Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity
Robert A Scott, Tove Fall, Dorota Pasko, Adam Barker, Stephen J Sharp, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Inês Barroso, Heiner Boeing, Françoise Clavel-Chapelon, Francesca L Crowe, Jacqueline M Dekker, Guy Fagherazzi, Ele Ferrannini, Nita G Forouhi, Paul W Franks, Diana Gavrila, Vilmantas Giedraitis, Sara Grioni, Leif C Groop, Rudolf Kaaks, Timothy J Key, Tilman Kühn, Luca A Lotta, Peter M Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J Ramón Quirós, Olov Rolandsson, Nina Roswall, Carlotta Sacerdote, Núria Sala, María-José Sánchez, Matthias B Schulze, Afshan Siddiq, Nadia Slimani, Ivonne Sluijs, Annemieke Mw Spijkerman, Anne Tjonneland, Rosario Tumino, Daphne L van der A, Hanieh Yaghootkar, RISC study group, EPIC-InterAct consortium, Mark I McCarthy, Robert K Semple, Elio Riboli, Mark Walker, Erik Ingelsson, Tim M Frayling, David B Savage, Claudia Langenberg, Nicholas J Wareham, Robert A Scott, Tove Fall, Dorota Pasko, Adam Barker, Stephen J Sharp, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Inês Barroso, Heiner Boeing, Françoise Clavel-Chapelon, Francesca L Crowe, Jacqueline M Dekker, Guy Fagherazzi, Ele Ferrannini, Nita G Forouhi, Paul W Franks, Diana Gavrila, Vilmantas Giedraitis, Sara Grioni, Leif C Groop, Rudolf Kaaks, Timothy J Key, Tilman Kühn, Luca A Lotta, Peter M Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J Ramón Quirós, Olov Rolandsson, Nina Roswall, Carlotta Sacerdote, Núria Sala, María-José Sánchez, Matthias B Schulze, Afshan Siddiq, Nadia Slimani, Ivonne Sluijs, Annemieke Mw Spijkerman, Anne Tjonneland, Rosario Tumino, Daphne L van der A, Hanieh Yaghootkar, RISC study group, EPIC-InterAct consortium, Mark I McCarthy, Robert K Semple, Elio Riboli, Mark Walker, Erik Ingelsson, Tim M Frayling, David B Savage, Claudia Langenberg, Nicholas J Wareham
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.
© 2014 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.
Figures
Source: PubMed