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.