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Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity

Lookup NU author(s): Professor Mark Walker


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We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (beta in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05,-0.02; P = 1.4x10(-6) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and gamma-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (P-interaction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (P-interaction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Publication metadata

Author(s): Scott RA, Fall T, Pasko D, Barker A, Sharp SJ, Arriola L, Balkau B, Barricarte A, Barroso I, Boeing H, Clavel-Chapelon F, Crowe FL, Dekker JM, Fagherazzi G, Ferrannini E, Forouhi NG, Franks PW, Gavrila D, Giedraitis V, Grioni S, Groop LC, Kaaks R, Key TJ, Kuhn T, Lotta LA, Nilsson PM, Overvad K, Palli D, Panico S, Quiros JR, Rolandsson O, Roswall N, Sacerdote C, Sala N, Sanchez MJ, Schulze MB, Siddiq A, Slimani N, Sluijs I, Spijkerman AMW, Tjonneland A, Tumino R, van der A DL, Yaghootkar H, McCarthy MI, Semple RK, Riboli E, Walker M, Ingelsson E, Frayling TM, Savage DB, Langenberg C, Wareham NJ, RISC Study Grp, EPIC-InterAct Consortium

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2014

Volume: 63

Issue: 12

Pages: 4378-4387

Print publication date: 01/12/2014

Online publication date: 19/06/2014

Acceptance date: 09/06/2014

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association


DOI: 10.2337/db14-0319


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Funder referenceFunder name
Danish Cancer Society
Diabetes UK
Dutch Prevention Funds
Dutch ZON (Zorg Onderzoek Nederland)
German Cancer Aid
German Ministry of Research
Imperial College Biomedical Research
MRC Centre for Obesity and Related Metabolic Disease
Swedish Heart-Lung Foundation
U.K. NIHR Cambridge Biomedical Research Centre
Uppsala University Hospital
Vasterboten County Council
Asturias Regional Government
board of the UMC Utrecht
Cancer Research UK
Compagnia di San Paolo
Dutch Ministry of Public Health, Welfare, and Sports
Health Research Fund (FIS) of the Spanish Ministry of Health
LK Research Funds
Netherlands Cancer Registry
Science for Life Laboratory, Uppsala
Sicilian Regional Government
Statistics Netherlands
Swedish Diabetes Association
U.K. National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
Uppsala University
World Cancer Research Fund
083270/Z/07/ZWellcome Trust
098051Wellcome Trust
70374401Swedish Research Council
6236Murcia Regional Government
80576801Swedish Research Council
LSHM_CT_2006_037197EU FP6 program
IGE05012NL Agency
QLG1-CT-2001-01252European Union