Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity
Year: 2014
Type: article
Study design: Observational Study
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.
Source: Diabetes
DOI: 10.2337/db14-0319
Authors: 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 M.W. Spijkerman, Anne Tjonneland, Rosario Tumino, Daphne L. van der A, Hanieh Yaghootkar, The RISC Study Group, Mark I. McCarthy, Robert K. Semple, Elio Riboli, Mark Walker, Erik Ingelsson, Tim M. Frayling, David B. Savage, Claudia Langenberg, Nicholas J. Wareham
Institutions: University of Cambridge, Wellcome/MRC Institute of Metabolic Science, MRC Epidemiology Unit, Uppsala University, Science for Life Laboratory, University of Exeter, Basque Government, Biogipuzkoa Health Research Institute, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Université Paris-Sud, Inserm, Centre de recherche en Epidémiologie et Santé des Populations, Wellcome Sanger Institute, German Institute of Human Nutrition, University of Oxford, Amsterdam UMC Location Vrije Universiteit Amsterdam, University of Pisa, Lund University, Umeå University, University of Helsinki, Institute for Molecular Medicine Finland, German Cancer Research Center, Aarhus University, Aalborg University Hospital, Federico II University Hospital, University of Naples Federico II, Gobierno del Principado de Asturias, Danish Cancer Society, Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, Italian institute for Genomic Medicine, University of Turin, Institut Català d'Oncologia, Instituto de Investigación Biosanitaria de Granada, Andalusian School of Public Health, Imperial College London, Centre international de recherche sur le cancer, University Medical Center Utrecht, National Institute for Public Health and the Environment, Azienda Socio Sanitaria Territoriale di Pavia, Centre for Human Genetics, Oxford Centre for Diabetes, Endocrinology and Metabolism, Newcastle University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: LIPODYSTROPHY-A PARADIGM FOR ELUCIDATING PATHOGENIC MECHANISMS IN THE METABOLIC SYNDROME., Characterising causal alleles for common disease., Genetic dissection of mechanisms linking cell dysfunction, insulin resistance & major human disease, G2826529823, Institute of Metabolic Science., An investigation of genes in key beta-cell pathways following the type 2 diabetes WTCCC genome wide association study., G5594960057, NIHR Senior Investigator Award, G6723261869, G6957823285, NIHR Senior Investigator Award, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers
OpenAlex ID: W2127294907