The glucose homeostasis system ensures that the circulating glucose level is maintained within narrow physiological limits both in the fasting (or basal) state and following a nutrient challenge. Although glucose homeostasis is traditionally conceptualized as a single overarching system, evidence reviewed here suggests that basal glycemia and glucose tolerance are governed by distinct control systems. Specifically, whereas glucose tolerance appears to be determined largely by interactions between insulin secretion and insulin sensitivity, basal-state glucose homeostasis is predominated by insulin-independent mechanisms governed largely by the brain. In addition to a new perspective on how glucose homeostasis is achieved, this “dual control system” hypothesis offers a feasible and testable explanation for observations that are otherwise difficult to reconcile and sheds new light on the integration of central and peripheral metabolic control mechanisms. The implications of this model for the pathogenesis and treatment of impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes are also discussed.

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