Role of Pituitary Adenylate Cyclase-Activating Polypeptide in the Pancreatic Endocrine System

In the pancreatic islets, pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed in beta cells and autonomic nerve terminals; the majority of these nerve terminals are parasympathetic. PACAP binds to three types of G protein-coupled receptors (GPCRs): VPAC1 receptors, VPAC2 receptors, and PAC1 receptors. All these receptor types are expressed in pancreatic islets. PACAP stimulates insulin and glucagon secretion. These actions are achieved in part through increased formation of cAMP after activation of adenylate cyclase and in part through increase in cytosolic calcium, achieved through increase in calcium uptake and release from intracellular calcium stores. Deletion of PAC1 receptors or VPAC2 receptors results in impaired insulin secretion and glucose intolerance. Studies in PAC1 receptor gene deleted mice have suggested that PACAP may be of physiological importance in mediating prandial insulin secretion and in contributing to the glucagon response to hypoglycemia. Animal studies have also suggested that activation of the receptors, in particular VPAC2 receptors, may be used as a therapeutic approach for the treatment of type 2 diabetes. Hence, PACAP is an islet neuropeptide with a potential role in islet physiology and as a basis for development of islet-promoting therapy in type 2 diabetes.