Role of common sequence variants in insulin secretion in familial type 2 diabetic kindreds - The sulfonylurea 1-receptor, glucokinase, and hepatocytenuclear factor 1 alpha genes

OBJECTIVE - We have demonstrated high heritability of insulin secretion mea sured as acute insulin response to glucose times insulin sensitivity (dispo sition index). Furthermore, me showed that obese normoglycemic family membe rs of a type 2 diabetic proband Failed to compensate for the insulin resist ance for obesity by increasing insulin secretion. In this study, we tested the primary hypotheses that previously described variants in the pancreatic sulfonylurea receptor gene (SUR1 or ABCC8), glucokinase (GCK) gent, or hep atocyte nuclear factor 1 alpha (TCF1 or HNF1 alpha) gene contribute to the inherited deficiencies of insulin secretion and beta -cell compensation to insulin resistance, as well as the secondary hypotheses that these variants altered insulin sensitivity. RESEARCH DESIGN AND METHODS - We typed 124 nondiabetic member 5 of 26 famil ial type 2 diabetic kindreds who had undergone tolbutamide-modified intrave nous glucose tolerance tests for two variants of the ABCC8 (sulfonylurea) g ene, two variants of the GCK gene, and one common amino acid variant in the TCF1 (HNF1 alpha) gene. All family members were classified as normal or ha ving impaired glucose tolerance based on oral glucose tolerance testing. We used minimal model analysis to calculate the insulin sensitivity index (S- 1) and glucose effectiveness (S-G), and acute insulin response to glucose w as calculated as the mean insulin excursion above baseline during the first 10 min after the glucose bolus. Disposition index (DI), a measure of beta -cell compensation for insulin sensitivity, was calculated as insulin sensi tivity times acute insulin response. Effects of polymorphisms were determin ed using mixed effects models that incorporated family membership and by a likelihood analysis that accounted for family structure through polygenic i nheritance. RESULTS - An intronic variant of the ABCC8 gene just upstream of exon 16 wa s a significant determinant of both DI and an analogous index based on acut e insulin response to tolbutamide. Surprisingly, heterozygous individuals s howed the lowest indexes, whereas the DI in the two homozygous states did n ot differ significantly. Neither the exon 18 variant nor the variants in th e GCK and TCF1 genes were significant in this model. However, combined geno types of ABCC8 exon 16 and 18 variants again significantly predicted both i ndexes of glucose and tolbutamide-stimulated insulin secretion. Unexpectedl y, a variant in the 3' untranslated region of the GCK gene interacted signi ficantly with BMI to predict insulin sensitivity. CONCLUSIONS - The exon 16 variant of the ABCC8 gene reduced beta -cell comp ensation to the decreased insulin sensitivity in the heterozygous state. Th is may explain the observation from several groups of an association of the ABCC8 variants in diabetes and is consistent with other studies showing a role of ABCC8 variants in pancreatic beta -cell function. However, our stud y focused on individuals from relatively few families, Ascertainment bias, family structure, and other interacting genes might have: influenced our un expected result, Additional studies are needed to replicate our observed de ficit in beta -cell compensation in individuals heterozygous for ABCC8 vari ants. Likewise, the role of the GCK 3' variant in the reduced insulin sensi tivity of obesity will require further study.