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

  1. Leen M. ‘t Hart1,
  2. Annemarie M. Simonis-Bik2,
  3. Giel Nijpels3,
  4. Timon W. van Haeften4,
  5. Silke A. Schäfer5,
  6. Jeanine J. Houwing-Duistermaat6,
  7. Dorret I. Boomsma7,
  8. Marlous J. Groenewoud1,
  9. Erwin Reiling1,
  10. Els C. van Hove1,
  11. Michaela Diamant2,
  12. Mark H.H. Kramer2,
  13. Robert J. Heine2,3,8,
  14. J. Antonie Maassen1,2,
  15. Kerstin Kirchhoff5,
  16. Fausto Machicao5,
  17. Hans-Ulrich Häring5,
  18. P. Eline Slagboom6,
  19. Gonneke Willemsen7,
  20. Elisabeth M. Eekhoff2,
  21. Eco J. de Geus7,
  22. Jacqueline M. Dekker3 and
  23. Andreas Fritsche5
  1. 1Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands;
  2. 2Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands;
  3. 3EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands;
  4. 4Department of Internal Medicine, Utrecht University Medical Center, Utrecht, the Netherlands;
  5. 5Department of Internal Medicine, Eberhard-Karls University of Tübingen, Tübingen, Germany;
  6. 6Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands;
  7. 7Department of Biological Psychology, VU University, Amsterdam, the Netherlands;
  8. 8Eli Lilly & Company, Indianapolis, Indiana.
  1. Corresponding author: L.M. ‘t Hart, l.m.t_hart{at}


OBJECTIVE At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-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 × 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 × 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 β-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.


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    • Received May 19, 2009.
    • Accepted September 18, 2009.
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