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Muscle Oxidative Capacity Is a Better Predictor of Insulin Sensitivity than Lipid Status

Exercise Metabolism Group (C.R.B., D.G.N., J.A.H.) and Skeletal Muscle Research Laboratory (A.L.C.), School of Medical Sciences, RMIT University, Bundoora, Victoria 3083, Australia; Exercise Physiology and Metabolism Laboratory, Department of Physiology (M.J.A.), The University of Melbourne, Parkville, Victoria 3052, Australia; Department of Kinesiology (A.B.), University of Waterloo, Waterloo, Ontario, Canada N2L 3G1; and Garvan Institute of Medical Research (A.D.K., G.J.C.), St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia

Address all correspondence and requests for reprints to: John A. Hawley, Ph.D., School of Medical Sciences, RMIT University, P.O. Box 71, Victoria 3083, Australia. E-mail: john.hawley{at}rmit.edu.au.

We determined whole-body insulin sensitivity, long-chain fatty acyl coenzyme A (LCACoA) content, skeletal muscle triglyceride (TG_m) concentration, fatty acid transporter protein content, and oxidative enzyme activity in eight patients with type 2 diabetes (TYPE 2); six healthy control subjects matched for age (OLD), body mass index, percentage of body fat, and maximum pulmonary O₂ uptake; nine well-trained athletes (TRAINED); and four age-matched controls (YOUNG). Muscle biopsies from the vastus lateralis were taken before and after a 2-h euglycemic-hyperinsulinemic clamp. Oxidative enzyme activities, fatty acid transporters (FAT/CD36 and FABPpm), and TG_m were measured from basal muscle samples, and total LCACoA content was determined before and after insulin stimulation. Whole-body insulin-stimulated glucose uptake was lower in TYPE 2 (P < 0.05) than in OLD, YOUNG, and TRAINED. TG_m was elevated in TYPE 2 compared with all other groups (P < 0.05). However, both basal and insulin-stimulated skeletal muscle LCACoA content were similar. Basal citrate synthase activity was higher in TRAINED (P < 0.01), whereas ß-hydroxyacyl CoA dehydrogenase activity was higher in TRAINED compared with TYPE 2 and OLD. There was a significant relationship between the oxidative capacity of skeletal muscle and insulin sensitivity (citrate synthase, r = 0.71, P < 0.001; ß-hydroxyacyl CoA dehydrogenase, r = 0.61, P = 0.001). No differences were found in FAT/CD36 protein content between groups. In contrast, FABPpm protein was lower in OLD compared with TYPE 2 and YOUNG (P < 0.05). In conclusion, despite markedly elevated skeletal muscle TG_m in type 2 diabetic patients and strikingly different levels of whole-body glucose disposal, both basal and insulin-stimulated LCACoA content were similar across groups. Furthermore, skeletal muscle oxidative capacity was a better predictor of insulin sensitivity than either TG_m concentration or long-chain fatty acyl CoA content.

This work was supported by a research grant from Masterfoods Australia-New Zealand, a Mars Incorporated company (to J.A.H.), an RMIT Faculty Research Grant (to J.A.H.), and a Canadian Institute of Health Research Grant (to A.B.).

Current address for A.B.: Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1.

Abbreviations: BMI, Body mass index; CoA, coenzyme A; DAG, diacylglycerol; FA, fatty acid; FFA, free FA; GIR, glucose infusion rate; ß-HAD, ß-hydroxyacyl CoA dehydrogenase; HbA_1C, glycosylated hemoglobin; LCACoA, long-chain fatty acyl CoA; LCFA, long-chain FA; TG, triglyceride; TG_m, im TG; v. lateralis, vastus lateralis; VO₂max, maximum pulmonary O₂ uptake.

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