Hypoglycemia, a frequent occurrence during mod-ern intensive insulin therapy, remains the major limiting factor in achieving optimal glucose control in type 1 diabetic patients as well as in patients with long-standing type 2 diabetes. This has been a challenge for clinicians and investigators since several large population-based studies such as the Diabetes Control and Complications Trial and UK Prospective Diabetes Study established the long-term benefits of tight glycemic control many years ago (1, 2). More recently, studies of intensive glucose control in patients with diabetes of several years duration have—to the surprise to many—been either terminated because of increased mortality in the intensive control arm or because worse outcomes were revealed in regard to the clinical end points (3, 4). In a parallel development, we have gone, over the course of 10 years, from embracing stringent inpatient glucose control via insulin infusion protocols in the intensive care setting (5) to realizing that not everybody may benefit equally from such an intervention, since the increased incidence of profound hypoglycemia is the limiting factor (6). In fact, a recent systematic review of 21 trials of intensive insulin therapy by Kansagara et al.(7) found a sixfold higher risk of severe hypoglycemic events in patients undergoing such therapy. Faced with a clinical dilemma of such proportion, it appears that we may need to readdress our hypotheses, and we need to conduct mechanistic studies that allow us to identify therapies that are effective but minimize the exposure of patients to the heightened risk of hypoglycemia. Understanding the regulation of glucose metabolism in the brain and how it responds to hypoglycemia in this context is of particular relevance because of the brain’s exquisite dependence on glucose as an energy substrate and its integrative function in whole body fuel homeostasis (8).