The Neuropeptide Pituitary Adenylate Cyclase–Activating Polypeptide and Islet Function

Abstract

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is ubiquitously distributed in both the central and peripheral nervous systems and exerts a variety of effects. PACAP is a neuropeptide in pancreatic islets, where it has been suggested as a parasympathetic and sensory neurotransmitter. PACAP stimulates insulin secretion in a glucose-dependent manner, by an effect executed mainly through augmenting the formation of cAMP and stimulating the uptake of calcium. Accumulating evidence in animal studies points to a physiological importance of PACAP in the regulation of the insulin response to feeding. This review summarizes the current knowledge of islet actions and mechanisms and the function of PACAP. Diabetes 50: 1959

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

“…Furthermore, VPAC 2 -/-mice exhibit reduced insulin secretion but maintained glucose tolerance after intravenous administration of glucose, suggesting peripheral effects on insulin sensitivity (Asnicar et al, 2002). Furthermore, PACAP and VIP both stimulate glucagon secretion as has been demonstrated both in humans, in animals and in vitro (Filipsson et al 2001). …”

“…These receptors are linked to the G s -protein with subsequent elevation of cAMP and stimulation of insulin secretion (Filipsson et al, 2001). Disruption of the PAC 1 receptor in mice results in impaired insulin secretion after PACAP administration (Jamen et al 2000).…”

Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors

“…It is a widespread neuropeptide that is secreted by intraislet nerves and stimulates insulin secretion (44). It is a substrate for DPP-4 (45), and therefore its rapid inactivation might be inhibited during treatment with DPP-4 inhibition.…”

What mediates the benefits associated with dipeptidyl peptidase-IV inhibition?

“…Neuropeptides that are stored in islet nerve terminals and affect islet function would be of particular relevance in this regard, and the islet autonomic nervous system is indeed sometimes overlooked as an important regulator of islet function [18]. One neuropeptide of potential importance is pituitary adenylate cyclase-activating peptide (PACAP), which is localised to islet nerves and has several actions relevant to glucose homeostasis [19]. For example, PACAP is a powerful stimulator of insulin secretion and may, like GLP-1, be of importance for islet mass.…”