Intra-islet PACAP protects pancreatic β-cells against glucotoxicity and lipotoxicity.

Pituitary adenylate cyclase-activating polypeptide (PACAP), a potent insulinotropin, is localized in pancreatic islets. Hyperglycemia and hyperlipidemia impair islet β-cell functions, being recognized as glucotoxicity and lipotoxicity. In this study, we examined whether endogenous PACAP protects islet β-cells against the toxicities. Pancreatic islets were prepared from wild-type and PACAP-null mice, and cultured for 2 days in control conditions containing 5.6 mM glucose, those with elevated 25 mM glucose and those supplemented with 0.4 mM palmitate. After culture in control conditions, a rise in the superfusate glucose concentration from 2.8 mM to a physiologic 8.3 mM increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in both wild-type and PACAP-null mouse islets. In contrast, after culture with high glucose or palmitate, the glucose-induced first phase [Ca(2+)](i) increases were severely impaired in islets of PACAP-null mice while they were preserved in islets of wild-type mice. Treatment with high glucose or palmitate also impaired glucose-induced insulin secretion in islets and increased mRNA expression of uncoupling protein 2 (UCP2) in islets of PACAP-null, but not wild-type, mice. These data indicate that islet-produced PACAP protects β-cells from deteriorating action of high glucose and palmitate at least partly by blocking the elevation of UCP2, suggesting an anti-diabetic role for PACAP.