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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

Title: 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
Authors: Sparso, T
Bonnefond, A
Andersson, E
Bouatia-Naji, N
Holmkvist, J
Wegner, L
Grarup, N
Gjesing, AP
Banasik, K
Cavalcanti-Proenca, C
Marchand, M
Vaxillaire, M
Charpentier, G
Jarvelin, M-R
Tichet, J
Balkau, B
Marre, M
Levy-Marchal, C
Faerch, K
Borch-Johnsen, K
Jorgensen, T
Madsbad, S
Poulsen, P
Vaag, A
Dina, C
Hansen, T
Pedersen, O
Froguel, P
Item Type: Journal Article
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 × 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.
Issue Date: 1-Jun-2009
Date of Acceptance: 12-Mar-2009
URI: http://hdl.handle.net/10044/1/85660
DOI: 10.2337/db08-1660
ISSN: 0012-1797
Publisher: American Diabetes Association
Start Page: 1450
End Page: 1456
Journal / Book Title: Diabetes
Volume: 58
Issue: 6
Copyright Statement: © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: G0600331
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
BETA-CELL FUNCTION
MELATONIN RECEPTORS
SENSITIVITY
POPULATION
TOLERANCE
SECRETION
VARIANT
ROLES
YOUNG
Adult
Aged
Blood Glucose
Denmark
Diabetes Mellitus, Type 2
European Continental Ancestry Group
Genetic Variation
Glucose
Humans
Insulin
Insulin Resistance
Insulin Secretion
Insulin-Secreting Cells
Introns
Liver
Quantitative Trait Loci
Receptor, Melatonin, MT1
Risk Factors
Twins
Liver
Humans
Diabetes Mellitus, Type 2
Insulin Resistance
Insulin
Glucose
Blood Glucose
Receptor, Melatonin, MT1
Risk Factors
Twins
Quantitative Trait Loci
Introns
Adult
Aged
European Continental Ancestry Group
Denmark
Insulin-Secreting Cells
Genetic Variation
Insulin Secretion
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
BETA-CELL FUNCTION
MELATONIN RECEPTORS
SENSITIVITY
POPULATION
TOLERANCE
SECRETION
VARIANT
ROLES
YOUNG
Endocrinology & Metabolism
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2009-05-21
Appears in Collections:School of Public Health



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