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

Author(s):
Hart, L.M. 't; Simonis-Bik, A.M.; Nijpels, G.; Haeften, T.W. van; Schafer, S.A.; Houwing-Duistermaat, J.J.; Boomsma, D.I.; Groenewoud, M.J.; Reiling, E.; Hove, E.C. van; Diamant, M.; Kramer, M.H.H.; Heine, R.J.; Maassen, J.A.; Kirchhoff, K.; Machicao, F.; Haring, H.U.; Slagboom, P.E.; Willemsen, G.; Eekhoff, E.M.; Geus, E.J. de; Dekker, J.M.; Fritsche, A.
Published
2010
Publication type
Article / Letter to editor

Abstract

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

genome-wide association beta-cell function susceptibility loci sensitivity variants tolerance mtnr1b polymorphisms replication dysfunction
Date issued
2010-01-31
Language
English
Is part of
Diabetes (2010), Vol. 59, no. 1, p. 287-292
hdl
1887/109707
doi
10.2337/db09-0736