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Mitochondrial Respiration Is Decreased in Skeletal Muscle of Patients With Type 2 Diabetes

¹ Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
² Stockholm University College of Physical Education and Sports, GIH, Stockholm, Sweden
³ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
⁴ Department of Endocrinology, Diabetes Research Centre, Odense University Hospital, Odense, Denmark

Address correspondence and reprint requests to Kurt Højlund, MD, PhD, Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Kloevervaenget 6, 3, DK-5000 Odense C, Denmark. E-mail: k.hojlund{at}dadlnet.dk

Abbreviations: ETC, electron transport chain; FFA, free fatty acid; HAD, 3-hydroxy-Acyl-CoA-dehydrogenase; HNE, 4-hydroxy-2-nonenal; HOMA-IR, homeostasis model assessment of insulin resistance; RCI, respiratory control index; ROS, reactive oxygen species; UCP, uncoupling protein

We tested the hypothesis of a lower respiratory capacity per mitochondrion in skeletal muscle of type 2 diabetic patients compared with obese subjects. Muscle biopsies obtained from 10 obese type 2 diabetic and 8 obese nondiabetic male subjects were used for assessment of 3-hydroxy-Acyl-CoA-dehydrogenase (HAD) and citrate synthase activity, uncoupling protein (UCP)3 content, oxidative stress measured as 4-hydroxy-2-nonenal (HNE), fiber type distribution, and respiration in isolated mitochondria. Respiration was normalized to citrate synthase activity (mitochondrial content) in isolated mitochondria. Maximal ADP-stimulated respiration (state 3) with pyruvate plus malate and respiration through the electron transport chain (ETC) were reduced in type 2 diabetic patients, and the proportion of type 2X fibers were higher in type 2 diabetic patients compared with obese subjects (all P < 0.05). There were no differences in respiration with palmitoyl-L-carnitine plus malate, citrate synthase activity, HAD activity, UCP3 content, or oxidative stress measured as HNE between the groups. In the whole group, state 3 respiration with pyruvate plus malate and respiration through ETC were negatively associated with A1C, and the proportion of type 2X fibers correlated with markers of insulin resistance (P < 0.05). In conclusion, we provide evidence for a functional impairment in mitochondrial respiration and increased amount of type 2X fibers in muscle of type 2 diabetic patients. These alterations may contribute to the development of type 2 diabetes in humans with obesity.

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