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

Thomas Sparsø, Amélie Bonnefond, Ehm Andersson, Nabila Bouatia-Naji, Johan Holmkvist, Lise Wegner, Niels Grarup, Anette P. Gjesing, Karina Banasik, Christine Cavalcanti-Proença, Marion Marchand, Martine Vaxillaire, Guillaume Charpentier, Marjo Riitta Jarvelin, Jean Tichet, Beverley Balkau, Michel Marre, Claire Lévy-Marchal, Kristine Færch, Knut Borch-JohnsenTorben Jørgensen, Sten Madsbad, Pernille Poulsen, Allan Vaag, Christian Dina, Torben Hansen, Oluf Pedersen, Philippe Froguel

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    Abstrakt

    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 × 10-31) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 × 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 β-cell dysfunction and hepatic insulin resistance.

    OriginalsprogEngelsk
    Sider (fra-til)1450-1456
    Antal sider7
    TidsskriftDiabetes
    Vol/bind58
    Udgave nummer6
    DOI
    StatusUdgivet - 1 jun. 2009

    Fingeraftryk Udforsk hvilke forskningsemner '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' indeholder.

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