OBJECTIVE -We have demonstrated high heritability of insulin secretion measured as acute insulin response to glucose times insulin sensitivity (disposition index). Furthermore, we showed that obese normoglycemic family members of a type 2 diabetic proband failed to compensate for the insulin resistance of 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) gene, or hepatocyte nuclear factor 1␣ (TCF1 or HNF1␣) gene contribute to the inherited deficiencies of insulin secretion and ␤-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 members of 26 familial type 2 diabetic kindreds who had undergone tolbutamide-modified intravenous glucose tolerance tests for two variants of the ABCC8 (sulfonylurea) gene, two variants of the GCK gene, and one common amino acid variant in the TCF1 (HNF1␣) gene. All family members were classified as normal or having impaired glucose tolerance based on oral glucose tolerance testing. We used minimal model analysis to calculate the insulin sensitivity index (S I ) and glucose effectiveness (S G ), and acute insulin response to glucose was calculated as the mean insulin excursion above baseline during the first 10 min after the glucose bolus. Disposition index (DI), a measure of ␤-cell compensation for insulin sensitivity, was calculated as insulin sensitivity times acute insulin response. Effects of polymorphisms were determined using mixed effects models that incorporated family membership and by a likelihood analysis that accounted for family structure through polygenic inheritance.RESULTS -An intronic variant of the ABCC8 gene just upstream of exon 16 was a significant determinant of both DI and an analogous index based on acute insulin response to tolbutamide. Surprisingly, heterozygous individuals showed the lowest indexes, whereas the DI in the two homozygous states did not differ significantly. Neither the exon 18 variant nor the variants in the GCK and TCF1 genes were significant in this model. However, combined genotypes of ABCC8 exon 16 and 18 variants again significantly predicted both indexes of glucose and tolbutamidestimulated insulin secretion. Unexpectedly, a variant in the 3Ј untranslated region of the GCK gene interacted significantly with BMI to predict insulin sensitivity.CONCLUSIONS -The exon 16 variant of the ABCC8 gene reduced ␤-cell compensation to the decreased insulin sensitivity in the heterozygous state. This 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 ␤-cell function. However, our study focused on individuals from relatively few families. Ascertainment bias, family structure, and other interacting genes might have influenced our unexpected result...

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Mutations of the hepatocyte nuclear factor-1 alpha (HNF1 alpha) gene are an important cause of autosomal dominant diabetes with onset before age 25 yr [maturity-onset diabetes of the young (MODY)], and some regions of the HNF1 alpha gene appear to be hot spots for mutations. To evaluate the role of HNF1 alpha in the more common familial type 2 diabetes, we studied 62 families of Northern European origin by linkage analysis and molecular screening. Linkage was rejected under dominant models consistent with either late-onset type 2 diabetes or early-onset dominant diabetes. We used single strand conformation polymorphism analysis to screen 53 diabetic members of 36 families who reported diabetes diagnosed before age 40 yr, 9 members of 2 Utah families with typical MODY, and 24 additional members of families with possible linkage. One MODY family showed the previously reported frameshift mutation (P291fsinsC) in exon 4. Among the individuals with more typical type 2 diabetes, we identified the previously reported common polymorphisms, a new intronic polymorphism, and 3 common amino acid variants. We also identified 2 novel missense mutations that segregated with type 2 diabetes in 1 family each: lysine for glutamic acid substitution at codon 619 in exon 10 (E619K), and an arginine for threonine substitution at codon 537 in exon 8 (R537T) in a second family. The exon 8 mutation showed relatively low penetrance, and the role in this family remains uncertain. No coding mutations were identified in the family members screened on the basis of linkage but without early-onset diabetes. Although HNF1 alpha mutations are not a common cause of familial type 2 diabetes, they may account for 5% of families in which at least 1 member has onset of type 2 diabetes before age 40 yr. Incomplete penetrance and a high sporadic frequency make linkage an inefficient screening tool.