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

Research output: Contribution to journalJournal articleResearchpeer-review

Karsten Müssig, Harald Staiger, Fausto Machicao, Kerstin Kirchhoff, Martina Guthoff, Silke A Schäfer, Konstantinos Kantartzis, Günther Silbernagel, Norbert Stefan, Jens J Holst, Baptist Gallwitz, Hans-Ulrich Häring, Andreas Fritsche

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 languageEnglish
JournalDiabetes
Volume58
Issue number7
Pages (from-to)1715-20
Number of pages5
ISSN0012-1797
DOIs
Publication statusPublished - 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