patient-oriented research Metabolic flexibility is conserved in diabetic myotubes

Abstract

The purpose of this study was to test the hypothesis that metabolic inflexibility is an intrinsic defect. Glucose and lipid oxidation were studied in human myotubes established from healthy lean and obese subjects and patients with type 2 diabetes (T2D). In lean myotubes, glucose oxidation is raised by increasing glucose concentrations (0– 20 mmol/l) and acute insulin stimulation (P, 0.05), whereas it is inhibited by palmitate (PA). PA oxidation is raised by increasing PA concentrations (0–0.6 mmol/l), whereas 1.0 mmol/l PA inhibits its own oxidation (P, 0.05). Furthermore, PA oxidation is increased by acute insulin stimulation (P , 0.05) and inhibited by glucose. Even 0.05 mM PA and 2.5 mM glucose significantly reduce glucose and PA oxidation (P , 0.05), respectively. Glucose and PA oxidation are insulin-sensitive in myotubes established from lean (46% and 17% glucose and PA oxidation, respectively; P , 0.05 vs. basal), obese (31% and 14%; P , 0.05), and T2D (17% and 8%; P , 0.05) subjects. PA supplementation reduces both basal and insulin-stimulated glucose oxidation by 33– 44% (P , 0.05), and myotubes are still insulin-sensitive in all three groups (P , 0.05). Therefore, the metabolic inflexibility described in obese and diabetic patients is not an intrinsic defect; rather, it is based on an extramuscular mechanism (i.e., the inability to vary extracellular fatty acid concentrations during insulin stimulation). Thus, skeletal muscles are metabolic-flexible per se.—Gaster, M. Metabolic flexibility is conserved in diabetic myotubes. J. Lipid Res. 2007. 48: 207–217. Supplementary key words fuel selection & glucose oxidation & insulin resistance & lipid oxidation & metabolic inflexibility & skeletal muscle & type 2 diabetes Metabolic inflexibility describes the inability of diabetic patients to shift between lipid and glucose oxidation during insulin stimulation and from carbohydrate to lipid oxidation during fasting (1, 2). Even though skeletal muscle substrate oxidation has been investigated for many years, the molecular background of metabolic inflexibility remains unclear. Ukropcova et al. (3) evaluated metabolic switching in human myotubes established from young, healthy subjects based on their ability to increase FA oxidation by increasing the FA concentration and the susceptibility of glucose to reduce lipid oxidation, hypothesizing that metabolic switching was an intrinsic property of skeletal muscle. The effect of insulin was not studied. Previous studies of myotubes established from patients with type 2 diabetes (T2D) revealed primarily reduced insulin-stimulated glucose uptake, oxidation, and glycogen synthesis, whereas palmitate (PA) exposure impaired insulin-stimulated glucose oxidation and insulinstimulated citrate synthase activity in control myotubes (4–9). The interplay between glucose and FAs on substrate oxidation in skeletal muscle in vivo has been studied for many years. First, the glucose-FA cycle was studied by Randle et al. (10), showing the ability of exogenous FAs to reduce glucose oxidation. Second came the observation that hyperglycemia can reduce FA oxidation in skeletal muscle, designated the reverse Randle cycle (11–13). Both high plasma glucose and/or plasma FFA are seen in obese and T2D subjects; therefore, increased substrate levels may be part of the mechanism responsible for metabolic inflexibility. Thus, metabolic inflexibility could be based on both a primary and an induced mechanism. Our current knowledge of oxidative metabolism in skeletal muscle originates mainly from in vivo studies. The oxidative capacity of skeletal muscle is highly influenced by physical activity, aging, hormonal status, and fiber type composition, making it difficult to determine the contribution of genetic or individual environmental factors to the alteration in oxidative metabolism. It is especially difficult to estimate the impact of insulin stimulation on oxidative metabolism in vivo, as insulin stimulation is followed by changes in the level of glucose and FFAs in plasma. Cultured myotubes offer a unique model in which to separate the genetic influence on substrate oxidation from environmental factors and allow study of the interaction of various substrates on their own oxidation (4, 6, 14). The purpose of this study was to test the hypothesis that metabolic inflexibility is an intrinsic defect in myotubes established from obese and T2D subjects. Glucose and lipid oxidation were studied in human myotubes Manuscript received 20 July 2006 and in revised form 28 September 2006. Published, JLR Papers in Press, October 24, 2006. DOI 10.1194/jlr.M600319-JLR200 Abbreviations: CPT1, carnitine palmitoyltransferase-1; FCS, fetal calf serum; PA, palmitate; PDH, pyruvate dehydrogenase; T2D, type 2 diabetes. To whom correspondence should be addressed. e-mail: michael.gaster@ouh.fyns-amt.dk Copyright D 2007 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr.org Journal of Lipid Research Volume 48, 2007 207 at P E N N S T A T E U N IV E R S IT Y , on F ebuary 2, 2013 w w w .j.org D ow nladed fom established from healthy lean and obese subjects and patients with T2D under various conditions of glucose, FA, and insulin stimulation.

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@inproceedings{Gaster2006patientorientedRM, title={patient-oriented research Metabolic flexibility is conserved in diabetic myotubes}, author={Michael Gaster}, year={2006} }