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      Diabetes

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          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.

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          Author and article information

          Journal
          Diabetes
          Diabetes
          1939-327X
          0012-1797
          Dec 2014
          : 63
          : 12
          Affiliations
          [1 ] MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, U.K. robert.scott@mrc-epid.cam.ac.uk.
          [2 ] Department of Medical Sciences, Molecular Epidemiology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
          [3 ] Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
          [4 ] MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
          [5 ] Public Health Division of Gipuzkoa, San Sebastian, Spain Instituto BioDonostia, Basque Government, San Sebastian, Spain Centro de Investigación Biomédica en Red Epidemiología y Salud Pública, Barcelona, Spain.
          [6 ] INSERM, Centre de recherché en Épidémilogie et Santé des Populations, U1018, Villejuif, France Université Paris-Sud, UMRS 1018, Villejuif, France.
          [7 ] Centro de Investigación Biomédica en Red Epidemiología y Salud Pública, Barcelona, Spain Navarre Public Health Institute, Pamplona, Spain.
          [8 ] Wellcome Trust Sanger Institute, Cambridge, U.K. University of Cambridge Metabolic Research Laboratories, Cambridge, U.K.
          [9 ] German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
          [10 ] University of Oxford, Oxford, U.K.
          [11 ] Department of Epidemiology and Biostatistics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
          [12 ] Department of Internal Medicine, University of Pisa, Pisa, Italy.
          [13 ] Lund University, Malmö, Sweden Umeå University, Umeå, Sweden.
          [14 ] Centro de Investigación Biomédica en Red Epidemiología y Salud Pública, Barcelona, Spain Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain.
          [15 ] Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
          [16 ] Epidemiology and Prevention Unit, Milan, Italy.
          [17 ] University Hospital Scania, Malmö, Sweden Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
          [18 ] German Cancer Research Centre, Heidelberg, Germany.
          [19 ] Lund University, Malmö, Sweden.
          [20 ] Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark Aalborg University Hospital, Aalborg, Denmark.
          [21 ] Cancer Research and Prevention Institute, Florence, Italy.
          [22 ] Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
          [23 ] Public Health Directorate, Asturias, Spain.
          [24 ] Umeå University, Umeå, Sweden.
          [25 ] Danish Cancer Society Research Center, Copenhagen, Denmark.
          [26 ] Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention, Torino, Italy Human Genetics Foundation, Torino, Italy.
          [27 ] Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, and Translational Research Laboratory, Catalan Institute of Oncology, Barcelona, Spain.
          [28 ] Centro de Investigación Biomédica en Red Epidemiología y Salud Pública, Barcelona, Spain Andalusian School of Public Health, Granada, Spain Instituto de Investigación Biosanitaria de Granada, Granada, Spain.
          [29 ] School of Public Health, Imperial College London, London, U.K.
          [30 ] International Agency for Research on Cancer, Lyon, France.
          [31 ] University Medical Center Utrecht, Utrecht, the Netherlands.
          [32 ] National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
          [33 ] Azienda Sanitaria Provinciale, Ragusa, Italy Aire Onlus, Ragusa, Italy.
          [34 ] Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. National Institute of Health Research Oxford Biomedical Research Centre, Oxford, U.K.
          [35 ] University of Cambridge Metabolic Research Laboratories, Cambridge, U.K.
          [36 ] Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
          Article
          db14-0319 EMS60480
          10.2337/db14-0319
          4241116
          24947364
          28faba9d-0bbd-46e7-a4e9-f25346867950
          © 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.
          History

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