Chittaranjan S. Yajnik

Neonatal anthropometry: the thin–fat Indian baby. The Pune Maternal Nutrition Study

OBJECTIVE: 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.DESIGN: Community-based observational study in rural India, and comparison with data from an earlier study in the UK, measured using similar methods.SUBJECTS: 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: Maternal weight and height, and neonatal weight, length, head, mid-upper-arm and abdominal circumferences, subscapular and triceps skinfold thicknesses, and placental weight.RESULTS: The Indian mothers were younger, lighter, shorter and had a lower mean body mass index (BMI) (mean age, weight, height and BMI: 21.4 y, 44.6 kg, 1.52 m, and 18.2 kg/m2) than Southampton mothers (26.8 y, 63.6 kg, 1.63 m and 23.4 kg/m2). They gave birth to lighter babies (mean birthweight: 2.7 kg compared with 3.5 kg). Compared to Southampton babies, the Indian babies were small in all body measurements, the smallest being abdominal circumference (s.d. score: −2.38; 95% CI: −2.48 to −2.29) and mid-arm circumference (s.d. score: −1.82; 95% CI: −1.89 to −1.75), while the most preserved measurement was the subscapular skinfold thickness (s.d. score: −0.53; 95% CI: −0.61 to −0.46). Skinfolds were relatively preserved in the lightest babies (below the 10th percentile of birthweight) in both populations.CONCLUSIONS: Small Indian babies have small abdominal viscera and low muscle mass, but preserve body fat during their intrauterine development. This body composition may persist postnatally and predispose to an insulin-resistant state.

Fetal Growth and Glucose and Insulin Metabolism in Four‐year‐old Indian Children

Studies in Britain have shown that adults who had a low birthweight 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 I−1 and 321 pmol I−1 in children whose birthweight had been 2.4 kg or less, compared with 7.5 mmol I−1 and 289 pmol I−1 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.

Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population

Aims and hypothesisIndia 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 methodsWe 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.ResultsWe 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 non-diabetic subjects.ConclusionsOur 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.

FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians

Aims and hypothesisVariants 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 diabetes and measures of obesity in South Asian Indians in Pune.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.

Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries

BACKGROUND 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, foetal 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. METHODS Using extant longitudinal birth cohorts (n=19) with data on birthweight, 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. RESULTS 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 birthweight was associated with 2.5-3.5-fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively. CONCLUSIONS 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.

Impact of ethnicity on gestational diabetes identified with the WHO and the modified International Association of Diabetes and Pregnancy Study Groups criteria: a population-based cohort study

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.

Maternal nutrition, intrauterine programming and consequential risks in the offspring

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 micronutrients 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.

Impact of Common Variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the Risk of Type 2 Diabetes in 5,164 Indians

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, HHEX-rs1111875, 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 × 10−3 to 4.6 × 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 × 10−34). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of β-cell function (P = 6.9 × 10−8 and 3 × 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.

Vitamin B12 status of pregnant Indian women and cognitive function in their 9-year-old children

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 childs 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.

Vitamin B 12 deficiency

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.