Beta-endorphin is present in the endocrine pancreas, suggesting that endorphins may have a role in islet-cell function. To evaluate this possibility, we infused synthetic human beta-endorphin intravenously in healthy volunteers and in insulin-dependent diabetic patients. In both groups, beta-endorphin increased plasma glucagon concentrations, and this rise was accompanied by a significant increase in plasma glucose concentrations. In nondiabetic subjects, beta-endorphin also increased plasma insulin concentrations. The threshold dose of beta-endorphin for producing increased plasma concentrations of glucose and glucagon was 0.005 mg--a dose that acutely increased plasma concentrations of beta-endorphin by approximately 40-fold. Glucose, glucagon, and insulin responses to beta-endorphin could not be blocked by intravenous naloxone. These studies suggest that endorphins may be involved in gluco-regulation, that their hyperglycemic action is mediated at least in part by glucagon, and that the effect of beta-endorphin on islet-cell function is relatively resistant to naloxone.