PAC1 receptor-deficient mice display impaired insulinotropic response to glucose and reduced glucose tolerance

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a ubiquitous neuropeptide of the vasoactive intestinal peptide (VIP) family that potenti ates glucose-stimulated insulin secretion. Pancreatic beta cells express tw o PACAP receptor subtypes, a PACAP-preferring (PAC1) and a VIP-shared (VPAC 2) receptor. We have applied a gene targeting approach to create a mouse la cking the PAC1 receptor (PAC1(-/-)). These mice were viable and normoglycem ic, but exhibited a slight feeding hyperinsulinemia. In vitro, in the isola ted perfused pancreas, the insulin secretory response to PACAP was reduced by 50% in PAC1(-/-) mice, whereas the response to VIP was unaffected. In vi vo, the insulinotropic action of PACAP was also acutely reduced, and the pe ptide induced impairment of glucose tolerance after an intravenous glucose injection. This demonstrates that PAC1 receptor is involved in the insulino tropic action of the peptide. Moreover, PAC1(-/-) mice exhibited reduced gl ucose-stimulated insulin secretion in vitro and in vivo, showing that the P AC1 receptor is required to maintain normal. insulin secretory responsivene ss to glucose. The defective insulinotropic action of glucose was associate d with marked glucose intolerance after both intravenous and gastric glucos e administration. Thus, these results are consistent with a physiological r ole for the PAC1 receptor in glucose homeostasis, notably during food intak e.