THE PYRUVATE-DEHYDROGENASE COMPLEX - NUTRIENT CONTROL AND THE PATHOGENESIS OF INSULIN-RESISTANCE

This review examines the molecular mechanisms underlying substrate com petition between glucose and lipid in starvation and in insulin-resist ant states. We demonstrate that lipid-derived substrates are oxidized in preference to glucose by skeletal muscle in vivo during prolonged s tarvation. An accelerated and exaggerated lipolytic and ketogenic resp onse to starvation in late pregnancy is associated with more rapid sup pression of glucose oxidation by the maternal skeletal-muscle mass. Th ese benign adaptations to changes in lipid availability (which occur s econdarily to changes in carbohydrate supply and demand) contrast with the well-documented detrimental effects to health of an inappropriate ly high supply of dietary lipid. We present results that indicate that the prolonged consumption of a diet high in saturated fat is associat ed with a stable enhancement of pyruvate dehydrogenase (PDH) kinase ac tivity at least in two oxidative tissues-liver and heart. This long-te rm enhancement of PDH kinase activity is concomitant with the developm ent of whole-body insulin resistance and adds a new dimension to the p otential role of dietary composition in the pathogenesis of insulin re sistance.