Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity

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

  • Diabetes

    Diabetes 63 (12), 4378-4387, 2014-11-13

    American Diabetes Association

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