Search. Read. Cite.

Easy to search. Easy to read. Easy to cite with credible sources.

Diabetes

Year: 2009  |  Volume: 58  |  Issue: 6  |  Page No.: 1450 - 1456

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

T Sparso, A Bonnefond, E Andersson, N Bouatia Naji, J Holmkvist, L Wegner, N Grarup, A. P Gjesing, K Banasik, C Cavalcanti Proenca, M Marchand, M Vaxillaire, G Charpentier, M. R Jarvelin, J Tichet, B Balkau, M Marre, C Levy Marchal, K Faerch, K Borch Johnsen, T Jorgensen, S Madsbad, P Poulsen, A Vaag, C Dina, T Hansen, O Pedersen and P. Froguel

Abstract

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 β-cell dysfunction and hepatic insulin resistance.

View Fulltext