Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity
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- Robert A. Scott
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
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- Tove Fall
- Department of Medical Sciences, Molecular Epidemiology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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- Dorota Pasko
- Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
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- Adam Barker
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
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- Stephen J. Sharp
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
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- Larraitz Arriola
- Public Health Division of Gipuzkoa, San Sebastian, Spain
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- Beverley Balkau
- INSERM, Centre de recherché en Épidémilogie et Santé des Populations, U1018, Villejuif, France
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- Aurelio Barricarte
- Centro de Investigación Biomédica en Red Epidemiología y Salud Pública, Barcelona, Spain
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- Inês Barroso
- Wellcome Trust Sanger Institute, Cambridge, U.K.
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- Heiner Boeing
- German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany
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- Françoise Clavel-Chapelon
- INSERM, Centre de recherché en Épidémilogie et Santé des Populations, U1018, Villejuif, France
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- Francesca L. Crowe
- University of Oxford, Oxford, U.K.
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- Jacqueline M. Dekker
- Department of Epidemiology and Biostatistics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
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- Guy Fagherazzi
- INSERM, Centre de recherché en Épidémilogie et Santé des Populations, U1018, Villejuif, France
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- Ele Ferrannini
- Department of Internal Medicine, University of Pisa, Pisa, Italy
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- Nita G. Forouhi
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
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- Paul W. Franks
- Lund University, Malmö, Sweden
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- Diana Gavrila
- Centro de Investigación Biomédica en Red Epidemiología y Salud Pública, Barcelona, Spain
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- Vilmantas Giedraitis
- Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden
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- Sara Grioni
- Epidemiology and Prevention Unit, Milan, Italy
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- Leif C. Groop
- University Hospital Scania, Malmö, Sweden
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- Rudolf Kaaks
- German Cancer Research Centre, Heidelberg, Germany
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- Timothy J. Key
- University of Oxford, Oxford, U.K.
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- Tilman Kühn
- German Cancer Research Centre, Heidelberg, Germany
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- Luca A. Lotta
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
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- Peter M. Nilsson
- Lund University, Malmö, Sweden
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- Kim Overvad
- Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark
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- Domenico Palli
- Cancer Research and Prevention Institute, Florence, Italy
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- Salvatore Panico
- Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
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- J. Ramón Quirós
- Public Health Directorate, Asturias, Spain
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- Olov Rolandsson
- Umeå University, Umeå, Sweden
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- Nina Roswall
- Danish Cancer Society Research Center, Copenhagen, Denmark
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- Carlotta Sacerdote
- Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention, Torino, Italy
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- Núria Sala
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, and Translational Research Laboratory, Catalan Institute of Oncology, Barcelona, Spain
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- María-José Sánchez
- Centro de Investigación Biomédica en Red Epidemiología y Salud Pública, Barcelona, Spain
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- Matthias B. Schulze
- German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany
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- Afshan Siddiq
- School of Public Health, Imperial College London, London, U.K.
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- Nadia Slimani
- International Agency for Research on Cancer, Lyon, France
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- Ivonne Sluijs
- University Medical Center Utrecht, Utrecht, the Netherlands
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- Annemieke M.W. Spijkerman
- National Institute for Public Health and the Environment, Bilthoven, the Netherlands
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- Anne Tjonneland
- Danish Cancer Society Research Center, Copenhagen, Denmark
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- Rosario Tumino
- Azienda Sanitaria Provinciale, Ragusa, Italy
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- Daphne L. van der A
- National Institute for Public Health and the Environment, Bilthoven, the Netherlands
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- Hanieh Yaghootkar
- Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
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- Mark I. McCarthy
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K.
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- Robert K. Semple
- University of Cambridge Metabolic Research Laboratories, Cambridge, U.K.
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- Elio Riboli
- School of Public Health, Imperial College London, London, U.K.
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- Mark Walker
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
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- Erik Ingelsson
- Department of Medical Sciences, Molecular Epidemiology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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- Tim M. Frayling
- Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
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- David B. Savage
- University of Cambridge Metabolic Research Laboratories, Cambridge, U.K.
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- Claudia Langenberg
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
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- Nicholas J. Wareham
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
抄録
<jats:p>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.</jats:p>
収録刊行物
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- Diabetes
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Diabetes 63 (12), 4378-4387, 2014-11-13
American Diabetes Association