Recent studies have demonstrated that leptin can prolong life chronically in rats with poorly-controlled type 1 diabetes (T1D). Multiple explanations have been proposed to explain leptin’s chronic antihyperglycemic effect, including suppression of glucagon release and/or signaling, reductions in hyperphagia and ectopic lipid content, and improvements in insulin sensitivity; it is leptin’s ability to reduce plasma glucose relies on all of these effects. In addition, leptin reverses hyperglycemia and diabetic ketoacidosis (DKA) acutely, within 6 hours of leptin infusion, by suppressing hypothalamic-pituitary-adrenal (HPA) axis activity in insulinopenic rats. Thus current evidence suggests that leptin’s acute, insulin-independent effect to reverse DKA by suppressing HPA axis activity occurs through a different mechanism from its chronic, pleotropic, insulin-dependent effect to reverse hyperglycemia and prolong survival in rodents with T1D. Leptin may therefore represent an attractive therapeutic target to improve glycemic control in humans with poorly-controlled T1D.