Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity

  1. Nicholas J Wareham1,*
  1. 1MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
  2. 2Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  3. 3Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK
  4. 4Public Health Division of Gipuzkoa, San Sebastian, Spain
  5. 5Instituto BIO-Donostia, Basque Government, San Sebastian, Spain
  6. 6CIBER Epidemiología y Salud Pública (CIBERESP), Spain
  7. 7Inserm, CESP, U1018, Villejuif, France
  8. 8Univ Paris-Sud, UMRS 1018, Villejuif, France
  9. 9Navarre Public Health Institute (ISPN), Pamplona, Spain
  10. 10The Wellcome Trust Sanger Institute, Cambridge, United Kingdom
  11. 11University of Cambridge Metabolic Research Laboratories, Cambridge, UK
  12. 12German Institute of Human Nutrition Potsdam-Rehbruecke, Germany
  13. 13University of Oxford, United Kingdom
  14. 14Department of Epidemiology and Biostatistics, VrijeUniversiteit Medical Center, Amsterdam, The Netherlands
  15. 15Department of Internal Medicine, University of Pisa, Pisa, Italy
  16. 16Lund University, Malmö, Sweden
  17. 17Umeå University, Umeå, Sweden
  18. 18Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain
  19. 19Department of Public Health and Caring Sciences, Geriatrics, Uppsala University Sweden
  20. 20Epidemiology and Prevention Unit, Milan, Italy
  21. 21University Hospital Scania, Malmö, Sweden
  22. 22Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland
  23. 23German Cancer Research Centre (DKFZ), Heidelberg, Germany
  24. 24Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark
  25. 25Aalborg University Hospital, Aalborg, Denmark
  26. 26Cancer Research and Prevention Institute (ISPO), Florence, Italy
  27. 27Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
  28. 28Public Health Directorate, Asturias, Spain
  29. 29Danish Cancer Society Research Center, Copenhagen, Denmark
  30. 30Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Torino, Italy
  31. 31Human Genetics Foundation (HuGeF), Torino, Italy
  32. 32Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, and Translational Research Laboratory, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain
  33. 33Andalusian School of Public Health, Granada, Spain
  34. 34Instituto de Investigación Biosanitaria de Granada (Granada.ibs), Granada (Spain)
  35. 35School of Public Health, Imperial College London, UK
  36. 36International Agency for Research on Cancer, Lyon, France
  37. 37University Medical Center Utrecht, Utrecht, the Netherlands
  38. 38National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  39. 39ASP Ragusa, Italy
  40. 40Aire Onlus, Ragusa, Italy
  41. 41Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, UK
  42. 42Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  43. 43Oxford NIHR Biomedical Research Centre, Oxford, UK
  44. 44Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
  1. Corresponding author:Robert Scott Email: robert.scott{at}


We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-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=1.4x10-6), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (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.


  • * These authors contributed equally to the manuscript

  • Received February 24, 2014.
  • Accepted June 9, 2014.

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