Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion

Abstract

Objective: KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered β-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 SNPs on insulin secretion upon different stimuli.

Research Design and Methods: We genotyped 1,578 non-diabetic subjects at increased type 2 diabetes risk for rs151290, rs2237892, rs2237895, and rs2237897. All participants underwent an oral glucose tolerance test (OGTT); GLP-1 secretion was measured in 170 participants. In 519 participants, a hyperinsulinemic—euglycemic clamp was performed, in 314 participants an intravenous glucose tolerance test (IVGTT), and in 102 subjects a hyperglycemic clamp combined with GLP-1 and arginine stimuli.

Results: rs151290 was nominally associated with 30-min C-peptide levels during OGTT, 1^st-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all p≤0.01). rs2237892, rs2237895, and rs2237897 were nominally associated with OGTT-derived insulin secretion indices (all p<0.05). No SNP was associated with β-cell function during intravenous glucose or GLP-1 administration. However, rs151290 was associated with glucose-stimulated GIP and GLP-1 increase after adjustment in the dominant model (p=0.0042 and p=0.0198, respectively). No associations were detected between the other SNPs and basal or stimulated incretin levels (all p≥0.05).

Conclusions: Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in our German population at increased type 2 diabetes risk. The discrepancy between orally and intravenously administered glucose seems not to be explained by altered incretin signalling, but most likely by changes in incretin secretion.