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Reduced Skeletal Muscle Uncoupling Protein-3 Content in Prediabetic Subjects and Type 2 Diabetic Patients: Restoration by Rosiglitazone Treatment

Departments of Human Biology (P.S., M.M., E.M.-K., E.E.B.) and Movement Sciences (G.S., E.M.-K., M.K.C.H.), Maastricht University, NL-6200 MD Maastricht, The Netherlands; Department of Endocrinology (J.-P.S.), Academic Hospital Maastricht, 6229 HX Maastricht, The Netherlands; and Clinique Romande de Readaptation SUVA Care (A.P.R.), 1951 Sion, Switzerland

Address all correspondence and requests for reprints to: Dr. P. Schrauwen, Nutrition and Toxicology Research Institute Maastricht, Department of Human Biology, Maastricht University, P.O. Box 616, NL-6200 MD Maastricht, The Netherlands. E-mail: p.schrauwen{at}hb.unimaas.nl.

Context: The mitochondrial uncoupling protein-3 (UCP3) has been implicated in the protection of the mitochondrial matrix against lipid-induced mitochondrial damage. Recent evidence points toward mitochondrial aberrations as a major contributor to the development of insulin resistance and diabetes, and UCP3 is reduced in diabetes.

Objective: We compared skeletal muscle UCP3 protein levels in prediabetic subjects [i.e. impaired glucose tolerance (IGT)], diabetic patients, and healthy controls and examined whether rosiglitazone treatment was able to restore UCP3.

Patients, Design, Intervention: Ten middle-aged obese men with type 2 diabetes mellitus [age, 61.4 ± 3.1 yr; body mass index (BMI), 29.8 ± 2.9 kg/m²], nine IGT subjects (age, 59.0 ± 6.6 yr; BMI, 29.7 ± 3.0 kg/m²), and 10 age- and BMI-matched healthy controls (age, 57.3 ± 7.4 yr; BMI, 30.1 ± 3.9 kg/m²) participated in this study. After baseline comparisons, diabetic patients received rosiglitazone (2 x 4 mg/d) for 8 wk.

Main Outcome Measures: Muscle biopsies were sampled to determine UCP3 and mitochondrial protein (complex I–V) content.

Results: UCP3 protein content was significantly lower in prediabetic IGT subjects and in diabetic patients compared with healthy controls (39.0 ± 28.5, 47.2 ± 24.7, and 72.0 ± 23.7 arbitrary units, respectively; P < 0.05), whereas the levels of the mitochondrial protein complex I–V were similar between groups. Rosiglitazone treatment for 8 wk significantly increased insulin sensitivity and muscle UCP3 content (from 53.2 ± 29.9 to 66.3 ± 30.9 arbitrary units; P < 0.05).

Conclusion: We show that UCP3 protein content is reduced in prediabetic subjects and type 2 diabetic patients. Eight weeks of rosiglitazone treatment restores skeletal muscle UCP3 protein in diabetic patients.

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