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Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program

¹ Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
² Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
³ Department of Medicine, Harvard Medical School, Boston, Massachusetts
⁴ Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
⁵ Biostatistics Center, George Washington University, Rockville, Maryland
⁶ Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington
⁷ Genetic Epidemiology and Clinical Research Group, Institute of Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden
⁸ Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
⁹ Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
¹⁰ Department of Genetics, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Jose C. Florez, Diabetes Prevention Program Coordinating Center, Biostatistics Center, George Washington University, 6110 Executive Blvd., Suite 750, Rockville, MD 20852. E-mail: dppmail{at}biostat.bsc.gwu.edu

Abbreviations: DPP, Diabetes Prevention Program; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; SNP, single nucleotide polymorphism

The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over 3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-to-diabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation.

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