Rare mutations in the glucokinase (GCK) gene cause fasting hyperglycemia and considerably influence birth weight when present in a mother or her offspring. The role of common variation of GCK is uncertain. A polymorphism at position ؊30 of the GCK ␤-cell-specific promoter, present in 30% of the population, has been variably associated with type 2 diabetes and diabetesrelated quantitative traits. Using 1,763 U.K. Caucasian normoglycemic adult subjects, we demonstrated that the A allele at GCK(؊30) is associated with a 0.06-mmol/l increase in fasting plasma glucose (FPG) (P ‫؍‬ 0.003). The A allele was also associated with an increase in FPG in 755 women who were 28 weeks pregnant (0.075 mmol/l, P ‫؍‬ 0.003). We then went on to analyze the effect of GCK(؊30) on birth weight using 2,689 mother/child pairs. The presence of the A allele in the mother was associated with a 64-g (25-102 g) increase in offspring birth weight (P ‫؍‬ 0.001). We did not detect a fetal genotype effect. The increase in offspring birth weight in the 30% of mothers carrying an A allele at GCK(؊30) is likely to reflect an elevated FPG during pregnancy. This study establishes that common genetic variation, in addition to rare mutations and environmental factors, can affect both FPG and birth weight. Diabetes 54:576 -581, 2005

Objective: Several studies suggest that taller children may be wrongly labelled as 'overweight' because body mass index (BMI) is not independent of height (Ht) in childhood, and recommend adjustment to render the index Ht independent. We used objective measures of %body fat and hormonal/metabolic markers of fatness to investigate whether BMI and the corresponding fat mass index (FMI) mislead in childhood, or whether taller children really are fatter. Design: Longitudinal observational study measuring children annually from age 7 to 12 years. Subjects: Two hundred and eighty healthy children (56% boys) from the EarlyBird study. Measurements: BMI (body mass (BM)/Ht2 ), FMI (fat mass (FM)/Ht 2 ), %body fat ((FM/BM) Â 100, where FM was measured by dual-energy X-ray absorptiometry), fasting leptin (a hormonal measure of body fatness) and insulin resistance (a metabolic marker derived from the validated homeostasis model assessment program for insulin resistance -HOMA2-IR) were all analysed in relation to Ht. Alternative Ht-independent indices of BM and FM were compared with BMI and FMI as indicators of true fatness and related health risk. Results: BMI and FMI correlated with Ht at each annual time point (rB0.47 and 0.46, respectively), yet these correlations were similar in strength to those between Ht and %fat (rB0.47), leptin (rB0.41) and insulin resistance (rB0.40). Also, children who grew the most between 7 and 12 years showed greater increases in BMI, FMI, leptin and insulin resistance (tertile 1 vs 3, all po0.05). BMI and FMI explained B20% more of the variation in %fat, B15% more in leptin and B10% more in insulin resistance than the respective Ht-independent reformulations (BM/Ht 3.5 and FM/Ht 7 , both po0.001). Conclusion: Taller children really are fatter than their shorter peers, have higher leptin levels and are more insulin resistant. Attempts to render indices of BM or FM independent of Ht in children seem inappropriate if the object of the index is to convey health risk. International Journal of Obesity (2011) 35, 541-547; doi:10.1038/ijo.2010 Although BMI defines neither body composition nor fat distribution, it is considered a sufficiently robust surrogate for fatness to be employed widely for the screening of metabolic risk in adults.Given the rise in childhood obesity, attention over recent years has turned to the use of BMI in children, and all 5-and 11-year olds in England are now screened for overweight and obesity, using BMI centile cut-points derived by extrapolation from the adult data. 4 The aim of the programme is to identify children at risk. However, where BMI is independent of Ht in adults, this is not the case in children. BMI correlates positively with Ht in childhood and this has led contemporary statisticians to act once more as Quetelet did nearly two centuries agoFand find an exponential for Ht that will render the expression for BM independent of Ht. Several studies have proposed such reformulation, 5-9 all of them using the slope coefficient obtained from regressing 'logtransfor...

For more than a decade, the fetal programming hypothesis has taught that insulin resistance and its associated metabolic disturbances result from poor gestational environment, for which low birth weight is a surrogate. Low birth weight, however, is now uncommon in industrialized societies. We have investigated the relevance of birth weight, "catch-up" weight, and current weight to insulin resistance in 300 contemporary British children. Insulin resistance at 5 years was not related to birth weight but was correlated with current weight and weight catch-up in both sexes, more strongly so in girls (r ‫؍‬ 0.33, P < 0.001 vs. r ‫؍‬ 0.18, P ‫؍‬ 0.03), who were intrinsically more insulin-resistant than boys. Weight change merely co-correlated with current weight (r ‫؍‬ 0.67, P < 0.01 in both sexes) and did not improve on the prediction of insulin resistance. Most important, insulin resistance at 5 years was the same in children of heavier birth weight, whose weight SD score had not changed, as in those of lighter birth weight, matched for current weight, who had experienced so-called catch-up (boys 0.89 and 0.88 units, respectively, P ‫؍‬ 0.96; girls 1.26 and 1.13 units, P ‫؍‬ 0.41). Insulin resistance in contemporary children seems to be a function of excess current weight rather than of low birth weight or change in weight. Diabetes 51:3468 -3472, 2002

The insulin gene variable number of tandem repeats minisatellite (INS-VNTR) class III allele is associated with altered fetal growth, type 2 diabetes risk (especially when paternally inherited), and insulin and IGF2 gene expression. Further studies are needed to establish the role of the INS-VNTR in fetal growth and assess whether its effects depend on the parent of origin. We analyzed the INS-VNTR-linked -23 Hph1 polymorphism in 2283 subjects, comprising 1184 children and 1099 parents. There were no differences (P < 0.05) in birth weight between offspring of the three genotypes: III/III (n = 108) vs. I/I (n = 558), effect size, -8 g (P = 0.87); and I/III (n = 464) vs. I/I, effect size, -19 g (P = 0.54). We observed no differences in head circumference [III/III (n = 95) vs. I/I (n = 470), effect size, -0.14 cm; P = 0.31] or birth length. No differences were observed when stratifying by postnatal growth realignments [nonchangers III/III (n = 37) vs. I/I (n = 170), effect size, -43 g; P = 1.00] or by parent of origin of the class III allele (presence of paternal III allele effect size, -15 g; P = 0.74). INS-VNTR was nominally associated (P < 0.05) with body mass index and insulin resistance, but not with beta-cell function, in young adults. In the largest study to date, we found a lack of support for a role for INS-VNTR in fetal growth and nominal association with type 2 diabetes-related intermediate traits.

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.