1The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the -cell ATPsensitive potassium (K ATP ) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16 -3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large (ϳ2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (
Aims/hypothesis: Fetal growth is influenced by genetic factors as well as the intra-uterine environment. We hypothesised that some genetic factors may 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, UK Caucasian 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.
We have not confirmed the initial observation in a larger replication cohort. Our results highlight the importance of replicating initial results from genetic association studies.
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