• K J Mather, C Kim, C A Christophi, V R Aroda, W C Knowler, S E Edelstein, J C Florez, F Labrie, S E Kahn, R B Goldberg, E Barrett-Connor, and Diabetes Prevention Program.
• Department of Medicine (K.J.M.), Indiana University, Indianapolis, Indiana 46202; Departments of Medicine and Obstetrics & Gynecology (C.K.), University of Michigan, Ann Arbor, Michigan 48109; Biostatistics Center (C.A.C., S.E.E.), George Washington University, Rockville, Maryland 20850; Medstar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; Diabetes Research Center (Diabetes Unit) and Center for Human Genetics Research (J.C.F.), Massachusetts General Hospital, Boston, Massachusetts 02114; Program in Medical and Population Genetics (J.C.F.), Broad Institute, Cambridge, Massachusetts 02142; Department of Medicine (J.C.F.), Harvard Medical School, Boston, Massachusetts 02115; Endoceutics Inc. (F.L.), Québec City, G1W 2J5, Canada; VA Puget Sound Health Care System and University of Washington (S.E.K.), Seattle, Washington 98108; University of Miami (R.B.G.), Miami, Florida 33124; and University of California, San Diego (E.B.-C.), San Diego, California 92093.
• J. Clin. Endocrinol. Metab. 2015 Oct 1; 100 (10): 3778-86.

ContextSteroid sex hormones and SHBG may modify metabolism and diabetes risk, with implications for sex-specific diabetes risk and effects of prevention interventions.ObjectiveThis study aimed to evaluate the relationships of steroid sex hormones, SHBG and SHBG single-nucleotide polymorphisms (SNPs) with diabetes risk factors and with progression to diabetes in the Diabetes Prevention Program (DPP).Design And SettingThis was a secondary analysis of a multicenter randomized clinical trial involving 27 U.S. academic institutions.ParticipantsThe study included 2898 DPP participants: 969 men, 948 premenopausal women not taking exogenous sex hormones, 550 postmenopausal women not taking exogenous sex hormones, and 431 postmenopausal women taking exogenous sex hormones.InterventionsParticipants were randomized to receive intensive lifestyle intervention, metformin, or placebo.Main OutcomesAssociations of steroid sex hormones, SHBG, and SHBG SNPs with glycemia and diabetes risk factors, and with incident diabetes over median 3.0 years (maximum, 5.0 y).ResultsT and DHT were inversely associated with fasting glucose in men, and estrone sulfate was directly associated with 2-hour post-challenge glucose in men and premenopausal women. SHBG was associated with fasting glucose in premenopausal women not taking exogenous sex hormones, and in postmenopausal women taking exogenous sex hormones, but not in the other groups. Diabetes incidence was directly associated with estrone and estradiol and inversely with T in men; the association with T was lost after adjustment for waist circumference. Sex steroids were not associated with diabetes outcomes in women. SHBG and SHBG SNPs did not predict incident diabetes in the DPP population.ConclusionsEstrogens and T predicted diabetes risk in men but not in women. SHBG and its polymorphisms did not predict risk in men or women. Diabetes risk is more potently determined by obesity and glycemia than by sex hormones.

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