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Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men

¹ Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Ho2spital, Boston, Massachusetts
² Broad Institute, Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts
³ Department of Biostatistics and General Clinical Research Center, Massachusetts General Hospital, Boston, Massachusetts
⁴ Department of Endocrinology, Wallenberg Laboratory, University Hospital MAS, Lund University, Malmo, Sweden
⁵ Department of Surgery, University of Massachusetts Medical Center, Worcester, Massachusetts

Address correspondence and reprint requests to Frances J. Hayes, MD, Reproductive Endocrine Unit, BHX 511 Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114. E-mail: fhayes{at}partners.org

OBJECTIVE— The goal of this study was to examine the relationship between serum testosterone levels and insulin sensitivity and mitochondrial function in men.

RESEARCH DESIGN AND METHODS—A total of 60 men (mean age 60.5 ± 1.2 years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring maximal aerobic capacity (VO_2max) and expression of oxidative phosphorylation genes in skeletal muscle.

RESULTS—A total of 45% of subjects had normal glucose tolerance, 20% had impaired glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated with insulin sensitivity (r = 0.4, P < 0.005). Subjects with hypogonadal testosterone levels (n = 10) had a BMI >25 kg/m² and a threefold higher prevalence of the metabolic syndrome than their eugonadal counterparts (n = 50); this relationship held true after adjusting for age and sex hormone–binding globulin but not BMI. Testosterone levels also correlated with VO_2max (r = 0.43, P < 0.05) and oxidative phosphorylation gene expression (r = 0.57, P < 0.0001).

CONCLUSIONS—These data indicate that low serum testosterone levels are associated with an adverse metabolic profile and suggest a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men.

Abbreviations: E₂, estradiol • IGT, impaired glucose tolerance • NGT, normal glucose tolerance • PGC-1, peroxisome proliferator–activated receptor- coactivator • OXPHOS, oxidative phosphorylation • SHBG, sex hormone–binding globulin • UQCRB, ubiquinol cytochrome c reductase–binding protein • WHR, waist-to-hip ratio

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