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

• 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

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.