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

Udgivelsesdato: 2009-Jun OBJECTIVE: 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...

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Published in:Diabetes
Main Authors: Sparsø, Thomas, Bonnefond, Amélie, Andersson, Ehm, Bouatia-Naji, Nabila, Holmkvist, Johan, Wegner, Lise, Grarup, Niels, Gjesing, Anette P, Banasik, Karina, Cavalcanti-Proença, Christine, Marchand, Marion, Vaxillaire, Martine, Charpentier, Guillaume, Jarvelin, Marjo-Riitta, Tichet, Jean, Balkau, Beverley, Marre, Michel, Lévy-Marchal, Claire, Faerch, Kristine, Borch-Johnsen, Knut, Jørgensen, Torben, Madsbad, Sten, Poulsen, Pernille, Vaag, Allan, Dina, Christian, Hansen, Torben, Pedersen, Oluf, Froguel, Philippe
Format: Article in Journal/Newspaper
Language:English
Published: 2009
Subjects:
Adult
Aged
Blood Glucose
Denmark
Diabetes Mellitus
Type 2
European Continental Ancestry Group
Genetic Variation
Glucose
Humans
Insulin
Insulin Resistance
Insulin-Secreting Cells
Introns
Liver
Quantitative Trait Loci
Receptor
Melatonin
MT1
Risk Factors
Twins
North Finland
Online Access:https://portal.findresearcher.sdu.dk/da/publications/aef69070-bfaf-11de-9bfd-000ea68e967b
https://doi.org/10.2337/db08-1660
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Summary:Udgivelsesdato: 2009-Jun OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

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