thrifty phenotype are two nonexclusive explanations. People in the Indian subcontinent have faced undernutrition for many generations, and Indian babies are among the smallest in the world. However, the diabetes epidemic is of recent origin, and diabetes is more common among urban than rural Indians despite the higher birth weight of urban babies. This suggests that postnatal factors must also contribute. Thus, a life-course model of evolution of insulin resistance and type 2 diabetes, incorporating fetal, postnatal and adult components, seems most appropriate. For a given BMI, Indians have a higher percentage of body fat and more visceral fat than members of other populations. This thin-fat phenotype is present at birth. Neonatal size and body composition are influenced by parental size, maternal food intake, physical activity and circulating concentrations of nutrients and metabolites (folate, glucose, triglycerides, cholesterol etc.). Maternal insulin resistance promotes transfer of nutrients to the fetus. Accelerated childhood growth is another risk factor for adiposity and insulin resistance, especially in children born small. Childhood growth seems to be more influenced by paternal genetic factors, whereas intrauterine growth is more influenced by maternal factors (intrauterine environment). Urban lifestyles, including poor diet and sedentary habits, promote further obesity, insulin resistance and type 2 diabetes. These factors may be amenable to correction. Prevention of type 2 diabetes must begin in utero and continue throughout the life course.
Abstract: The two authors (S Yajnik, John S Yudkin) share a near identical body-mass index (BMI), but as dual X-ray absorptiometry imagery shows that is where the similarity ends. The first author (figure, right) has substantially more body fat than the second author (figure, left). Lifestyle may be relevant: the second author runs marathons whereas the first author’s main exercise is running to beat the closing doors of the elevator in the hospital every morning. The contribution of genes to such adiposity is yet to be determined, although the possible relevance of intrauterine undernutrition is supported by the first author’s low birthweight. The image is a useful reminder of the limitations of BMI as a measure of adiposity across populations.
Abstract: A WHO expert consultation addressed the debate about interpretation of recommended body-mass index (BMI) cut-off points for determining overweight and obesity in Asian populations, and considered whether population-specific cut-off points for BMI are necessary. They reviewed scientific evidence that suggests that Asian populations have different associations between BMI, percentage of body fat, and health risks than do European populations. The consultation concluded that the proportion of Asian people with a high risk of type 2 diabetes and cardiovascular disease is substantial at BMIs lower than the existing WHO cut-off point for overweight (25 kg/m2). However, available data do not necessarily indicate a clear BMI cut-off point for all Asians for overweight or obesity. The cut-off point for observed risk varies from 22 kg/m2 to 25 kg/m2 in different Asian populations; for high risk it varies from 26 kg/m2 to 31 kg/m2. No attempt was made, therefore, to redefine cut-off points for each population separately. The consultation also agreed that the WHO BMI cut-off points should be retained as international classifications. The consultation identified further potential public health action points (23·0, 27·5, 32·5, and 37·5 kg/m2) along the continuum of BMI, and proposed methods by which countries could make decisions about the definitions of increased risk for their population.
Abstract: How likely are people in the United States to contract diabetes mellitus? For people born in 2000, the lifetime risk of contracting diabetes mellitus was about 1 in 3 (in females 38.5%, 95% Cl 36.0% to 41.5%; in males 32.8%, 95% Cl 30.3%to 35.8%). For virtually all age groups, the residual risk appeared lower in males than females and in the white population compared with other ethnic groups. Diabetes mellitus is common. It should be a public health priority.
Abstract: In 1989, reports suggested that the fetal environment, as reflected in birth size, was related to the risk of noncommunicable diseases in adult life. This association was first described for coronary heart disease but rapidly extended to include type 2 diabetes, osteoporosis, and metabolic and endocrine homeostasis. This led to the development of the fetal origins of adult disease paradigm, which resulted in a refocusing of research effort over the next 10 y to consider the lifelong consequences of perinatal influences on chronic diseases. Previously, perinatal influences had largely been seen in terms of teratogenic effects or acute birth injury rather than whether trajectories and responses made during early development had lifelong consequences. Indeed, in developmental biology, it is widely recognized that adaptive plastic responses during early development often have consequences for function in later adulthood. Although the relative importance of this newly recognized set of phenomena to the burden of human disease has been controversial, the research precipitated by those early observations has confirmed their robustness and started to provide a mechanistic basis to this biology. Two world congresses have been held to review progress in this research. Both have been characterized by a unique multidisciplinary attendance ranging from molecular, experimental, and developmental biologists to epidemiologists and health economists.
Author Name: Chittaranjan Yajnik , Publication Year: 2004 , Journal Name: Proceedings of the Nutrition Society
Abstract: The epidemic of ‘obesity’ in India is not appreciated because BMI underestimates the adiposity of Indians. Specific adiposity measurements are necessary for recognition of the adiposity of ‘thin’ Indians. The origin of this adiposity is only beginning to be understood. In addition to a possible genetic predisposition, intrauterine ‘programming’ might be responsible, although in the ‘thrifty phenotype’ hypothesis the adiposity of the ‘thin’ fetus has not been appreciated. Dutch men who faced ‘winter hunger’ during the first trimester of their in utero life have become more obese as adults. Low birth weight predicts central obesity in some studies, including studies in urban children. It has also been shown that small and thin Indian newborns (weight 2.7 kg and ponderal index 2.4 kg/m3) have poor muscle and visceral mass but higher adiposity for a given weight compared with white Caucasian babies. This body composition is influenced by maternal adiposity before pregnancy and by aspects of maternal nutritional intake and circulating nutrient concentrations during pregnancy. There are no strong paternal determinants of adiposity at birth. Adiposity may be an integral part of the orchestrated adjustments made to support ‘brain preservation’ during intrauterine growth, because brain tissue is predominantly fat. Increased nutrition in the face of a genetic predisposition or multigenerational undernutrition increases maternal insulin resistance in late pregnancy and promotes fetal adiposity even in absence of marked hyperglycaemia. Further research is necessary to define the role of specific nutrients and metabolites in the intrauterine processes promoting adiposity before maternal interventions to curtail the epidemic of obesity and diabetes are planned.
Abstract: We found very high rates of diabetes and impaired glucose tolerance at the young age of 34 years in women who were diagnosed GDM. One in six of our GDM women continued to be diabetic after pregnancy and three more developed hyperglycaemia within 4 years of delivery. The former group probably consists of women with pre-gestational diabetes. Two in five GDM women had metabolic syndrome at this young age and this suggests a high risk of cardiovascular disease in future. Risk of diabetes was increased by positive family history of diabetes, older age, higher glycaemia in pregnancy and higher WHR at review. Our results suggest that young Indian women should be screened for diabetes in pregnancy and also highlight the need to introduce a programme to prevent diabetes and metabolic syndrome in those diagnosed with GDM.
Body size, body composition, and fat distribution a comparison of young New Zealand men of European, Pacific Island, and Asian Indian ethnicities
Author Name: Chittaranjan Yajnik , Publication Year: 2004 , Journal Name: New Zealand Medical Journal
Abstract: Aims To investigate body size and body fat relationships and fat distribution in young healthy men drawn from New Zealand European, Pacific Island, and Asian Indian populations.
Method: A total of 114 healthy men (64 European, 31 Pacific Island, 19 Asian Indian) aged 17–30 years underwent measurements of height, weight, and body composition by total body dual-energy X-ray absorptiometry (DXA). Body mass index (BMI) was then calculated. Percent body fat (%BF), fat-free mass, bone mineral content, bone mineral density, abdominal fat, thigh fat, and appendicular skeletal muscle mass (ASMM) were obtained from the DXA scans.
Results: For the same BMI, %BF for Pacific Island men was 4% points lower and for Asian Indian men was 7–8% points higher compared to Europeans. Compared to European men for the same %BF, BMI was 2–3 units higher for Pacific Island, and 3–6 units lower for Asian Indian. The ratio of abdominal fat to thigh fat, adjusted for height, weight, and %BF, was significantly higher for Asian Indian men than European (p=0.022) and Pacific Island (p=0.002) men. ASMM, adjusted for height and weight, was highest in Pacific Island and lowest in Asian Indian men.
Conclusions: The relationship between %BF and BMI is different for European, Pacific Island, and Asian Indian men which may, at least in part, be due to differences in muscularity. Asian Indians have more abdominal fat deposition than their European and Pacific Island counterparts. Use of universal BMI cut-off points are not appropriate for comparison of obesity prevalence between these ethnic groups.
Abstract: There is a rapidly rising epidemic of Type 2 diabetes throughout the world. It is particularly severe in developing countries. In 1995, 62% of people with diabetes in the world lived in developing countries. By 2025 this is predicted to rise to more than 75%. In India there are an estimated 25 million people with diabetes, and this will rise to more than 60 million by 2025. One in five people with diabetes in the world will then be Indian. A parallel rise in ischaemic heart disease (IHD) is also projected. Other developing countries will be similarly affected. The picture is more complicated than a simple relationship between small size at birth and later diabetes. Indian babies are fat even though they are thin. Preventative measures are likely to succeed at different stages in life. In summary, aberrations of intra-uterine as well as post-natal growth increase the risk of diabetes. Increasing adiposity is an important component of these aberrations. Nutritional and metabolic factors in mothers and the baby's genes are also involved. Diabetes prevention will have to start in early life (in utero) and continue in later years.
A system modeling approach for the prevention and treatment of diabetic retinopathy
Author Name: Chittaranjan Yajnik , Publication Year: 2003 , Journal Name: European Journal of Operations Research
Abstract: Diabetic patients may suffer from a number of long-term complications. One such complication is the onset of diabetic retinopathy, which damages the eyes adn can lead to blindness. We describe the use of a systems modelling approach for the progression of diabetic retinopathy that has been used for cost-effectiveness evaluations of various prevention and patient care options. The adopted framework incorporates retinopathy risk groupings, created using classification and regression tree (CART) analysis, which are then fed into a developed simulation model, at the level of individual diabetic patients. A multidisciplinary task group, comprising of clinicians and health care modellers, guided the necessary modular development involving the definition and treatment. Data has been taken from a prospective Wellcom Diabetes Study at the Diabetes Unit, King Edward Memorial Hospital, Pune, India. India has the highest number of diabetic patients in any one country, approximately 25 million in 2000, and this number is predicted to rise to 57 million by the year 2025.
Abstract: One of the key concepts underlying discussions of the pathogenesis of Type 2 diabetes is that of the ‘thrifty’ organism, whether speaking of its genes or its phenotypes. But what’s the evidence for thrift? To block one diversion, we are considering ‘usual’ Type 2 diabetes in which patients are obese or over-weight at diagnosis or at least, if diagnosed very late, have been so previously. A different explanation of the basic postulated ability to maintain weight in the face of famine would be success in obtaining resources when they’re scarce. Many characteristics could underlie this but, given the importance of ‘motivation’ or ‘drive’, increased hunger could be an important component. Not surprisingly for biology, what is under consideration is (i) an organism adapting to be ‘effective’ in a given environment, which it ‘anticipates’ living in because of certain early signals; and whether or not the ‘effectiveness’ is a consequence of an up-regulation of a metabolic pathway, hunger sensations, hunting skills or whatever, and (ii) what happens when that environment changes from what is ‘anticipated’, which is one time when the struggle accelerates.
Neonatal anthropometry The thin-fat Indian baby, The Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2003 , Journal Name: International Journal of Obesity and Related Metabolic Disorders
Abstract: The objective was to examine body size and fat measurements of babies born in rural India and compare them with white Caucasian babies born in an industrialised country. The design was community-based observational study in rural India, and comparison with data from an earlier study in the UK, measured using similar methods. The subjects were a total of 631 term babies born in six rural villages, near the city of Pune, Maharashtra, India, and 338 term babies born in the Princess Anne Hospital, Southampton, UK. Measurements taken were maternal weight and height, and neonatal weight, length, head, mid-upper-arm and abdominal circumferences, subscapular and triceps skinfold thicknesses, and placental weight. Small Indian babies have small abdominal viscera and low muscle mass, but preserve body fat during their intrauterine development. This body composition may persist post-natally and predispose to an insulin-resistant state.
Abstract: Nutritional and genetic factors interact in the etiology of type 2 diabetes. Undernutrition followed by overnutrition increases adiposity and the risk of diabetes. The thrifty hypotheses suggest that the nutritional challenges could have happened thousands of year ago (thrifty gene selection) or during one’s intrauterine life (thrifty phenotype). Current strategies for the prevention of diabetes are related to avoiding overnutrition.
Maternal activity in relation to birth size in rural India. The Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2003 , Journal Name: European Journal of Clinical Nutrition-Nature
Abstract: The objective was to describe the relationship of the mother’s physical activity to the birth size of her baby in a rural Indian population. The Design was a Prospective observational study. Setting was six villages near Pune, Maharashtra, India. Subjects: A total of 797 women were studied after excluding abortions and termination of pregnancies (112), foetal anomalies (8), multiple pregnancies (3), incomplete pre-pregnancy anthropometry (14) and pregnancies detected later than 21 weeks of gestation (168). The activity questionnaire was used to classify women into light, moderate and heavy activity categories. Maternal activity did not influence the incidence of prematurity or stillbirth, or the duration of gestation. It was inversely related to maternal weight gain up to 28 weeks of gestation (P ¼0.002). Higher maternal activity in early, as well as mid gestation, was associated with lower mean birth weight (P ¼0.05 and 0.02, respectively ), and smaller neonatal head circumference (P ¼0.005 and 0.009) and mid-arm circumference (P ¼0.03 and 0.01) after adjusting for the effect of major confounding factors. Conclusions: The Findings suggest that excessive maternal activity during pregnancy is associated with smaller foetal size in rural India, The approach described for developing an activity questionnaire has potential for adoption in other settings. Sponsorship: Wellcome Trust, London, UK, and the Medical Research Council, UK.
Abstract: Fetal undernutrition affects large numbers of infants in developing countries, with adverse consequences for their immediate survival and lifelong health. It manifests as intrauterine growth retardation (IUGR), defined as birth weight ,10th percentile, which probably underestimates the number failing to achieve full growth potential. Birth weight is a crude measure of the dynamic process of fetal growth and does not capture effects of fetal undernutrition on body composition and the development of specific tissues. The link between maternal nutrition and fetal nutrition is indirect. The fetus is nourished by a complex supply line that includes the mother’s diet and absorption, endocrine status and metabolism, cardiovascular adaptations to pregnancy and placental function. Micronutrients are essential for growth, and maternal micronutrient deficiency, frequently multiple in developing countries, may be an important cause of IUGR. Supplementation of undernourished mothers with micronutrients has several benefits but there is little hard evidence of improved fetal growth. However, this has been inadequately tested. Most trials have only used single micronutrients and many were inconclusive because of methodological problems. Several food-based studies (some uncontrolled) suggest benefits from improving maternal dietary quality with micronutrient-dense foods. One trial of a multivitamin supplement (HIV-positive mothers, Tanzania) showed increased birth weight and fewer fetal deaths. Well-conducted randomized controlled trials of adequate sample size and including measures of effectiveness are needed in populations at high risk of micronutrient deficiency and IUGR and should include food-based interventions and better measurements of fetal growth, maternal metabolism, and long-term outcomes in the offspring.
Abstract: We followed 191 normal glucose tolerant (NGT; 1985 World Health Organization criteria) non-diabetic subjects (115 men) as control subjects in the Wellcome Diabetes Study. Their mean age was 41 years (SD 11.2), BMI 23.6 kg/m2 (34%25 kg/m2), and 31% had a first-degree relative with diabetes. These results, from a first prospective study of such duration among Indians in India, confirm studies from elsewhere in associating deterioration of glucose tolerance in the NGT with obesity, weight gain, insulin resistance, higher circulating triglycerides, and 2-h glucose concentrations. Therefore, among Indians reduction in adiposity must be a prime target for diabetes prevention. This will have to start at levels that are accepted in the west without demur. This is necessary at all ages, but will be made difficult by our recent observation that central obesity and hyperinsulinemia are present in Indians at birth.
Abstract: In Europid populations, low birth weight of offspring predicts insulin resistance in the mother and cardiovascular disease in both parents. We investigated the association between birth weight of offspring and obesity and cardiovascular risk in the parents of 477 8-year-old children born at the King Edward Memorial Hospital, Pune, India. Eight years after the birth of the child, mothers (33 years of age, n 459) of heavier babies were taller and more obese (BMI, fat mass, and waist circumference, all P < 0.001) than mothers of lighter babies. Increasing offspring birth weight predicted higher homeostasis model assessment for insulin resistance (P < 0.01) and metabolic syndrome in mothers (P < 0.001) (adjusted for offspring sex and birth order, maternal age, and socioeconomic status) but not hyperglycemia. Fathers (39 years of age, n 398) of heavier babies were taller and heavier, independent of maternal size (P < 0.01, both), but were not more insulin resistant. Unlike other reports, lower offspring birth weight did not predict insulin resistance in fathers. Thus, urban Indian parents have a higher risk of being obese 8 years after delivery of a heavier child. Mothers but not fathers of heavier babies also have a higher risk of being insulin resistant and developing the metabolic syndrome. Our findings highlight the need for a better understanding of the relation between fetal growth and future health before contemplating public health interventions to improve fetal growth.
Comparison of three methods of body fat measurement in Indian men
Author Name: Chittaranjan Yajnik , Publication Year: 2002 , Journal Name: Not known
Abstract: Under the framework of this collaboration, we used stable isotope dilution technique as a reference to calibrate population specific Bio-electrical impedance equation to calculate total body water for Indians, since they differ in body composition from Western population. The methods were performed according to set guidelines and all precautions were taken to minimise the errors and bias during the test. The range of values of TBW determined by prediction equations may yield erroneous results. Thus, prediction formulas for body composition estimates should be chosen from properly sampled population based study for a given sex and age and the guidelines should be followed with great care. We propose our new prediction equation for BIA will help to estimate body composition more precisely than the western equations.
Abstract: Dr Murphy and his colleagues raise interesting potential methodological points about our observation of a positive relation between paternal insulin resistance and fetal birth weight in a rural Indian population. They have suggested that the relation between paternal BMI, insulin resistance and fetal birth weight is confounded by socio-economic status (SES) rather than having a genetic basis. We present the figure with confidence intervals for birth weight. The purpose of our letter was to show that an inverse relationship between paternal insulin resistance and fetal birth weight as predicted in the fetal insulin hypothesis was absent in our study. In fact, the relationship was direct. We suggested that this relationship could operate through paternal size which has been reported before [7] and probably has a genetic basis. This view is strengthened by the above analysis of SES. Further investigation of this relationship will depend on study of
appropriate molecular genetic markers.
Abstract: This study was undertaken to review the links between maternal nutrition, offspring’s birth weight and the propensity to early insulin resistance and high diabetes rates in Indian adults. Studies included a comparison of maternal size and nutrition with birth weights in Pune, India, and Southampton, UK. In Pune, the growth, insulin resistance and blood pressure of four-year-old children were assessed. Adults >40 years of age, who were resident in rural areas, were compared with adults living in urban areas for size, glucose handling, lipid status and blood pressure. Maternal intake of green vegetables, fruit and milk, and their circulating folate and vitamin C levels, predicted larger fetal size. Rapid childhood growth promoted insulin resistance and higher blood pressure. Type 2 diabetes was common in urban adults younger than 35 years of age. Hence, there is evidence of a remarkably powerful, inter-generational effect on body size and total and central adiposity. Indians are highly susceptible to insulin resistance and cardiovascular risks, with babies being born small but relatively fat. Insulin resistance is amplified by rapid childhood growth. Dietary factors seem to have profound long-term metabolic influences in pregnancy. Overcrowding with infections and central obesity may amplify cytokineinduced insulin resistance and early diabetes in Indian adults with a low BMI.
Abstract: Economic development in developing societies characterized by industrialization, urbanization, and globalization has seen the emergence of an epidemic of diet-and-lifestyle-related chronic degenerative diseases. A research project was initiated under the aegis of the International Atomic Energy (IAEA), Vienna, Austria under its Coordinated Research Programme(CRP) to promote the use of stable isotopic techniques to document the extent of the problem and to understand the determinants of this epidemic. These comparative international studies of obesity and NIDDM are looking at the effects of childhood malnutrition (Brazil) and socioeconomic differentials (Mexico) on adult risk factors; the composition of the daily diet on obesity (Chile); levels of patterns of physical activity of older adults (China) as well as their influence on weight gain and obesity (Cuba, Nigeria); the impact of body composition and energy expenditure on the evolution frank diabetes from impaired glucose tolerance (Jamaica), and of body compositional changes and the role of inflammatory cytokines on impaired glucose tolerance (India). The last study conducted in New Zealand was aimed at comparing the energy expenditures of Maori (Pacific Island) with New Zealanders of European descent.
Abstract: We studied cardiovascular risk factors in 149 rural, 142 slum dwellers, and 150 urban middle class Indian men in relation to their body fat. All cardiovascular risk factors were strongly related to the percentage of body fat and waist to hip ratio. Two hour plasma glucose concentration and blood pressure were, in addition, independently related to geographical location (urban middle class were higher than slums who were higher than rural men). Our results suggest that urbanisation increases the risk of hyperglycemia and hypertension independent of the percentage of body fat or its central distribution.
Abstract: We studied body size and cord blood leptin and insulin concentrations in newborn urban Indian (Pune, India) and white Caucasian (London, UK) babies to test the hypothesis that the adiposity and hyperinsulinemia of Indians are present at birth. Indian babies were lighter in weight compared with white Caucasian babies and had smaller abdominal mid-arm, and head circumferences. However, their skinfold was better preserved than triceps skinfold. Cord plasma leptin and insulin concentrations were comparable in the two populations but were higher in Indians when adjusted for birth weight, confirming relative adiposity and hyperinsulinemia of Indian babies. Indian mothers were smaller in all respects, compared with white Caucasian mothers, except subscapular skinfold, which was similar in the two populations. Our results support the intrauterine origin of adiposity, central adiposity, and hyperinsulinemia in Indians. Further research should concentrate on elucidating genetic and environmental influences on fetal growth and body composition. Prevention of insulin resistance syndrome in Indians will need to address regulation of fetal growth in addition to prevention of obesity in later life.
Abstract: In India, there is a rapidly escalating epidemic of insulin resistance syndrome (diabetes and coronary heart disease). Contribution of genes and environment is under debate. Small size at birth coupled with subsequent obesity increases risk for insulin resistance syndrome in later life. The tendency of Indians to have higher body fat and central adiposity compared with other races may be programmed in-utero. The adipose tissue releases not only fatty acids but also a number of pro-inflammatory cytokines, which increase insulin resistance and cause endothelial dysfunction. Crowding, infections, and environmental pollution in Indian cities may increase cardiovascular risk by stimulating fat cells. Prevention of diabetes and coronary heart disease in India will have to be approached throughout the life cycle.
Author Name: Chittaranjan Yajnik , Publication Year: 2001 , Journal Name: international journal diabetes developing countries
Abstract: The ‘fetal origins’ hypothesis would predict that the rising epidemic of diabetes and CHD in India would be due to poor intrauterine growth of the India babies. While this explanation may be valid to an extent, the higher prevalence of these disorders in urban compared with rural India (where birth weights are lower) would suggest a significant role for postnatal factors. In a cohort of 477 children
born in the King Edward Memorial Hospital, Pune, we found that at eight years of age, current obesity strongly predicted insulin resistance. When this effect was allowed for, low birth weight was significantly associated with insulin-resistance variables and other cardiovascular risk factors. The thinness of the Indian
babies is due to poor muscle and small abdominal viscera. We have proposed this composition as the ‘thrifty phenotype’ of Indian babies. Maternal size and intake of certain food groups during pregnancy were important determinants of the baby’s phenotype. Thus, the small Indian babies are programmed to deposit fat from their intrauterine life. Exaggeration of this tendency in later life is associated with Insulin resistance syndrome. Control of the insulin-resistance epidemic in India might depend on improved intrauterine development and prevention of childhood obesity.
Commentary Fetal origins of cardiovascular risk-nutritional and non-nutritional
Author Name: Chittaranjan Yajnik , Publication Year: 2001 , Journal Name: International Epidemiological Association
Abstract: A paper in this issue of the IJE adds to the already long list of papers which show an association between small size at birth and cardiovascular risk in later life. Barker's idea of the ‘fetal origins’ has survived and strengthened through the last decade, albeit undergoing a degree of metamorphosis to include contributions from childhood growth. The multicentre study confirms the relationship of small size at birth with blood pressure in young children from three developing countries (China, Guatemala and Chile). Thus, any disturbance of growth in utero: either throughout gestation (children from developing countries) or in the later stages (Sweden), occurring in malnourished as well as well nourished mothers, is associated with elevated blood pressure in later life. Aetiological factors in these different situations are likely to be different. We need to know more about gene-environment interaction (nutritional and non-nutritional) during the intrauterine period which may hold important answers to this novel mechanism of disease. Only then may we think about public health interventions for primordial prevention.
Intake of micronutrient-rich foods in rural Indian mothers is associated with the size of their babies at birth Pune Maternal Nutrition Study
Author Name: Chittaranjan Yajnik , Publication Year: 2001 , Journal Name: American Society for Nutritional Sciences.
Abstract: One third of the Indian babies are of low birth weight (,2.5 kg), and this is attributed to maternal undernutrition. We therefore examined the relationship between maternal nutrition and birth size in a prospective study of 797 rural Indian women, focusing on macronutrient intakes, dietary quality and micronutrient status. Maternal intakes (24-h recall and food frequency questionnaire) and erythrocyte folate, serum ferritin and vitamin C concentrations were measured at 18 6 2 and 28 6 2 wk gestation. birth size was strongly associated with the consumption of milk at wk 18 (P , 0.05) and of green leafy vegetables (P , 0.001) and fruits (P , 0.01) at wk 28 of gestation even after adjustment for potentially confounding variables. Erythrocyte folate at 28 wk gestation was positively associated with birth weight (P , 0.001). The lack of association between size at birth and maternal energy and protein intake but strong associations with folate status and with intakes of foods rich in micronutrients suggest that micronutrients may be important limiting factors for fetal growth in this undernourished community.
Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians
Author Name: Chittaranjan Yajnik , Publication Year: 2001 , Journal Name: American Society for Clinical Nutrition
Abstract: In India, most people adhere to a vegetarian diet, which may lead to cobalamin deficiency. The objective was to examine indicators of cobalamin status in Asian Indians. About 75% of the subjects had metabolic signs of cobalamin deficiency, which was only partly explained by the vegetarian diet. If impaired cobalamin status is confirmed in other parts of India, it may have important health implications.
Abstract: There has been no reported national survey of diabetes in India in the last three decades, although several regional studies show a rising prevalence of diabetes. The aim of this study was to assess the prevalence of diabetes and impaired glucose tolerance in six major cities, covering all the regions of the country. Age standardised prevalences of diabetes and impaired glucose tolerance were 12.1% and 14.0% respectively, with no gender difference. Diabetes and impaired glucose tolerance showed increasing trend with age. Subjects under 40 years of age had a higher prevalence of impaired glucose tolerance than diabetes. Diabetes showed a positive and independent association with age, BMI, WHR, family history of diabetes, monthly income and sedentary physical activity. Age, BMI and family history of diabetes showed associations with impaired glucose tolerance. This national study shows that the prevalence of diabetes is high in urban India. There is a large pool of subjects with impaired glucose tolerance at a high risk of conversion to diabetes.
Abstract: Hattersley and Tooke proposed a genetic explanation, "the fetal insulin hypothesis" for the relationship between poor intrauterine growth and increased risk of diabetes and cardiovascular disease. They suggest that this relationship could be due to a common genetic antecedent rather than intrauterine malnutrition (fetal origins). The genetic mechanisms which regulate insulin secretion and/or insulin action can influence fetal growth because insulin is a growth factor during in-utero life. The hypothesis predicts that a child's birth weight and the more specific measures of insulin-mediated growth would show an inverse correlation with paternal insulin resistance. A study in Pima Indians demonstrated that the children born to diabetic fathers had low birth weight after the influence of maternal gestational diabetes was removed. We tested the paternal prediction of the 'fetal insulin hypothesis' in data from the Pune Maternal Nutrition Study, a study of fetal growth in rural India. In our study, both maternal and paternal size, glycaemia and insulin resistance were directly related to baby's birth weight and to mid-upper arm circumference. Maternal influence on fetal growth can be genetic and/or through the intra-uterine environment. Paternal influence will operate through genetic mechanisms provided the effect of 'assortative mating' is ruled out. Our results suggest that both maternal and paternal size and metabolic factors predict fetal size. Insulin resistance could be an important mechanism influencing fetal growth. This observation could have important implications for future research in 'fetal origins' and the possible interventions for future research in 'fetal origins' and the possible interventions to influence fetal growth.
Abstract: We have demonstrated earlier that a low-protein (8% protein) diet during gestation alters fetal -cell development. Here, we investigated the effect of a low-protein diet as compared with a control (20% protein) diet, during gestation, on the sensitivity of fetal -cells against nitric oxide (NO) or interleukin-1 (IL-1), and assessed the protective effect of taurine in vitro and in vivo. Taurine supplementation of the maternal diet reduced the rate of apoptosis induced by IL-1 in control islets and suppressed that induced by IL-1 in LP islets. Our findings indicate that a low-protein diet during gestation augments the sensitivity of fetal islet cells to NO and IL-1. However, through in vitro and in vivo experiments our studies indicate that such effects can be rescued using amino acids such as taurine.
Low BMI Predicts Mortality in Indian Patients with Fibrocalculous Pancreatic Diabetes (FCPD)
Author Name: Chittaranjan Yajnik , Publication Year: 2000 , Journal Name: international journal diabetes developing countries
Abstract: We followed 77 consecutive FCPD patients (49 men, 28 women) during the period 1984 to 1997 who were referred to us at the King Edward Memorial (K.E.M.) Hospital, a medium-sized referral hospital in Pune, Maharashtra, India. Kaplan Meier survival curve revealed that survival was significantly lower in rural compared to urban patients. Multiple logistic regression analysis showed that mortality was predicted by lower BMI (p = 0.00035) and higher age (p = 0.056) while the place of residence did not relate significantly. It is possible that poor nutrition related to the pancreatic disorder as well as socioeconomic status is
responsible for the high mortality in these FCPD patients.
Abstract: We followed 321 villagers >40 years of age in a village near Pune after
5 years of baseline study. This is one of the few reports of a prospective risk evaluation in rural Indian subjects. Our results suggest that individuals who had poor growth in early life (smaller height and head circumference) but had a positive energy balance in later life (larger waist circumference) are at a higher risk of dying than their counterparts. The risk could be mediated by heightened sympathetic activity and insulin resistance. Microalbuminuria was a significant predictor of death.
Abstract: We sought to study mid-pregnancy placental volume in rural Indian women, its maternal determinants, and its relationship to neonatal size. The mothers were short and underweight (mean height, 1.52 m; weight, 42 kg; body mass index,
18 kg/m2) and produced small babies (mean birth weight, 2648 g). Mid-pregnancy placental volume (median, 144 mL) was related to the mother’s pre-pregnancy weight (r = 0.15; P < .001) but not to weight gain during pregnancy, blood pressure, or circulating hemoglobin, ferritin, red blood cell folate, or glucose concentrations. Mid-pregnancy placental volume was related to placental weight at birth (r = 0.29; P < .001) and birth weight (r = 0.25; P < .001) independent of maternal size. In Indian mothers mid-pregnancy placental volume is significantly associated with pre-pregnant maternal weight and is an independent predictor of birth weight. Our findings may provide clues to the high prevalence of low-birth-weight infants in India.
Interactions of perturbations in intrauterine growth and growth during childhood on the risk of adult-onset disease
Author Name: Chittaranjan Yajnik , Publication Year: 2000 , Journal Name: Proceedings of the Nutrition Society
Abstract: The ‘fetal origins’ hypothesis (Barker, 1995) would predict that the rising epidemic of diabetes and CHD in India would be due to poor intrauterine growth of the Indian babies. While this explanation may be valid to an extent, the higher prevalence of these disorders in urban compared with rural India (where birth weights are lower) would suggest a significant role for postnatal factors. In a cohort of 477 children born in the King Edward Memorial Hospital, Pune, we found that at 8 years of age current obesity strongly predicted insulin resistance. When this effect was allowed for, low birth weight was significantly associated with insulin-resistance variables and other cardiovascular risk factors. Children who were born small but had grown heavy (or tall) were the most insulin resistant and had the highest levels of cardiovascular risk factors. Accelerated growth in relation to mid parental height was similarly predictive. Poor intrauterine growth also predicted higher central adiposity at 8 years of age. We have also studied maternal nutrition and fetal growth in six villages near Pune. The thinness of the Indian babies is due to poor muscle and small abdominal viscera. We have proposed this composition as the ‘thrifty phenotype’ (Hales & Barker, 1992) of Indian babies. Maternal size and intake of certain food groups during pregnancy were important determinants of the baby’s phenotype. Thus, the small Indian babies are programmed to deposit fat from their intrauterine life. Exaggeration of this tendency in later life is associated with insulin resistance syndrome. Control of the insulin-resistance epidemic in India might depend on improved intrauterine development and prevention of childhood obesity.
Abstract: Mitochondrial mutation is associated with maternally inherited diabetes and deafness, MIDD. Recently, a mitochondrial polymorphism has been associated with intrauterine growth retardation and adult insulin resistance. We report a pedigree of MIDD family which demonstrates that bad obstetric history and reduced postnatal growth are its additional features. Identical phenotype in diabetic and non-diabetic members suggests that the phenotype is determined by the mt3243 mutation rather than the diabetic state. Thus, this is a clear example of a genetic predisposition altering growth as well as predisposing to diabetes and suggests that mitochondrial function may play a critical role in intra-uterine and post natal growth. This finding may have important implication for the 'thrifty phenotype/genotype' hypotheses.
Abstract: This chapter describes the findings of a community-based study of 633 women living in six rural villages near the city of Pune, Maharashtra, India, whose anthropometry was measured before and during pregnancy and whose babies were measured in detail at birth. The mothers were short and thin and their babies were under-weight. Compared with babies born in Southampton, UK, the Indian babies were small in all dimensions, but there was a pattern in their smallness. They showed a marked deficit in non-fat soft tissues, while subcutaneous fat was relatively spared. Maternal height predicted neonatal skinfold thicknesses, an effect which was strongest in mothers of short stature; the fattest babies were born to short, fat mothers. Maternal head circumference correlated with all neonatal measurements. The findings suggest that optimal fetal growth requires that mothers be well-nourished in good head and height growth. The propensity of Indian babies to lay down fat at the cost of muscle and abdominal tissues may underlie adult insulin resistance, diabetes and coronary heart disease and may be exacerbated by obesity in short mothers. There may be disadvantages to the long-term health of the fetus in increasing the body fat of mothers whose growth was stunted in early life.
Abstract: Presentation of abstracts at scientific meetings is a valid and popular way to disseminate research findings. However, the ultimate way to have research methodology and results validated is publication in a peer-reviewed journal. No information is available in the diabetes literature regarding the ultimate fate of abstracts presented at national meetings. The aim of this study was to determine the publication rates of abstracts presented at diabetes meetings.
Abstract: We have studied 477 8-year-old Indian children to define the relationship between birth weight and cardiovascular risk factors, including insulin resistance syndrome (IRS) variables and plasma total and LDL cholesterol concentrations. All risk factors were strongly related to current weight. The highest levels of IRS variables and total and LDL cholesterol were in children of low birth weight but high fat mass at 8 years. Taller height at 8 years predicted higher fasting plasma insulin concentrations, insulin resistance, and plasma total and LDL cholesterol concentrations. The most insulin-resistant children were those who had short parents but had themselves grown tall. Although the implications of our findings in relation to height are unclear, interventions to improve fatal growth and to control obesity in childhood are likely to be important factors in the prevention of cardiovascular disease and IRS in India.
Foetal solutions to a fatal epidemic the relevance in India
Author Name: Chittaranjan Yajnik , Publication Year: 1998 , Journal Name: The national medical journal of india
Abstract: David Barker's suggestion that the seeds of adult diabetes and cardiovascular disease (CHD) are sown during 'lean periods' in foetal life is a novel thought in cardiovascular medicine. The increased risk of diabetes and CHD in small babies has been confirmed in different populations of the world. Unlike the thrifty genes which were thought to have evolved over thousands of years, the 'foetal origins' owe to disturbances in the few days of gestation. Risk of maternal gestational hyperglycaemia for future diabetes and obesity in the offspring was demonstrated previously but its application to the general population was not appreciated. Maternal nutrition in India is amongst the poorest in the world and Indian babies are amongst the smallest. An epidemic of type 2 diabetes and CHD has swept across India in the last few decades. India is an ideal ground to test the relevance of the 'foetal origins' of adult diabetes and CHD. If the 'thrifty phenotype' were to explain some of these peculiarities, it would have profound implications in the prevention of these disorders.
Abstract: Today an estimated 18-20 million people in India have diabetes. It is projected that by the year 2025 the number of people with diabetes in the world will double, rising from a figure of 120 million to 250 million. Of this figure, 75% will be from the developing countries and the largest number of people with diabetes in any single country will be India. The high susceptibility of Indians to Type 2 diabetes is largely unexplained and we remain mute spectators to the rapidly rising epidemic. Premature deaths due to undiagnosed diabetes and CHD are a major concern in India. Whichever ever way, the health of young women and mothers may well become important targets for prevention of diabetes and CHD in near future. Perhaps Mahatma Gandhi's vision of a self-sufficient rural India supported by the 'spinning wheel' would appear more appropriate than the 'automobile' (not to mention 'atomic') model of development borrowed from the West.
Abstract: A majority of patients with fibrocalculous pancreatic diabetes (FCPD) do not become ketotic even in adverse conditions. It is not clear whether this ketosis resistance is due to reduced fatty acid release from adipose tissue or to impaired hepatic ketogenesis. We tested hepatic ketogenesis in FCPD patients using a ketogenic challenge of oral medium-chain triglycerides (MCTs) and compared it with that in matched insulin-dependent diabetes mellitus (IDDM) patients and healthy controls. It is concluded that the failure to stimulate ketogenesis under these conditions could be partly due to inhibition of a step beyond fatty acid entry into the mitochondria.
Abstract: Circulating concentrations of total cholesterol, triglycerides, non-esterified fatty acids (NEFA), glycerol, and 3-hydroxybutyrate (3-HB) were measured in 133 subjects with normal glucose tolerance (NGT), 78 with impaired-glucose-tolerance (IGT) and 189 non-insulin dependent (Type2) diabetic (NIDDM) patients. Plasma cholesterol concentrationin these subjects is lower than that reported in white Caucasians in the UK and USA and migrant Indian NIDDM patients in the UK. In NIDDM patients plasma cholesterol concentration was related to age, body mass index (BMI), and plasma glucose concentration while plasma triglyceride concentration was related to plasma NEFA and insulin (IRI) concentration. Evidence of ischaemia on electrocardiography in patients with diabetes was associated with higher age, blood pressure, plasma triglyceride, glucose, and IRI concentrations.
Author Name: Chittaranjan Yajnik , Publication Year: 1996 , Journal Name: international journal diabetes developing countries
Abstract: Classification of subjects into different categories of glucose tolerance has clinical significance. The present WHO classification into normal, impaired glucose tolerant and diabetic is based on epidemiological studies relating the outcome (morbidity and mortality) to plasma glucose levels, supported by the bimodal distribution of plasma glucose levels in populations with very high prevalence of diabetes. Expectedly, the twilight zone of IGT has generated much debate and arguments. Diabetes in the developing countries has different aspects than those described in the developed countries. Many developing countries show a high prevalence of IGT and it is thought that this represents a stage in the evolution of metabolic and vascular morbidity in these populations. There have been a few reports of IGT, especially long term follow-up studies in the Indian literature. In this paper, we describe the clinical features, biochemical and endocrine characteristics and follow-up of glucose tolerance over 5-years in subjects with IGT.
Abstract: The International Workshop on types of Diabetes Peculiar to the Tropics was held in Cuttack, India, 17-19 October 1995. The workshop was attended by 60 delegates, most from four developing countries (India, Bangladesh, China, and Ethiopia), with observers from Europe and the u.s. It is now well recognized that diabetes in tropical regions and in some developing countries presents clinically differently from IDDM and NIDDM in the Western world and developed countries. The World Health Organization (WHO) acknowledged this in 1985 by recognizing a third class of diabetes; designated malnutrition-related diabetes mellitus (MRDM) and subdivided into fibrocalculous pancreatic diabetes (FCPD) and protein- deficient pancreatic diabetes (PDPD) (subsequently often called protein deficient diabetes mellitus (PDDM)). Since then, information has been collected about diabetes in tropical regions. Such knowledge was presented and discussed at the workshop to serve as a stimulus to the further research that is necessary into the etiologic, epidemiological, and clinical aspects of this class of diabetes.
Complications in Fibro-calculus pancreatic diabetes- The Pune and Madras experience
Author Name: K. M. Shelgikar, C.S. Yajnik, V. Mohan , Publication Year: 1995 , Journal Name: International of Journal Diabetes in Developing Countries
Abstract: Fibro-calculous pancreatic diabetes (FCPD) is a type of diabetes secondary to tropical calcific pancreatitis. Although described originally by Zuidema in 1959 it has received its due attention
only since its recognition as a specific subclass of 'malnutrition related diabetes' (MRDM) by WHO in 1985. FCPD represents a relatively small proportion of diabetes in tropical countries. This article describes the epidemiology and clinical
spectrum of such complications, their pathogenesis,
diagnosis, treatment and prevention. The information is based on data obtained from two clinics in India (K.E.M. Hospital Research Centre, Pune and M.V. Diabetes Specialities Centre, Madras). The number of FCPD patients studied and followed up so far at Pune is 65 and that in Madras is 393. community based epidemiological data is not available.
Abstract: Studies in Britain 'have shown that adults who had a low birth~eight have high plasma glucose concentrations 30 and 120 min after an oral glucose load, and an increased risk of Type 2 diabetes and impaired glucose tolerance. Both Type 2 diabetes and low birthweight are common in India. To determine whether low birthweight is associated with reduced glucose tolerance in Indian children. glucose tolerance tests were carried out on 379 4-year-old children, whose birthweights were recorded. in Pune, India. Among 201 children who had been looked after on the routine postnatal wards at birth, those with lower birthweights had higher plasma glucose and insulin concentrations 30 min after an oral glucose load, independently of their current size (p =0.01 and 0.04, respectively). Mean glucose and insulin concentrations were 8.1 mmol l-I and 321 pmol l-' in children whose birthweight had been 2.4 kg or less, compared with 7.5 mmol l-' and 289 pmol l-' in those who weighed more than 3.0 kg. Among 178 children who had been looked' after in the Special Care Baby Unit, those with lower birthweights also had higher plasma insulin concentrations at 30 min but there were no trends with plasma glucose. Our findings suggest that Indian children with reduced intra-uterine growth have reduced glucose. homeostasis after a glucose challenge. This is consistent with the hypothesis that Type 2 diabetes mellitus in India'may be programmed in fetal life.
Pancreatic pathology in non-insulin dependent diabetes (NIDDM)
Author Name: A Clark, EJ de Koning, AT Hattersley, BC Hansen, CS Yajnik, J Poulton , Publication Year: 1995 , Journal Name: Diabetes Res Clin Pract
Abstract: NIDDM is a heterogeneous disease and subgroups of NIDDM include MODY (Maturity Onset Diabetes of the Young), Malnutrition-related diabetes (MRDM) and Fibrocalculus pancreatic diabetes (FCPD). Endocrine cell population is relatively unchanged in NIDDM. Islet amyloid is found in 96%of subjects occupying up to 80% of the islet associated with a reduction in B-cells. Amyloid formation is unlikely to cause diabetes but progressive accumulation increases the severity of the disease. Diabetes and mutations of mitochondrial DNA is associated with poorly developed islet structure. Exocrine pancreatic size is reduced and there is evidence of sub-clinical chronic pancreatitis in NIDDM. In MRDM and FCPD, chronic pancreatitis and exocrine necrosis is associated with reduced insulin secrestion. Unlike cystic fibrosis where islet amyloid is present in diabetic individuals, amyloid is absent from subjects with FCPD. Pathological changes in the exocrine and endocrine pancreas in NIDDM results from and contributes to the pathophysiology of insulin secretion in NIDDM.
Abstract: Children of lower birth weight develop higher circulating concentrations of IGF-1 than expected for their height and weight. This is consistent with the hypothesis that undernutrition
in utero leads to reprogramming of the IGF-1 axis. The increase of plasma IGF-1 concentrations in low birthweight children may also be linked to postnatal catch-up growth. High IGF-1 concentrations may be one of the mechanisms linking reduced fetal growth and high blood pressure in later life.
Diabetes And Insulin Resistance Syndrome In Indians
Author Name: C.S.Yajnik , Publication Year: 1995 , Journal Name: Nutrition Foundation of India
Abstract: Diabetes is on the increase in
India' (Table 1). The oft-quoted multicentre
ICMR study (1972) showed a
prevalence of 2.5 per cent in the urban
and 1.8 per cent in the rural population
above the age of 15 years.
Most studies after 1986 have,
however, shown a much higher prevalence
of diabetes, especially in the
urban populations. While a part of the
reported rise in the prevalence of diabetes
could be due to the differences
in the methods used, there seems to
be a rapid rise in the true prevalence
of diabetes, especially in urban India.
Even in clinical practice the increasing
burden of diabetes is obvious.
The predominant type of diabetes
in India is the Type 2, non-insulin
dependent variety (NIDDM). Type 1,
insulin dependent (IDDM) is relatively
rare. An unusual variety was described
in the 1960s, now called the malnutrition
related diabetes (MRDM) by the
WH02. These patients present with
severe malnutrition at the time of diagnosis
(8MI <18kg/m2) and require
relatively large doses of insulin for
glycaemic control. An interesting characteristic
is the absence of ketosis
when insulin is stopped for long periods
of time. The aetiological role of
malnutrition, the time course of the
pathogenetic processes and the overlap
with other more common varieties
of diabetes (Type 1 and 2) are a matter
of much debate3,4. Population-based -studies have
not shown increased risk of diabetes
in malnourished subjects and there
are few prospective studies of diabetes
in subjects who suffered malnutrition
in childhood. Clearly, further studies
are needed in a country like India
where malnutrition and diabetes are
both commonly seen.
Abstract: High prevalence of type 2 diabetes and associated cardiovascular disease in India is a matter of concern. This high prevalence is seen in bot, the native residents of India and also in those who have migrated to the more affluent countries. It is generally believed that natural selection has allowed a 'thrifty genotype' to concentrate in the underprivileged population which helps survival in the famine conditions by promoting anabolism. When food is available in plenty, this genotype becomes detrimental, leading to obesity and diabetes. This hypothesis envisages a process of natural selection over millions of years with little possibility of changing in the near future. Though the argument is attractive, no genetic markers have yet been found. Thrifty genotype remains a working hypothesis. We have been involved in the study of the so called 'malnutrition related diabetes (MRDM)' for the last few years, objected to its present day definition, and commented on the lack of prospective data of the nutritional status of the so called MRDM patients. Prof. Barker's hypothesis offers a unique opportunity to test the interaction of early life nutrition with later development of diabetes and related disorders in Indian population whichhas a high prevalence of low birthweight, type 2 diabetes and coronary aretery disease. I present a preliminary analysis of our results in 4 year old Indian children in a prospective study of diabetes and cardiovascular risk factors in collaboration with Prof. Barker and his colleagues at the Environmental Epidemiology Unit of the Medical Research Council and the Department of Human Nutrition in Southhampton, U.K.
Abstract: Diabetes is called "primary" when no known etiological cause is found and "secondary" when hyperglycemia is thought to have developed in relation to a known etiological factor. Our knowledge of how and why diabetes occurs is still evolving and in practice a clear distinction between primary and secondary diabetes is not always possible. It is believed that timely diagnosis of "secondary" diabetes and successful treatment of the causative factor might "cure" diabetes. At present, the vast majority of diabetic patients are classified as primary. Even in these patients, a number of life-style factors are responsible for precipitating diabetes. Successful treatment of these factors improves glycemic control.
Abstract: The association of blood pressure with clinical and biochemical measures was studied in 185 newly diagnosed Type-2 diabetic patients, 74 impaired-glucose-tolerant (IGT), and 128 non-diabetic control subjects. Hyperglycemic subjects were older than control subjects. They were also more obese and with greater waist-hip ratio. Blood pressure was significantly higher in both IGT and diabetic patients compared to non-diabetic controls. Univariate analysis showed that in diabetic patients systolic blood pressure was related to age, BM, and plasma immunoreactive insulin, but not to C-peptide concentrations. Multivariate analysis revealed that systolic blood pressure in diabetic patients was related to BMI and fasting immunoreactive insulin, while diastolic blood pressure was related to BMI and waist-hip ratio. Thus, blood pressure is associated with plasma immunoreactive insulin concentrations. The mechanism of these associations remains to be established.
Author Name: C S Yajnik, K M Shelgikar , Publication Year: 1993 , Journal Name: Diabetes Care
Abstract: The objective was to study clinical features of fibrocalculous pancreatic diabetes from this clinic, to compare these with the published criteria of malnutrition-related diabetes mellitus, and to conduct serial follow-up of these patients to study difficulties in their treatment. Many patients did not fit the accepted criteria of malnutrition-related diabetes. The two pathognomonic complaints (pancreatic pain and steatorrhea) were not always present. Many patients took very irregular treatment, but none suffered diabetic tissue damage when first seen. Clinical features of these fibrocalculous pancreatic diabetes patients were somewhat different than the classic descriptions. A need exists to reconsider classification of FCPD under malnutrition-related diabetes mellitus. Many patients receive irregular treatment, and a substantial proportion die within a few years of diagnosis, many as a result of preventable causes.
Editorial. Diabetes Bulletin. International Journal of Diabetes in Developing Countries
Author Name: C.S. Yajnik , Publication Year: 1993 , Journal Name: international journal diabetes developing countries
Abstract: Diabetes and nutrition are inseparably linked. It is
usually accepted that overnutrition and obesity play
an important role in the pathogenesis of ‘type 2’
diabetes, especially in the developed world. It was
therefore, a surprise when workers in the developing
countries reported a ‘type’ of diabetes common
amongst the poor and the undernourished. In 1950’s
and 60’s Hugh Jones, Zuidema, Tripathy, Ahuja and
Geevarghese reported from different tropical
countries a number of severely malnourished young
patients with diabetes. These patients were severely
hyperglycaemic and needed insulin treatment,
sometimes in large doses. Surprisingly, they did not
develop ketosis when insulin treatment was stopped
for prolonged periods (because of socioeconomic
reasons). Some of these patients suffered from
chronic pancreatitis and pancreatic calculi could be
demonstrated on X-ray of the abdomen (tropical
pancreatic diabetes), in others there was no evidence
of exocrine pancreatic involvement (J – type). Since
severe malnutrition was the most striking clinical
feature of these patients it was suggested that
malnutrition was an aetiological factor, though there
was no proof of this. The temporal relationship
between nutritional deprivation and development of
diabetes was not known. The relationship, if any,
between the two major types described (‘J-type’ and
the ‘tropical pancreatic diabetes’) was also not clear.
‘Nutritional diabetes’ remained an intriguing clinical
syndrome.
Stronger representation from the developing countries
in the international organizations led to a broad
recognition that diabetes in the developing countries
(‘third world’) could have a different profile than that
in the developed world . It was suggested that
undernutrition must be an important factor in these
differences. The above mentioned two types of
diabetes (‘protein deficient pancreatic diabetes-
PDPD’ and ‘fibrocalculous pancreatic diabetes-
FCPD’) were clubbed under a new class of diabetes
called ‘malnutrition related diabetes (MRDM)’.
Geopolitical rather than scientific interests diverted
the attention from the basic and the more interesting
issues of aetiopathogenesis of diabetes in the
developing world to definition of a new syndrome.
Changing nutritional status in different populations
altered the clinical picture and over a period of time
fewer patients with classical description were seen.
Aetiological role of malnutrition in human diabetes
remained unproven for lack of good prospective
studies, the term MRDM reflected more an article of
faith.
The ketosis-resistance in fibro-calculous-pancreatic-diabetes
Author Name: C S Yajnik, K M Shelgikar, S S Naik, S V Kanitkar, H Orskov, K G Alberti, T D Hockaday , Publication Year: 1992 , Journal Name: Diabetes Res Clin Pract
Abstract: We measured circulating levels of C-peptide, pancreatic glucagon, cortisol, growth hormone and metabolites in fibro-calculous-pancreatic diabetic insulin-dependent diabetic and non-diabetic control subjects during an oral glucose tolerance test. There was no difference in the two diabetic groups in age, BMI, triceps skin-fold thickness, glycaemic status, fasting plasma C-peptide, peak plasma C-peptide during OGTT and fasting plasma glucagon. FCPD patients, however, showed lower circulating concentrations of non-esterified fatty acids and 3-hydroxybutyrate compared to IDDM patients. This could be due to enhanced sensitivity of adipose tissue lipolysis to the suppressive action of circulating insulin and possibly also to insensitivity of hepatic ketogenesis to glucagon. Our results also demonstrate preservation of α-cell function in FCPD patients when β-cell function is severely diminished, suggesting a more selective β-cell dysfunction or destruction than hitherto believed.
Urinary albumin excretion rate (AER) in newly-diagnosed type 2 Indian diabetic patients is associated with central obesity and hyperglycaemia
Author Name: Chittaranjan Yajnik , Publication Year: 1992 , Journal Name: Diabetes Research and Clinical Practice.
Abstract: Urinary albumin excretion rate (AER) was measured in non-diabetic controls and newly diagnosed impaired glucose tolerant and non-insulin-dependent (type 2) diabetic patients. AER progressively increased from non-diabetic and diabetic groups. Eight percent of non-diabetic, 19% of IGT and 23% of type 2 diabetic patients showed 'microalbuminuria'. AER was directly related to waist-hip ratio. Association of AER with waist-hip ratio was present in men as well as women. Thus, in the newly diagnosed type 2 Indian diabetic patients AER is associated with central obesity in addition to its well known association with hyperglycaemia. Our finding offer a possible explanation for the increased risk of proteinuria in diabetic men than in women because men are centrally more obese. It could also explain previous reports of higher AER in migrant Asian diabetic patients in the U.K. compared to native white Caucasian diabetic patients because Asians are known to be more centrally obese.
Abstract: Diabetes is on the increase in India' (Table 1). The oft-quoted multicentre ICMR study (1972) showed a prevalence of 2.5 per cent in the urban and 1.8 per cent in the rural population above the age of 15 years. Most studies after 1986 have, however, shown a much higher prevalence of diabetes, especially in the
urban populations. While a part of the reported rise in the prevalence of diabetes could be due to the differences in the methods used, there seems to be a rapid rise in the true prevalence of diabetes, especially in urban India. Even in clinical practice the increasing burden of diabetes is obvious. Population-based -studies have not shown increased risk of diabetes in malnourished subjects and there are few prospective studies of diabetes in subjects who suffered malnutrition in childhood. Clearly, further studies are needed in a country like India
where malnutrition and diabetes are both commonly seen. We have investigated different aspects of diabetes in patients attending our diabetic clinic. Our hospital caters to the middle and lower clases population and 25 per cent of the patients are treated free.
Abstract: Diabetes and nutrition are inseparably linked. It is usually accepted that over-nutrition and obesity play an important role in the pathogenesis of ‘type 2’ diabetes, especially in the developed world. It was therefore, a surprise when workers in the developing countries reported a ‘type’ of diabetes common amongst the poor and the undernourished. In recent years young workers in the developing countries have helped improve our understanding of the so called MRDM. Diabetes secondary to early life malnutrition and mal-development appears a real possibility. In this issue various authors contribute their views on different aspect of MRDM.
Diabetes in tropical developing countries (Part 1)
Author Name: C. S. Yajnik , Publication Year: 1990 , Journal Name: The Diabetes Annual -5
Abstract: Diabetes in tropical developing countries continues to attract epidemiologists, clinicians and basic scientists alike, because of the prospects it offers of not only improviing patient care but also its constribution to the general understanding of diabetes itself. The major type of diabetes in the tropics remains non-insulin-dependent diabetes (NIDDM), the insulin-dependent (IDDM) type being relatively rare. The most fascinating type however, is so-called malnutrition-related diabetes (MRDM) to which most attention is devoted below.
Pancreatic C-peptide response to oral glucose in fibrocalculous pancreatic diabetes
Author Name: Chittaranjan S. Yajnik, Sudha V. Kanitkar, Kishor M. Shelgikar, Sadanand S. Naik, K. George M.M. Alberti, Derek Hockaday , Publication Year: 1990 , Journal Name: Diabetes Care
Abstract: β-cell function (plasma C-peptide) in 17 fibrocalculous pancreatic diabetic (FCPD) subjects (14 newly diagnosed) was not different at presentation from that in 14 matched insulin-dependent diabetic subjects. After insulin treatment and improvement in the patients' nutritional and metabolic status, fasting and postglucose plasma C-peptide concentrations showed a significant increase. Thus, severely diminished β-cell function in FCPD is partially reversible after treatment. This could contribute to the clinical metabolic peculiarities of this group of patients.
Abstract: Exocrine pancreatic marker (immunoreactive-trypsin) and endocrine β-cell function (plasma insulin and C-peptide during an oral glucose tolerance test) were studied in 40 subjects with tropical-calcific-pancreatitis [seven non-diabetic (fibro-calculous-pancreatic-diabetes)]. In non-diabetic and impaired-glucose-tolerance subjects there was evidence of active pancreatitis in some and exocrine function was partially preserved. Fibro-calculous-pancreatic-diabetic subjects showed severely diminished exocrine pancreatic function; non showed 'pancreatic' elevation of immunoreactive-trypsin. Beta-cell function was preserved in non-diabetic and impaired-glucose-tolerance subjects; diabetic subjects showed variable Beta-cell function, but it was severely diminished in more than 75%. Immunoreactive-trypsin and C-peptide were directly correlated. This cross sectional study demonstrates, for the first time, that the Beta-cell loss in tropical calcific-pancreatitis is related to the exocrine loss. It suggests that diabets in tropica-calcific pancreatitis is either secondary to pancreatitis or that a common factor(s) acts simultaneously on bot components.
Abstract: Intravenous glucose tolerance was measured at diagnosis and during the subsequent 10 years in 103 Type-2 diabetic patients not treated with insulin. KG (the rate constant for clearance of intravenous glucose) was inversely related to fasting plasma glucose at all review times, and at times to the circulating concentrations of ketone bodies and glycerol. In the first year of treatment, most metabolic abnormalities improved. One to 10 years after diagnosis, fasting glucose concentration and intravenous glucose tolerance deteriorated. Likewise, the 'homeostatic model assessment' of insulin insensitivity deteriorated over the same period but first-phase insulin secretion remained steady or improved. This suggests that increases in insulin insensitivity have a predominant effect on slowly deteriorating glucose tolerance from 1 to 10 years after diagnosis in Type-2 diabetes.
Exocrine pancreatic function (serum immunoreactive trypsin, fecal chymotrypsin, and pancreatic isoamylase) in Indian diabetics
Author Name: Chittaranjan S. Yajnik, Ranjana A. Sahasrabudhe, Sadanand S. Naik, Amita Katrak, et al , Publication Year: 1990 , Journal Name: Pancreas
Abstract: Forty-nine patients with tropical calcific pancreatitis (TCP), 51 insulin-dependent diabetics (IDDMs), 87 non-insulin-dependent diabetics (NID-DMs), and 66 nondiabetic controls were studied to evaluate their exocrine pancreatic function by measurement of serum immunoreactive trypsin (IRT), pancreatic isoamylase (PIA), and fecal chymotrypsin (FCT). The majority of the subjects were studied within 1 year of diagnosis. Our results suggest that TCP and FCPD represent advanced disease and that a subclinical "pancreatopathy" appears to be common in tropical subjects. Endocrine impairment in TCP parallels exocrine damage.
Serum immunoreactive trypsin in tropical pancreatic diabetes syndrome
Author Name: C.S. Yajnik, A. Kartik, S.V. Kanitkar, S.S. Naik, V. D'Souza, and P. Dandona , Publication Year: 1989 , Journal Name: Ann Clinn Biochem
Abstract: Fifteen patients with tropical pancreatic diabetes syndrome (TPDS), 16 insulin-dependent diabetics (IDD), 27 non-insulin-dependent diabetics (NIDD) and 14 normal subjects, all from India, were investigated for markers of β-cell (C-peptide) and exocrine (immunoreactive trypsin; IRT) reserve. IRT and C-peptide concentrations were the lowest in TPDS, lower than normal in IDD, and not significantly different from normal in NIDDs. These data suggest that exocrine pancreatic reserve is markedly diminished in TPDS and that a subnormal IRT concentration may be a useful biochemical marker for this form of diabetes.
Abstract: Fibro-calculous-Pancreatic-Diabetes (FCPD) subjects are known to be 'ketosis-resistant',
despite severe hyperglycemia which requires large doses of insulin for its control. This contrasts with 'ketosis-prone' behaviour of classic IDDM patients. Ketosis Resistance in FCPD has been explained on the of basis various hypotheses, including preservation of /3-cell function,1 simultaneous a-cell destruction, decreased availability of substrate for ketogenesis due to decreased adipose tissue 'volume', hepatic carnitine deficiency in patients with malnutrition, etc. We studied j3-cell function and intermediates of fat metabolism, in fasting state and after oral glucose, in FCPD and matched IDDM subjects to highlight the differences between the two groups.
Abstract: This study presents preliminary observations on dietary intake of 52 young diabetics
representing different types of diabetes i.e. FCPD, IDDM and NIDDM. FCPDs consumed less amount of calories and protein compared to the other diabetics and when compared with their respective recommended dietary allowances, their intake of calories and proteins was quite poor. Besides a low calorie and protein intake jawar was their common staple food.
Treatment of malnutrition related diabetes mellitus
Author Name: Dr. C.S. Yajnik M.D. , Publication Year: 1988 , Journal Name: Wellcome Diabetes Study, K.E.M. Hospital and Research Centre, Pune
Abstract: Peculiarities of diabetes in tropical and developing countries have been known for some time, but it was the WHO study SMP that focused attention on these as a clinically important entity, the so called Malnutrition Related Diabetes Mellitus (MRDM). Some of the main features of MRDM in relation to treatment are - onset in youth, usually a moderate to severe hyperglycemia, exocrine pancreatic involvement (FCPD), associated malnutrition and other diseases, poor socio-economic background and low levels of education. Management of any individual has to take into account all these facts to set realistic targets for achievement.
Abstract: Fibrocalculous pancreatic diabetes (FCPD) is unique form of diabetes secondary to chronic pancreatitis seen in developing countries of the world associated with either overt protein-calorie malnutrition or, more likely, with deficiency of certain micronutrients. FCPD affects young individuals and runs an aggressive course to reach the endpoints of diabetes, pancreatic calculi and exocrine pancreatic dysfunction (stetorrhoea) in the majority of cases. There are characteristic features of FCPD radiologically, ultrasonographically, on endoscopic retrograde cholangiopancreatography and on histopathology which distinguish it from chronic pancreatitis of other aetiologies seen in temperate zones, e.g. alcoholic chronic pancreatitis. Although a secondary form of diabetes, specific diabetes-related complications like retinopathy and nephropathy do occur in FCPD . There appears to be a high risk of developing pancreatic carcinoma. Although the aetiology of FCPD, a good model of a secondary form of diabetes, could lead to improved understanding of other primary forms of diabetes as well. If the underlying aetiological factors are identified, it may also be possible to prevent this type of diabetes.
Chlorpropamide-alcohol flushing, aldehyde dehydrogenase activity, and diabetes complications
Author Name: R. M. Hillson, R. F. Smith, C. S. Yajnik, and T. D. R. Hockaday , Publication Year: 1987 , Journal Name: British Medical Journal
Abstract: We have conducted a study in which six fasting
non-diabetic subjects attended twice for an ethanol test: the first time, unknown to the subjects, having taken placebo tablets; and the second having taken 500 mg chlorpropamide four hours previously. The results from this small group of nondiabetic subjects suggest that erythrocyte aldehyde dehydrogenase activity influences cheek temperature rise after ethanol in men but provide no evidence to implicate the enzyme in the chlorpropamide component of chlorpropamide-alcohol flushing.
Malnutrition related diabetes mellitus- Diagnosis and treatment
Author Name: C. S. Yajnik , Publication Year: 1985 , Journal Name: IDF Bulletin
Abstract: Most often doctors expect to find fibrocalculous pancreatic diabetes (FCPD) only if the patient is young, severely malnourished, from a poor socioeconomic background, and has a history of abdominal pain. Such a classic picture is now seen in only a few patients and represents the extreme end of a spectrum. FCPD can occur in the absence of these features. In fact, some patients with FCPD belong to well-to-do families. It is therefore, not surprising that some are treated as having primary diabetes until the underlying condition is diagnosed. A high index of suspicion is the key to diagnosis. Management of these patients consists of the treatment of diabetes and exocrine pancreatic deficiency, and other general measures.
Three Halogens and Their Plasma Concentrations in Diabetics
Author Name: T.D.R. Hockaday, B. Pim, N. Ward, and Chittaranjan Yajnik , Publication Year: 1984 , Journal Name: Medical Research Society
Abstract: Concentrations of chlorine (Cl), iodine (I) and
bromine (Br) were determined by neutron
activation analysis of fasting lithium-heparin
plasma from 31 insulin-treated diabetics (ITD).
53 non-insulin-treated diabetics (NITD) and 22
non-diabetics (ND). Br concentrations were lower
in diabetics as a single group, and particularly
in NITD (40.8 ?S.D. 5.9pMoles) than in ND (45.5
2 3.1, p p>0.05) to
the MLRA for log KG.
Fasting plasma magnesium concentrations and glucose disposal in diabetes
Author Name: C. S. Yajnik, R. F. Smith, T. D. R. Hockaday, N. I. Ward , Publication Year: 1984 , Journal Name: British Medical Journal
Abstract: Fasting plasma concentrations of magnesium were
measured by neutron activation analysis in 30 nondiabetics
and 87 diabetics (55 non-insulin-treated, 32
insulin treated). Plasma concentrations of magnesium
were lowest in the insulin treated group (mean 0 84
(SEM 0 01) mmol/l; 2 0 (0 02) mg/100 ml), intermediate
in the non-diabetics (mean 0 89 (SEM 0 01) mmol/l;
2 2 (0-02) mg/100 ml), and highest in the non-insulintreated
diabetics (mean 0-95 (SEM 0 02) mmol/l; 2 3
(005) mg/100 ml). In all diabetics plasma magnesium
concentrations were inversely related to plasma glucose
values (rs=-0 33; p <0 01) and in non-insulin-treated
patients to plasma insulin concentrations (rs=-0 28;
p <0 05), the former confirming previous observations.
In 67 of the diabetics the KG constant for disposal rate
of glucose during a standard intravenous glucose
tolerance test was directly related to fasting plasma
magnesium concentrations, and this relation persisted
after controlling for age, sex, body mass index, type of
treatment, and glucose and insulin values.
This direct relation of plasma magnesium concentration
with glucose disposal was unexplained by its influence
on insulin secretion but was related to insulin
sensitivity; hence magnesium may be an important
determinant of insulin sensitivity in maturity onset
diabetes.
Chlorpropamide-Alcohol Flushing, Aldehyde Dehydrogenase Activity, and Diabetic Complications
Author Name: R. M. Hillson, R. F. Smith, C. S. Yajnik, and T. D. R. Hockaday , Publication Year: 1982 , Journal Name: British Medical Journal
Abstract: Chlorpropamide has been shown to inhibit aldehyde dehydrogenase activity,'l 2 and might thus be expected to decrease further any genetic or permanently acquired reduction in aldehyde dehydrogenase activity. The results from this small group of nondiabetic subjects suggest that erythrocyte aldehyde dehydrogenase activity influences cheek temperature rise after ethanol in men but provide no evidence to implicate the enzyme in the chlorpropamide component of chlorpropamide-alcohol flushing.
Maternal Lipids Are as Important as Glucose for Fetal Growth: Findings From the Pune Maternal Nutrition Study.
Author Name: Smita R. Kulkarni, K. Kumaran, Shobha R. Rao, Suresh D. Chougule et al. , Publication Year: 2014 , Journal Name: Diabetes Care
Abstract: Our study was performed between
1993–1996, similar to the time frame of
Clausen et al. We have continued to
follow up the birth cohort, which has
allowed us a unique opportunity to
undertake a lifecourse analysis of the
effect of maternal lipids during
pregnancy on offspring outcomes at
18 years. We have already started
examining the effect of maternal
metabolism during pregnancy on
offspring outcome characteristics
during childhood, adolescence, and
young adulthood. We hope to submit a
manuscript in due course. We believe
ours is the first study to prospectively
collect data on the influence ofmaternal
nutrition and metabolism during
pregnancy on offspring outcomes
adopting a lifecourse approach. Our
findings will have significant implications
for the understanding and management
of lipid levels during pregnancy.
Author Name: Chittaranjan S Yajnik , Publication Year: 2013 , Journal Name: International Journal of Epidemiology
Abstract: When David Barker first visited Pune in 1991 and explained the ‘low birthweight’ story, I was incredulous. Didn’t they teach us that the macrosomic babies of diabetic mothers were at higher risk of diabetes?
Fetal undernutrition and diabetes was the unintuitive idea. However, it took only a few minutes to appreciate the embarrassing fact that India, the undisputed capital of low birthweight babies was marching fast towards becoming the world’s capital of diabetes! Soon Hales and Barker published the ‘thrifty phenotype hypothesis: ‘type 2 diabetes (T2D) is the outcome of the fetus and early infant having to be nutritionally thrifty’.
Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries
Author Name: Parul Christian, Sun Eun Lee, Moira Donahue Angel, Linda S Adair et al. , Publication Year: 2013 , Journal Name: International Journal of Epidemiology
Abstract: Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30–40% of all children in 2011. In many of these countries, fetal
growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain.
Using extant longitudinal birth cohorts (n ¼ 19) with data on birth weight, gestational age, and child anthropometry (12–60 months), we estimated study-specific and pooled risk estimates of stunting, wasting, and underweight by small-for-gestational-age (SGA) and preterm birth.
We grouped children according to four combinations of SGA and gestational age: adequate size for gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66), and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birth weight
was associated with 2.5–3.5-fold higher odds of wasting, stunting, and being underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively.
This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth.
Foetal growth restriction, preterm birth, stunting, wasting, childhood.
A Critical Evaluation of the Fetal Origins Hypothesis and Its Implications for Developing Countries
Author Name: C. S. Yajnik , Publication Year: 2004 , Journal Name: American Society for Nutritional Sciences.
Abstract: There is a rapidly increasing epidemic of type 2 diabetes in India and other Asian countries. The thrifty
genotype and the thrifty phenotype are two nonexclusive explanations. People in the Indian subcontinent have
faced undernutrition for many generations, and Indian babies are among the smallest in the world. However, the
diabetes epidemic is of recent origin, and diabetes is more common among urban than rural Indians despite the
higher birth weight of urban babies. This suggests that postnatal factors must also contribute. Thus, a life-course
model of evolution of insulin resistance and type 2 diabetes, incorporating fetal, postnatal and adult components,
seems most appropriate. For a given BMI, Indians have a higher percentage of body fat and more visceral fat than
members of other populations. This thin-fat phenotype is present at birth. Neonatal size and body composition are
influenced by parental size, maternal food intake, physical activity and circulating concentrations of nutrients and
metabolites (folate, glucose, triglycerides, cholesterol etc.). Maternal insulin resistance promotes transfer of
nutrients to the fetus. Accelerated childhood growth is another risk factor for adiposity and insulin resistance,
especially in children born small. Childhood growth seems to be more influenced by paternal genetic factors,
whereas intrauterine growth is more influenced by maternal factors (intrauterine environment). Urban lifestyles,
including poor diet and sedentary habits, promote further obesity, insulin resistance and type 2 diabetes. These
factors may be amenable to correction. Prevention of type 2 diabetes must begin in utero and continue throughout
the life course.
Author Name: Chittaranjan Yajnik and Shilpa Joshi , Publication Year: , Journal Name: Diabetes in India
Abstract: Glucose is the main source of energy of the body and is released as we digest food. The pancreatic hormone, insulin, helps glucose to enter into the cells, where it is metabolized to produce energy.
In diabetes the pancreas produces insufficient insulin or available insulin is not able to act on the cells (insulin resistance). So glucose accumulates in the blood causing high blood sugar (hyperglycemia) and some might spill into the urine causing diabetic symptoms – see below. However many people with diabetes either have no symptoms, or mild symptoms, and do not seek medical help. They remain undiagnosed, allowing the diabetes to progress causing complications. In pregnancy, various hormones increase insulin resistance and in some women glucose level rises to diabetic levels; this is called gestational diabetes.
Non-coding RNA biomarkers of diabetes complications
Author Name: M.V. Joglekar, A.A. Hardikar, R.J. Farr, A. Januszewski et al. , Publication Year: , Journal Name: National Health and Medical Research Council
Abstract: Type 2 Diabetes (T2D) increases the risk of cardiovascular disease (CVD), and other vascular complications including retinopathy and neuropathy and is now well-accepted to be an outcome of intra-uterine programming and exposure to environmental (lifestyle) factors during post-natal life. It is essential and timely to identify early biomarkers of T2D and its complications. In recent years microRNAs (miRNAs), a subset of small non-coding (nc) RNAs, have been detected in circulation and demonstrated as promising biomarkers, mostly in cancer research. We aim to validate circulating ncRNA and DNA methylation signatures for T2D and its vascular complications using two unique longitudinal cohorts i) the Pune Maternal Nutrition study (PMNS) comprising of 18 year follow up study of undernourished children and their parents from preconception period, 20% of whom have now developed insulin resistance at 18 years of age ii) the FIELD study, which demonstrated that, relative to placebo, long-term fenofibrate improved some CVD and all microvascular complications with 9,795 subjects enrolled in study and analysed at baseline, 1 and 5 years and in 1,744 of these individuals at 12 years. We present epigenetic (DNA methylation) and ncRNA signatures for T2D and its complications over lifetime and response to therapy, enabling early management of at-risk individuals and facilitating development of novel therapeutics.
Circulating miRNAs in plasma were assessed from i) PMNS study subjects at 18, 12 and 6 years as well as at their birth and from their parents (at conception) and ii) T2D subjects in the FIELD cohort (Fenofibrate Intervention and Event Lowering in Diabetes) with retinopathy, neuropathy, low eGFR, ACR, non-fatal stroke or non-fatal myocardial infarction and were compared to individuals without complications using ultra-high throughput qPCR profiling. DNA methylation in both study cohorts was assessed on Illumina 450K DNA methylation arrays.
We observed that circulating miRNAs in five T2D complication groups Vs no complications were differentially expressed as seen in volcano plot (Figure 1A). Some of the miRNAs identified in the initial high throughput analysis (+/- 2-fold change and P<0.05) were also found to be significantly different in multiple samples when validated using low-throughput high sensitivity quantitative (q)PCR. We also found serum levels of four candidate microRNAs related to vascular health to be lower in FIELD T2D subjects at visit 20 (5 years) Vs visit 1 (baseline). Conclusion: miRNAs are found to be differentially expressed in individuals with diabetic complications, which could allow early identification of at risk individuals, thereby providing a vital opportunity to improve heath prior to clinical onset.
Abstract: LBW is a major public health problem in India. Iron and folic acid intervention is the only maternal intervention administered in India Though food based interventions are ideal they are rarely explored in view of the complexity involved in its’ administration. Earlier research from PMNS highlights the importance of maternal intake of milk, fruits and green leafy vegetables. We examined the associations of maternal intakes of milk calcium with maternal body size during pregnancy and birth size.
PMM.52 Lower circulating B12 in pregnancy is associated with higher maternal adiposity and insulin resistance in non-diabetic Caucasian women during and after pregnancy
Author Name: BA Knight, BM Shields, AT Hattersley, CR Yajnik , Publication Year: , Journal Name:
Abstract: Background Recent studies from India have suggested that low vitamin B12 (<150 pmol/l) concentrations in pregnancy are associated with obesity, gestational diabetes, and permanent diabetes 5 years later.1 These associations may not be present in a Western European Caucasian population, where micronutrient deficiencies are thought to be less common.
Aims To assess the associations between maternal adiposity and insulin resistance (IR) and circulating serum B12 levels in a non-diabetic pregnant Caucasian population.
Methods Detailed anthropometric measurements and biochemistry data were available on 995 women recruited as part of the Exeter Family Study of Childhood Health.2 Height, weight, sum of skin-fold thickness (SS) and fasting bloods were taken at 28 weeks of pregnancy (+/-5 days). A subset of 567 women was followed up at 5 years post pregnancy.
Results The geometric mean (standard deviation range) serum concentration of B12 was 201 (159–263) pmol/l. 198(20%) had B12 <150 pmol/l. These mothers had higher (geometric mean (SD range): BMI(29.5 vs. 27.1 kg/m2), IR(1.6 vs1.2) Triglycerides (2.3 vs. 2.0 mmol/l) and SS (58.2 vs 50.2 mm), p < 0.001 for all during pregnancy, and higher BMI(26.5 vs 24.1 kg/m2), SS(54.6 vs 46.7mm), and IR(0.97 vs 0.68), p < 0.001 for all at 5 year follow up:
Conclusions Our study has replicated the Indian findings of associations between lower serum B12 during pregnancy and higher adiposity and insulin resistance in this non-diabetic Caucasian population. These associations may represent micronutrient deficiencies resulting from poor quality diet or absorption problems associated with obesity. These findings may have important implications for fetal and maternal health in obese pregnancies.
Abstract: It is generally believed that individual susceptibility to
type 2 diabetes mellitus (T2DM) has its roots in genes.
The genetic susceptibility is thought to be exacerbated by
lifestyle behaviors such as high energy and fat intake and
reduced physical activity, leading to the development of
the disease (Fig. 18.1). Of the known risk factors, obesity
or excessive body mass index (BMI) is one of the most
common features associated with T2DM.1 The prevalence
of obesity has been increasing in many populations.2 Even
in individuals who are not apparently obese, or meet
definitions of obesity by western standards, there may
be a high proportion of body fat relative to muscle mass
(adiposity). The accumulation of body fat in the abdominal
areas leads to higher diabetes risks.3 This strong interrelation
between obesity or adiposity and T2DM is now
well recognized and together called “diabesity”.1
Most of the current preventive strategies and
recommendations to reduce the burden of T2DM focus
mainly on reducing adult lifestyle risk factors in middleaged
individuals with pre-existing disease or risk factors.
However, these measures can at best be termed secondary
prevention and do not address the impact of the disease
on future generations. Genetic research has so far also
failed to provide any major breakthrough towards primary
prevention. In order to stem the epidemic of T2DM, it is
imperative to find etiologic clues that will help develop
strategies to prevent the condition in unborn generations.
Abstract: Multinutrient insufficiencies as a consequence of nutritional and economic factors
are common in India and other developing countries. We have examined the impact of multi
nutrient insufficiency on markers of one carbon metabolism in the blood, and response to a
methionine load in clinically healthy young women.
Young women from Pune, India (n=10) and Cleveland, USA (n=13) were
studied. Blood samples were obtained in the basal state and following an oral methionine load
(50mg/kg of body weight in orange juice). Plasma concentrations of vitamin B12, folate and B6
were measured in the basal state. The effect of methionine load on the levels of methionine, total
homocysteine, cysteine, glutathione and amino acids was examined.
Indian women were significantly shorter and lighter compared with the American
women and had lower plasma concentration of vitamins B12, folate and B6, essential amino
acids and glutathione, but higher concentration of total homocysteine. The homocysteine
response to methionine load was higher in Indian women. The plasma concentrations of glycine
and serine increased in the Indian women after methionine (in juice) load. A significant negative
correlation between plasma B6 and homocysteine (r= -0.70), and plasma folate and glycine and
serine levels were observed in the Indian group (P<0.05) but not in the American group.
Multi-nutrient insufficiency in the Indian women caused unique changes in markers
of whole body protein and one carbon metabolism. These data would be useful in developing
nutrient intervention strategies.