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High-Fat/Low-Carbohydrate Diet Reduces Insulin-Stimulated Carbohydrate Oxidation but Stimulates Nonoxidative Glucose Disposal in Humans: An Important Role for Skeletal Muscle Pyruvate Dehydrogenase Kinase 4

Center for Integrated Systems Biology and Medicine (K.C., K.J., L.N., J.L., I.A.M., K.T.), Institute of Clinical Research, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom; Department of Diabetes and Endocrinology (K.C., P.M.), Queen’s Medical Center, Nottingham NG7 2UH, United Kingdom; and Department of Movement Sciences (L.J.C.v.L.), Nutrition and Toxicology Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands

Address all correspondence and requests for reprints to: K. Tsintzas, Center for Integrated Systems Biology and Medicine, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom. E-mail: kostas.tsintzas{at}nottingham.ac.uk.

Aim: The aim of this report was to study the effect of high-fat (HF)/low-carbohydrate (CHO) diet on regulation of substrate metabolism in humans.

Methods: Ten healthy men consumed either a HF (75% energy as fat) or control (35%) diet for 6 d in random order. On d 7, blood glucose disappearance rate (R_d) was determined before and during a hyperinsulinemic euglycemic clamp. Substrate oxidation was determined by indirect calorimetry. Muscle biopsies were obtained prediet, postdiet, and postclamps.

Results: R_d was similar under basal conditions but slightly elevated (10%, P < 0.05) during the last 30 min of the clamp after the HF diet. HF diet reduced CHO oxidation under basal (by 40%, P < 0.05) and clamp conditions (by 20%, P < 0.05), increased insulin-mediated whole-body nonoxidative glucose disposal (by 30%, P < 0.05) and muscle glycogen storage (by 25%, P < 0.05). Muscle pyruvate dehydrogenase complex activity was blunted under basal and clamp conditions after HF compared with control (P < 0.05) and was accompanied by an approximately 2-fold increase (P < 0.05) in pyruvate dehydrogenase kinase 4 (PDK4) mRNA and protein expression.

Conclusion: Short-term HF/low-CHO dietary intake did not induce whole-body insulin resistance, but caused a shift in im glucose metabolism from oxidation to glycogen storage. Insulin-stimulated CHO oxidation and muscle pyruvate dehydrogenase complex activity were blunted after the HF diet. Up-regulation of muscle PDK4 expression was an early molecular adaptation to these changes, and we showed for the first time in healthy humans, unlike insulin-resistant individuals, that insulin can suppress PDK4 but not PDK2 gene expression in skeletal muscle.

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