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The Pyruvate Dehydrogenase Complex: Nutrient Control and the Pathogenesis of Insulin Resistance¹

Department of Biochemistry (Basic Medical Sciences), Queen Mary and Westfield College, University of London, London, E1 4NS, U.K.

This review examines the molecular mechanisms underlying substrate competition between glucose and lipid in starvation and in insulin-resistant states. We demonstrate that lipid-derived substrates are oxidized in preference to glucose by skeletal muscle in vivo during prolonged starvation. An accelerated and exaggerated lipolytic and ketogenic response to starvation in late pregnancy is associated with more rapid suppression of glucose oxidation by the maternal skeletal-muscle mass. These benign adaptations to changes in lipid availability (which occur secondarily to changes in carbohydrate supply and demand) contrast with the well-documented detrimental effects to health of an inappropriately high supply of dietary lipid. We present results that indicate that the prolonged consumption of a diet high in saturated fat is associated with a stable enhancement of pyruvate dehydrogenase (PDH) kinase activity at least in two oxidative tissues—liver and heart. This long-term enhancement of PDH kinase activity is concomitant with the development of whole-body insulin resistance and adds a new dimension to the potential role of dietary composition in the pathogenesis of insulin resistance.

KEY WORDS: • insulin • glucose/fatty acid cycle • high-fat diet • PDH kinase • insulin resistance

¹ Presented as part of the symposium "Alpha-Keto Acid Dehydrogenase Complexes: Nutrient Control, Gene Regulation and Genetic Defects" given at the Experimental Biology '94 meeting, Anaheim, CA, on April 27, 1994. This symposium was sponsored by the American Institute of Nutrition. Guest editors for this symposium were Mulchand S. Patel, State University of New York at Buffalo, Buffalo, NY and Robert A. Harris, Indiana University School of Medicine, Indianapolis, IN.

² To whom correspondence should be addressed: Department of Biochemistry, Faculty of Basic Medical Sciences, Queen Mary and Westfield College, Mile End Road, London E1 4NS, U.K.