| Title: |
Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity. |
| Authors: |
Scott, Robert A; Fall, Tove; Pasko, Dorota; Barker, Adam; Sharp, Stephen J; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Boeing, Heiner; Clavel-Chapelon, Françoise; Crowe, Francesca L; Dekker, Jacqueline M; Fagherazzi, Guy; Ferrannini, Ele; Forouhi, Nita G; Franks, Paul W; Gavrila, Diana; Giedraitis, Vilmantas; Grioni, Sara; Groop, Leif C; Kaaks, Rudolf; Key, Timothy J; Kühn, Tilman; Lotta, Luca A; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J Ramón; Rolandsson, Olov; Roswall, Nina; Sacerdote, Carlotta; Sala, Núria; Sánchez, María-José; Schulze, Matthias B; Siddiq, Afshan; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke Mw; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; Yaghootkar, Hanieh; RISC study group; EPIC-InterAct consortium; McCarthy, Mark I; Semple, Robert K; Riboli, Elio; Walker, Mark; Ingelsson, Erik; Frayling, Tim M; Savage, David B; Langenberg, Claudia; Wareham, Nicholas J |
| Publisher Information: |
American Diabetes Association; //doi.org/10.2337/db14-0319 |
| Publication Year: |
2014 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
Adult; Aged; Alanine Transaminase; Body Composition; Body Fat Distribution; Body Mass Index; Cohort Studies; Diabetes Mellitus; Type 2; Female; Genetic Predisposition to Disease; Genetic Variation; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Obesity; Overweight; Polymorphism; Single Nucleotide; Waist Circumference; gamma-Glutamyltransferase |
| Description: |
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. ; The MRC-Ely Study was funded by the Medical Research Council (MC_U106179471) and Diabetes UK. We are grateful to all the volunteers, and to the staff of St. Mary’s Street Surgery, Ely and the study team. The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/247305 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/247305 |
| Rights: |
Attribution-NonCommercial-NoDerivs 2.0 UK: England & Wales ; https://creativecommons.org/licenses/by-nc-nd/2.0/uk/ |
| Accession Number: |
edsbas.A1EBE63 |
| Database: |
BASE |