ALARGE number of retrospective and prospective studies have documented that chronic hyperglycemia is closely linked to diabetic microvascular complications, especially retinopathy and neuropathy (1). The incidence and prevalence of diabetic nephropathy also are higher if glycemic control is poor (1), although the development of nephropathy may be limited to patients with a genetic predisposition to hypertension (2). An increased susceptibility to infections is another wellknown consequence of chronic hyperglycemia (3, 4). Although the occurrence of all these complications as well as macrovascular disease have been associated with chronic hyperglycemia, the proposed biochemical mechanisms underlying the structural and functional changes vary widely (Table 1 and Refs. 1–10).

Recently, it has become clear that chronic hyperglycemia is not only a marker of poor metabolic control but is itself a regulator of both insulin secretion and action. In contrast to acute hyperglycemia, which stimulates insulin secretion and glucose utilization, chronic hyperglycemia inhibits both and thereby self-perpetuates the diabetic state. These harmful metabolic effects of chronic hyperglycemia have been referred to as “glucose toxicity” (11–13). The ensuing discussion is focused on reviewing our present understanding of the occurrence, pathophysiology, and clinical significance of this phenomenon which already has widened our view of the causes and reversibility of defects in insulin secretion and action in insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM).