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Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity
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2014 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, 4378-4387 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 63, no 12, 4378-4387 p.
Keyword [en]
FRONZO RA, 1979, AMERICAN JOURNAL OF PHYSIOLOGY, V237, PE214 thelius B, 2003, DIABETOLOGIA, V46, P20 ssenko Valeriya, 2007, JOURNAL OF CLINICAL INVESTIGATION, V117, P2155 vage David B., 2007, PHYSIOLOGICAL REVIEWS, V87, P507 iderman Allan D., 2007, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, V36, P220 ms EAH, 2001, METABOLISM-CLINICAL AND EXPERIMENTAL, V50, P1499
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-98557DOI: 10.2337/db14-0319ISI: 000345335500046PubMedID: 24947364OAI: oai:DiVA.org:umu-98557DiVA: diva2:784599
Available from: 2015-01-30 Created: 2015-01-23 Last updated: 2017-12-05Bibliographically approved

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