Short Communication

Diabetologia

, Volume 51, Issue 9, pp 1659-1663

Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps

  • M. J. GroenewoudAffiliated withDepartment of Molecular Cell Biology, Leiden University Medical Center (LUMC)
  • , J. M. DekkerAffiliated withEMGO Institute, Vrije Universiteit Medical Center
  • , A. FritscheAffiliated withDepartment of Internal Medicine, Eberhard-Karls University of Tübingen
  • , E. ReilingAffiliated withDepartment of Molecular Cell Biology, Leiden University Medical Center (LUMC)
  • , G. NijpelsAffiliated withEMGO Institute, Vrije Universiteit Medical Center
  • , R. J. HeineAffiliated withEMGO Institute, Vrije Universiteit Medical Center
  • , J. A. MaassenAffiliated withDepartment of Molecular Cell Biology, Leiden University Medical Center (LUMC)EMGO Institute, Vrije Universiteit Medical Center
  • , F. MachicaoAffiliated withDepartment of Internal Medicine, Eberhard-Karls University of Tübingen
  • , S. A. SchäferAffiliated withDepartment of Internal Medicine, Eberhard-Karls University of Tübingen
    • , H. U. HäringAffiliated withDepartment of Internal Medicine, Eberhard-Karls University of Tübingen
    • , L. M. ’t HartAffiliated withDepartment of Molecular Cell Biology, Leiden University Medical Center (LUMC) Email author 
    • , T. W. van HaeftenAffiliated withDepartment of Internal Medicine, Utrecht University Medical Center

Abstract

Aims/hypothesis

Genome-wide association studies have recently identified novel type 2 diabetes susceptibility gene regions. We assessed the effects of six of these regions on insulin secretion as determined by a hyperglycaemic clamp.

Methods

Variants of the HHEX/IDE, CDKAL1, SLC30A8, IGF2BP2 and CDKN2A/CDKN2B genes were genotyped in a cohort of 146 participants with NGT and 126 with IGT from the Netherlands and Germany, who all underwent a hyperglycaemic clamp at 10 mmol/l glucose.

Results

Variants of CDKAL1 and IGF2BP2 were associated with reductions in first-phase insulin secretion (34% and 28%, respectively). The disposition index was also significantly reduced. For gene regions near HHEX/IDE, SLC30A8 and CDKN2A/CDKN2B we did not find significant associations with first-phase insulin secretion (7–18% difference between genotypes; all p > 0.3). None of the variants showed a significant effect on second-phase insulin secretion in our cohorts (2–8% difference between genotypes, all p > 0.3). Furthermore, the gene variants were not associated with the insulin sensitivity index.

Conclusions

Variants of CDKAL1 and IGF2BP2 attenuate the first phase of glucose-stimulated insulin secretion but show no effect on the second phase of insulin secretion. Our results, based on hyperglycaemic clamps, provide further insight into the pathogenic mechanism behind the association of these gene variants with type 2 diabetes.

Keywords

CDKAL1 First phase insulin secretion Genes Gene variants Hyperglycaemic clamp IGF2BP2 Type 2 diabetes