Journal
DIABETES
Volume 59, Issue 1, Pages 287-292Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db09-0736
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Funding
- Dutch Diabetes Research Foundation
- Netherlands Organization for Health Research and Development
- Research Institute for Diseases in the Elderly (RIDE Program)
- Deutsche Forschungsgeineinschaft [KF0 114, Fr 1561/5-1]
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OBJECTIVE-At least 20 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-A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKV2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting. RESULTS-The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 X 10(-6)). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 X 10(-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 first-phase GSIS. Second-phase GSIS, insulin sensitivity index 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 first-phase GSIS and the disposition index. The slower second-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. Diabetes 59:287-292, 2010
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