| Literature DB >> 24947364 |
Claudia Langenberg1, Nicholas J Wareham1, Robert A Scott1, Tove Fall2, Dorota Pasko3, Adam Barker1, Stephen J Sharp1, Larraitz Arriola4,5,6, Beverley Balkau7,8, Aurelio Barricarte9,6, Inês Barroso10,11, Heiner Boeing12, Françoise Clavel-Chapelon7,8, Francesca L Crowe13, Jacqueline M Dekker14, Guy Fagherazzi7,8, Ele Ferrannini15, Nita G Forouhi1, Paul W Franks16,17, Diana Gavrila18,6, Vilmantas Giedraitis19, Sara Grioni20, Leif C Groop21,22, Rudolf Kaaks23, Timothy J Key13, Tilman Kühn23, Luca A Lotta1, Peter M Nilsson16, Kim Overvad24,25, Domenico Palli26, Salvatore Panico27, J Ramón Quirós28, Olov Rolandsson17, Nina Roswall29, Carlotta Sacerdote30,31, Núria Sala32, María-José Sánchez33,6,34, Matthias B Schulze12, Afshan Siddiq35, Nadia Slimani36, Ivonne Sluijs37, Annemieke Mw Spijkerman38, Anne Tjonneland29, Rosario Tumino39,40, Daphne L van der A38, Hanieh Yaghootkar3, Mark I McCarthy41,42,43, Robert K Semple11, Elio Riboli35, Mark Walker44, Erik Ingelsson2, Tim M Frayling3, David B Savage11.
Abstract
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 (β 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 = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 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.Entities:
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Year: 2014 PMID： 24947364 PMCID： PMC4241116 DOI： 10.2337/db14-0319
Source DB: PubMed Journal: Diabetes ISSN： 0012-1797 Impact factor: 9.461