Role of Common Sequence Variants in Insulin Secretion in Familial Type 2 Diabetic Kindreds

Abstract

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...

Evaluation of Common Variants in the Six Known Maturity-Onset Diabetes of the Young (MODY) Genes for Association With Type 2 Diabetes

“…However, the GCK G(Ϫ30)A association is also supported by a number of other previous reports of diabetes/diabetes-related traits for this allele (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) and thus may be considered less likely to be a false positive than an SNP without such evidence.…”

“…The G(Ϫ30)A variant upstream from the GCK promoter has been inconsistently associated with diabetes, but it has frequently been found to be associated with increased fasting glucose (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). There have also been several published nominal associations for variants in IPF1 with the common form of type 2 diabetes (34 -37).…”

Evaluation of apolipoprotein A-II as a positional candidate gene for familial Type II diabetes, altered lipid concentrations, and insulin resistance

“…Analysis of subjects who had undergone frequently sampled intravenous glucose tolerance tests was done using mixed effects linear regression analysis in SPSS v 10.1 (SPSS, Chicago, Ill., USA) [34]. Family membership was a random factor, genotype and diagnosis (normal and IGT) were fixed factors, and age and ln-transformed BMI were covariates, as we have described previously [35]. BMI, insulin sensitivity index (S I ), acute insulin response to glucose (AIR g ), and disposition index (S I *AIR g ) [36] were all ln-transformed prior to analysis.…”

Glucokinase gene promoter -30G>A polymorphism: a cross-sectional association study with obesity, diabetes Mellitus, hyperlipidemia, hypertension and metabolic syndrome in an Iranian hospital

“…These associations may be partly due to the impact of this polymorphism on insulin sensitivity, as an association with high insulin resistance has been reported for the -30G>A allele 15 . However, this is not a universal finding since Elbein et al found no significant influence of this polymorphism on the insulin sensitivity index 20 . In the present study on Iranian subjects, an association between this polymorphism and BMI was not found.…”

“…However, these findings are challenged by those of other studies 12,24,[30][31][32] and so are not consistent. Furthermore, previous studies have failed to find any significant effect of this polymorphism on insulin secretion 20,24 . Nevertheless, Rose et al 15 found that the -30G>A allele is associated with high FPG and Post-Oral Glucose Tolerance Test (OGTT) glycemia, as well as impaired glucose regulation and other features of WHO-defined metabolic syndrome 15 .…”