Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans

  1. on behalf of the MAGIC investigators*
  1. Corresponding authors: Erik Ingelsson, erik.ingelsson{at}ki.se; Leif Groop, Leif.Groop{at}med.lu.se; Richard M. Watanabe, rwatanab{at}usc.edu; Jose C. Florez, jcflorez{at}partners.org.
  1. E.I., C.L., and M.-F.H. contributed equally to this article.

Abstract

OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action.

RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084).

RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction.

CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.

Footnotes

  • *The complete list of authors' affiliations can be found in the appendix.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • 1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

  • 2 Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden

  • 3 Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.

  • 4 Centre de Recherche Medicale de l'Universite de Sherbrooke, Sherbrooke, Quebec, Canada

  • 5 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.

  • 6 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.

  • 7 Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden

  • 8 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts

  • 9 Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan

  • 10 Department of Medicine, Stanford University School of Medicine, Stanford, California

  • 11 General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts

  • 12 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California

  • 13 Health Care Centre of the Medical Faculty Carl-Gustav-Carus of the Technical University, Dresden, Germany

  • 14 Department of Medical Sciences, Uppsala University, Uppsala, Sweden

  • 15 Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland

  • 16 Prevention and Care of Diabetes Division, Department of Medicine III, University of Dresden, Dresden, Germany

  • 17 Division of Endocrinology and Diabetes, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California

  • 18 Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K.

  • 19 Department of Medicine, University of Leipzig, Leipzig, Germany

  • 20 Medical Research Council Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, U.K.

  • 21 Department of Internal Medicine, University of Pisa, Pisa, Italy

  • 22 Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts

  • 23 Division of Endocrinology, Diabetes, and Hypertension, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts;

  • 24 Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co., Inc., Seattle, Washington

  • 25 Folkhalsan Research Centre, Helsinki, Finland

  • 26 Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland

  • 27 Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany

  • 28 Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland

  • 29 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina

  • 30 Diabetes Research Center (Diabetes Unit) and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts

  • 31 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.

  • 32 Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K.

  • 33 British Heart Foundation Cardiovascular Research Centre, University of Glasgow, U.K.

  • 34 Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland

  • 35 Hjelt Institute, Department of Public Health, University of Helsinki and the Unit of Diabetes Prevention, National Institute for Health and Welfare Helsinki, Finland

  • 36 South Ostrobothnia Central Hospital, Seinajoki, Finland

  • 37 Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany

  • 38 Department of Medicine, Harvard Medical School, Boston, Massachusetts;

  • 39 Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK;

  • 40 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California

  • 41 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; and the

  • 42 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.

    • Received October 26, 2009.
    • Accepted February 18, 2010.

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. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 59 no. 5 1266-1275
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