The CENTRAL nervous system (CNS) can neither synthesize nor store glucose, its predominant metabolic fuel. Thus, it is dependent upon a continuous supply of glucose from the circulation. Hypoglycemia can cause profound dysfunction of the brain, even brain death. The fact that hypoglycemia is an uncommon clinical event, except in persons who use drugs that lower the plasma glucose concentration, is testimony to the efficacy of the physiological mechanisms that normally prevent or correct hypoglycemia. Glucoregulation is normally the result of the glucoselowering actions of insulin and the glucose-raising actions of glucose-counterregulatory factors (1, 2). It has long been recognized that deficient insulin secretion is the fundamental abnormality in patients with insulindependent diabetes mellitus (IDDM). The contribution of counterregulatory systems to glycemic excursions ranging from hypoglycemia to hyperglycemia, in the context of imperfect insulin replacement, has been documented more recently in patients with IDDM and is the subject of this review.