title: Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants.
abstract: Large genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (β = -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (β = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants.
authors.affiliation: Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hivert
authors.affiliation: The Biostatistics Center, George Washington University, Rockville, MD.
authors.forename: Costas A
authors.initials: CA
authors.lastname: Christophi
authors.affiliation: Genetic & Molecular Epidemiology Unit, Lund University Diabetes Center, Department of Clinical Sciences, Lund University, Malmö, Sweden Department of Nutrition, Harvard School of Public Health, Boston, MA Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, Umeå, Sweden.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.affiliation: The Biostatistics Center, George Washington University, Rockville, MD.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Jablonski
authors.affiliation: Department of Medicine, The University of Chicago School of Medicine, Chicago, IL.
authors.forename: David A
authors.initials: DA
authors.lastname: Ehrmann
authors.affiliation: Division of Metabolism, Endocrinology & Nutrition, VA Puget Sound Health Care System and University of Washington, Seattle, WA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
authors.affiliation: Section on Clinical, Behavioral & Outcomes Research, Joslin Diabetes Center, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Horton
authors.affiliation: Departments of Medicine and Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, MD Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
authors.affiliation: Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Kieren J
authors.initials: KJ
authors.lastname: Mather
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: Leigh
authors.initials: L
authors.lastname: Perreault
authors.affiliation: Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Barrett-Connor
authors.affiliation: Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ.
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.affiliation: Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA dppmail@bsc.gwu.edu.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D018570:Risk Assessment; D012307:Risk Factors; D040242:Risk Reduction Behavior; D014481:United States
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin