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- Title
G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans.
- Authors
Sparsø T; Bonnefond A; Andersson E; Bouatia-Naji N; Holmkvist J; Wegner L; Grarup N; Gjesing AP; Banasik K; Cavalcanti-Proença C; Marchand M; Vaxillaire M; Charpentier G; Jarvelin MR; Tichet J; Balkau B; Marre M; Lévy-Marchal C; Faerch K; Borch-Johnsen K
- Abstract
<bold>Objective: </bold>Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity.<bold>Research Design and Methods: </bold>We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461).<bold>Results: </bold>The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10(-31)) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017).<bold>Conclusions: </bold>The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.
- Publication
Diabetes, 2009, Vol 58, Issue 6, p1450
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db08-1660