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

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Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men Pathophysiology/Complications ORIGINAL ARTICLE Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men 1 4 NELLY PITTELOUD, MD DEVJIT TRIPATHY, MD, DM nsulin resistance has assumed increas- 2 1 VAMSI K. MOOTHA, MD MARIA YIALAMAS, MD ing importance as a risk factor for car- 1 4 ANDREW A. DWYER, BA LEIF GROOP, MD, PHD 1 diovascular disease coincident with the EGAN ARDIN BA 5 I M H , DARIUSH ELAHI, PHD dramatic increase in the prevalence of 3 1 HANG LEE, PHD RANCES AYES MB, BCH, BAO 4 F J. H , obesity in the Western world. Recent KARL-FREDRIK ERIKSSON, MD studies using genetic analysis (1,2), func- tional imaging (3,4), and animal models of differential aerobic capacity (5) have shed light on the role of mitochondrial function in inducing the metabolic distur- OBJECTIVE — The goal of this study was to examine the relationship between serum bances characteristic of insulin-resistant testosterone levels and insulin sensitivity and mitochondrial function in men. states. Using gene set enrichment analysis RESEARCH DESIGN AND METHODS — A total of 60 men (mean age 60.5 Ϯ 1.2 to look for changes in sets of genes com- years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using piled on the basis of function, Mootha et a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring max- al. (1) showed decreased maximal aerobic O imal aerobic capacity (VO2max) and expression of oxidative phosphorylation genes in skeletal capacity (V 2max) and decreased expres- muscle. sion of mitochondrial genes involved in oxidative phosphorylation (OXPHOS) in RESULTS — A total of 45% of subjects had normal glucose tolerance, 20% had impaired men of Northern European descent with glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated impaired glucose tolerance (IGT) and with insulin sensitivity (r ϭ 0.4, P Ͻ 0.005). Subjects with hypogonadal testosterone levels (n ϭ type 2 diabetes. Using quantitative real- 10) had a BMI Ͼ25 kg/m2 and a threefold higher prevalence of the metabolic syndrome than time PCR, Patti et al. (2) reported de- their eugonadal counterparts (n ϭ 50); this relationship held true after adjusting for age and sex creased OXPHOS gene expression in a ϭ hormone–binding globulin but not BMI. Testosterone levels also correlated with VO2max (r Mexican-American population of type 2 Ͻ ϭ Ͻ 0.43, P 0.05) and oxidative phosphorylation gene expression (r 0.57, P 0.0001). diabetic subjects as well as insulin- resistant first-degree relatives of type 2 di- CONCLUSIONS — These data indicate that low serum testosterone levels are associated abetic subjects with normal glucose with an adverse metabolic profile and suggest a novel unifying mechanism for the previously tolerance (NGT). Magnetic resonance independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men. spectroscopy has shown that decreased mitochondrial oxidative and phosphory- Diabetes Care 28:1636–1642, 2005 lation activity underlies the insulin resis- tance seen with aging (3) and in lean offspring of patients with type 2 diabetes (4). Recent data from rats bred to have low aerobic capacity also implicate im- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● paired mitochondrial function in the de- From the 1Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, velopment of the cardiovascular risk Boston, Massachusetts; the 2Broad Institute, Harvard University and Massachusetts Institute of Technology, profile characteristic of the metabolic syn- Cambridge, Massachusetts; the 3Department of Biostatistics and General Clinical Research Center, Massa- drome (5). chusetts General Hospital, Boston, Massachusetts; the 4Department of Endocrinology, Wallenberg Labora- Little is known about the interaction 5 tory, University Hospital MAS, Lund University, Malmo, Sweden; and the Department of Surgery, between testosterone levels and insulin University of Massachusetts Medical Center, Worcester, Massachusetts. Address correspondence and reprint requests to Frances J. Hayes, MD, Reproductive Endocrine Unit, sensitivity in men, in contrast to the abun- BHX 511 Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114. E-mail: [email protected]. dant literature on this relationship in Received for publication 11 November 2004 and accepted in revised form 22 March 2005. women (6). Cross-sectional studies dem- L.G. has served on an advisory panel for Bristol-Myers Squibb. ␣ onstrate an inverse relationship between Abbreviations: E2, estradiol; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; PGC-1 , peroxisome proliferator–activated receptor-␥ coactivator; OXPHOS, oxidative phosphorylation; SHBG, sex testosterone and fasting insulin levels in hormone–binding globulin; UQCRB, ubiquinol cytochrome c reductase–binding protein; WHR, waist-to- men independent of age, obesity, and hip ratio. body fat distribution (7–11). A link be- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion tween testosterone deficiency and diabe- factors for many substances. tes has also been suggested with the © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby demonstration that men with type 2 dia- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. betes have lower testosterone levels than 1636 DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005 Pitteloud and Associates weight-matched nondiabetic control sub- provided written informed consent be- were 497 Ϯ 15 pmol/l and 1,188 Ϯ 75 Ϫ jects (12,13). In addition, six large pro- fore the initiation of any study proce- pmol/l for insulin doses of 40 mU ⅐ m 2 ⅐ Ϫ Ϫ Ϫ spective studies have shown that low dures. min 1 and 80 mU ⅐ m 2 ⅐ min 1, respec- testosterone levels predict development tively. All statistical analyses using insulin of type 2 diabetes in men (14–19). Two Anthropometric measures sensitivity as a parameter were corrected studies demonstrate a positive relation- Height and weight were measured by for insulin levels during the clamp. ship between total testosterone levels and standard procedures to calculate BMI as insulin sensitivity in normal (20) and di- weight (kg) divided by height squared Maximal aerobic capacity 2 abetic men (21). In contrast, data on the (m ). Waist-to-hip ratio (WHR) was cal- VO2max was measured in the Swedish sub- relationship between free testosterone culated by measuring waist circumfer- jects using an incremental work- levels and insulin sensitivity are conflict- ence at the level of the umbilicus and hip conducted upright exercise test with a ing, with two studies showing no correla- circumference at the level of the greatest bicycle ergometer (Monark Varberg, Swe- tion (21,22), whereas a third study hip girth. In the 42 Swedish subjects, per- den) combined with continuous analysis demonstrates a weak positive relationship cent body fat was measured using bioel- of expiratory gases and minute ventila- (20). ectrical impedance analysis. tion. Exercise was started at a workload Given that low testosterone levels varying between 30 and 100 W depend- predict development of type 2 diabetes in Oral glucose tolerance test ing on the history of endurance training men (14–19) and that aging is accompa- A standardized 2-h oral glucose tolerance or exercise habits and increased by 20–50 nied by insulin resistance and a decline in test using 75 g glucose was performed on W every 3 min, until a perceived exhaus- testosterone secretion (23–25), we hy- the basis of which subjects were classified tion or a respiratory quotient of 1.0 was pothesized that testosterone is an impor- as having NGT, IGT, or type 2 diabetes reached. Maximal aerobic capacity was tant modulator of insulin sensitivity and using 1985 criteria from the World defined as the VO2 during the last 30 s of mitochondrial function in men. Thus, the Health Organization (27). exercise and is expressed per lean body aims of this study were to 1) examine the mass calculated by bioelectrical imped- relationship between serum testosterone Insulin sensitivity ance analysis. levels and insulin sensitivity in men Insulin sensitivity was determined by the across a wide spectrum of insulin sensi- hyperinsulinemic-euglycemic clamp Percutaneous muscle biopsy tivity, 2) dissect the role of obesity and technique (28). For 3 days before the Percutaneous muscle biopsies (20–50 alterations in sex hormone–binding glob- study, all subjects consumed a weight- mg) were taken from the vastus lateralis ulin (SHBG) levels in mediating this rela- maintaining diet containing 300 g carbo- muscle of the Swedish subjects. Biopsies tionship, and 3) determine if there is an hydrate per day. The clamp studies were were performed under local anesthesia association between serum testosterone performed at 7:30 A.M. after a 12-h fast. (1% lidocaine) using a Bergstro¨m needle levels and mitochondrial function re- An intravenous cannula was inserted into after the hyperinsulinemic-euglycemic flected by VO2max and OXPHOS gene ex- an antecubital vein for the infusion of in- clamp. Fiber-type composition and pression in skeletal muscle. sulin and glucose. A second catheter was whole-muscle glycogen concentration inserted retrogradely into a hand vein for were determined
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