Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion
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OBJECTIVE: KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered beta-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different stimuli. RESEARCH DESIGN AND METHODS: We genotyped 1,578 nondiabetic subjects at increased risk of type 2 diabetes for rs151290, rs2237892, rs2237895, and rs2237897. All participants underwent an oral glucose tolerance test (OGTT); glucagon-like peptide (GLP)-1 and gastric inhibitory peptide 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, first-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all P < or = 0.01). rs2237892, rs2237895, and rs2237897 were nominally associated with OGTT-derived insulin secretion indexes (all P < 0.05). No SNPs were associated with beta-cell function during intravenous glucose or GLP-1 administration. However, rs151290 was associated with glucose-stimulated gastric inhibitory polypeptide 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 > or = 0.05). CONCLUSIONS: Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems to be explained not by altered incretin signaling but most likely by changes in incretin secretion.
Original language | English |
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Journal | Diabetes |
Volume | 58 |
Issue number | 7 |
Pages (from-to) | 1715-20 |
Number of pages | 5 |
ISSN | 0012-1797 |
DOIs | |
Publication status | Published - 2009 |
Bibliographical note
Keywords: Adult; Chromosome Mapping; Chromosomes, Human, Pair 11; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Exons; Female; Genetic Variation; Germany; Glucose Tolerance Test; Humans; Incretins; Insulin; KCNQ1 Potassium Channel; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Protein Subunits
ID: 18700754