Combined risk allele score of eight type 2 diabetes genes is associated with reduced first-phase glucose-stimulated insulin secretion during hyperglycemic clamps

Diabetes. 2010 Jan;59(1):287-92. doi: 10.2337/db09-0736. Epub 2009 Oct 6.


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, CDKN2A/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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Body Mass Index
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genotype
  • Germany / epidemiology
  • Glucose / pharmacology*
  • Glucose Clamp Technique
  • Glucose Intolerance / epidemiology
  • Glucose Intolerance / genetics
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / chemically induced
  • Insulin / metabolism*
  • Insulin Secretion
  • Male
  • Middle Aged
  • Netherlands / epidemiology
  • Polymorphism, Single Nucleotide*
  • Reference Values
  • Risk Assessment
  • Risk Factors


  • Insulin
  • Glucose