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Insulin-dependent individuals with diabetes are at risk for a severe hypoglycemic event that may predispose them to several repeat episodes during which the normal counter regulatory mechanisms that protect against hypoglycemia fail to be activated. This state of hypoglycemia unawareness is characterized by a failure of glucagon release, preventing mobilization of endogenous glucose stores from the liver. We describe the discovery of a novel hormone, produced in pancreatic delta cells, which stimulates glucagon production and release, particularly under low glucose conditions. We hypothesize that this hormone, called neuronostatin, may be effective as a co-therapy with insulin to prevent repeated, potentially fatal episodes of recurrent hypoglycemia.

During the initial autoimmune response in type 1 diabetes, islets are exposed to a damaging mix of pro-inflammatory molecules that stimulate the production of nitric oxide by beta-cells. Nitric oxide causes extensive but reversible cellular damage. In response to nitric oxide, the cell activates pathways for functional recovery and adaptation as well as pathways that direct beta-cell death. The molecular events that dictate cellular fate following nitric oxide-induced damage are currently unknown. In this study, we provide evidence that AMPK plays a primary role controlling the response of beta-cells to nitric oxide-induced damage. AMPK is transiently activated by nitric oxide in insulinoma cells and rat islets following IL-1 treatment or by the exogenous addition of nitric oxide. Active AMPK promotes the functional recovery of beta-cell oxidative metabolism and abrogates the induction of pathways that mediate cell death such as caspase-3 activation following exposure to nitric oxide. Overall, these data show that nitric oxide activates AMPK and that active AMPK suppresses apoptotic signaling allowing the beta-cell to recover from nitric oxide-mediated cellular stress.