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Although the brain is clearly capable of affecting blood glucose levels, whether such effects are important in day-to-day blood glucose control remains a matter of controversy. In this Perspective, we update and expand on a previously described brain-centric model of glucose homeostasis (1), highlighting recent evidence of the brain’s capacity to influence the biologically defended level of circulating glucose in part through rapid and highly coordinated adjustments of both insulin sensitivity and insulin secretion. We also discuss the possibility that dysfunction of this brain-centric system contributes to the pathogenesis of type 2 diabetes by raising the defended level of glycemia. Finally, we discuss the implications of these concepts for the future of diabetes treatment.Traditionally, the interaction between pancreatic islets and insulin-sensitive tissues has been deemed sufficient to explain most aspects of glucose homeostasis. Whether the brain participates in the physiological control of circulating glucose levels therefore remains a matter of controversy, and the possibility that a dysfunctional central control system contributes to the pathogenesis of diabetes is only beginning to be explored. The overarching goal of this Perspective is to synthesize work from our laboratory and elsewhere that highlights recent progress and identifies emerging research and therapeutic opportunities in these areas.There is little question about the brain’s ability to influence key determinants of glucose homeostasis (e.g., rates of glucose production or utilization) in response to input from humoral signals, including glucose (2–4) and other nutrients (e.g., amino acids [5] or free fatty acids [6,7]), and nutritionally relevant hormones (e.g., insulin, leptin, ghrelin, and GLP-1 [8–10]). What remains uncertain is the extent to which such effects participate in day-to-day glucoregulation. Studies that use loss-of-function strategies (e.g., targeted gene deletion, receptor blockade, enzyme inhibitors, etc.) are perhaps most …

How Should We Think About the Role of the Brain in Glucose Homeostasis and Diabetes?