TY - JOUR
T1 - 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
AU - Sparsø, Thomas
AU - Bonnefond, Amélie
AU - Andersson, Ehm
AU - Bouatia-Naji, Nabila
AU - Holmkvist, Johan
AU - Wegner, Lise
AU - Grarup, Niels
AU - Gjesing, Anette P
AU - Banasik, Karina
AU - Cavalcanti-Proença, Christine
AU - Marchand, Marion
AU - Vaxillaire, Martine
AU - Charpentier, Guillaume
AU - Jarvelin, Marjo-Riitta
AU - Tichet, Jean
AU - Balkau, Beverley
AU - Marre, Michel
AU - Lévy-Marchal, Claire
AU - Faerch, Kristine
AU - Borch-Johnsen, Knut
AU - Jørgensen, Torben
AU - Madsbad, Sten
AU - Poulsen, Pernille
AU - Vaag, Allan
AU - Dina, Christian
AU - Hansen, Torben
AU - Pedersen, Oluf
AU - Froguel, Philippe
AU - Sparsø, Thomas
AU - Bonnefond, Amélie
AU - Andersson, Ehm
AU - Bouatia-Naji, Nabila
AU - Holmkvist, Johan
AU - Wegner, Lise
AU - Grarup, Niels
AU - Gjesing, Anette P
AU - Banasik, Karina
AU - Cavalcanti-Proença, Christine
AU - Marchand, Marion
AU - Vaxillaire, Martine
AU - Charpentier, Guillaume
AU - Jarvelin, Marjo-Riitta
AU - Tichet, Jean
AU - Balkau, Beverley
AU - Marre, Michel
AU - Lévy-Marchal, Claire
AU - Faerch, Kristine
AU - Borch-Johnsen, Knut
AU - Jørgensen, Torben
AU - Madsbad, Sten
AU - Poulsen, Pernille
AU - Vaag, Allan
AU - Dina, Christian
AU - Hansen, Torben
AU - Pedersen, Oluf
AU - Froguel, Philippe
N1 - Keywords: 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
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
U2 - 10.2337/db08-1660
DO - 10.2337/db08-1660
M3 - Journal article
C2 - 19324940
SN - 0012-1797
VL - 58
SP - 1450
EP - 1456
JO - Diabetes
JF - Diabetes
IS - 6
ER -
