The ability of the average individual to survive long periods of food deprivation is made possible through a complex series of hormonal and biochemical signals that ensure the appropriate interorgan redirection and utilization of major fuels. In the early stages of a fast there is a shift of liver metabolism from glucose storage to glucose production, coupled with other adaptations that conserve the glucose released for maintenance of brain and CNS function. Crucial is the ability of most tissues in the body to switch from a carbohydrate to a lipid-based economy, utilizing fatty acids mobilized from fat depots as their main source of energy. Liver responds uniquely by enhancing its capacity to convert incoming fatty acids into ketone bodies (acetoacetic and p-hydroxybutyric acids), which serve as auxiliary fuels of respiration for nonhepatic tissues. As starvation progresses the blood ketone body concentration gradually rises to the region of 5 mM, allowing these compounds to make an increasing contribution to the energy needs of the brain. The requirement for hepatic gluconeogenesis is thus reduced, which in turn allows significant sparing of muscle protein, an event of obvious survival benefit. Physiological ketosis, although initiated by a fall in circulating insulin, is kept in check because the/I-cell remains responsive to stimulation by rising concentrations of free fatty acids and ketones even in the face of nonstimulatory concentrations of glucose in plasma (relative hypoglycemia). Low-level secretion of the p-cell hormone throughout the starvation period modulates free fatty acid release and prevents progression to full-blown ketoacidosis. However, this delicately