H ypoglycemia commonly causes brain fuel deprivation, resulting in functional brain failure, which can be corrected by raising plasma glucose concentrations. Rarely, profound hypoglycemia causes brain death that is not the result of fuel deprivation per se. In this issue of the JCI, Suh and colleagues use cell culture and in vivo rodent studies of glucose deprivation and marked hypoglycemia and provide evidence that hypoglycemic brain neuronal death is in fact increased by neuronal NADPH oxidase activation during glucose reperfusion (see the related article beginning on page 910). This finding suggests that, at least in the setting of profound hypoglycemia, therapeutic hyperglycemia should be avoided.