Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First-Phase Glucose-Stimulated Insulin Secretion During Hyperglycemic Clamps

Abstract Objective- At least twenty type 2 diabetes loci have now been identified and several of these are associated with altered beta-cell function. In this study we have investigated the combined effects of eight known beta cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps. Research design and methods- 447 subjects originating from four independent studies in the Netherlands and Germany (256 NGT/191 IGT) underwent a hyperglycemic clamp. A subset had an extended clamp with additional GLP-1 and arginine (n=224). We next genotyped SNPs in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8 and MTNR1B and calculated a risk allele score by risk allele counting. Results- The risk allele score was associated with lower 1 st phase glucose stimulated insulin secretion (GSIS) (p=7.1*10 -6 ). The effect size was equal in NGT and IGT subjects. We also noted an inverse correlation with the disposition index (p=1.6*l10 -3 ). When we stratified the study population according to the number of risk alleles into three groups those with a medium or high risk allele score had 9% and 23% lower 1 st phase GSIS. 2 nd phase GSIS, ISI and GLP-1 or arginine stimulated insulin release were not significantly different. Conclusions- A combined risk allele score for eight known beta cell genes is associated with the rapid 1 st phase GSIS and the disposition index. The slower 2 nd phase GSIS, GLP-1 and arginine stimulated insulin secretion are not associated suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci.