PACAP contributes to insulin secretion after gastric glucose gavage in mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is localized to pancreatic ganglia governing the parasympathetic nerves, which contribute to prandial insulin secretion. We hypothesized that this contribution involves PACAP and show here that the PACAP receptor antagonist PACAP-(6---27) (1.5 nmol/kg iv) reduces the 15-min insulin response to gastric glucose (150 mg/mouse) by 18% in anesthetized mice (P = 0.041). The reduced insulinemia was not due to inhibited release of the incretin factor glucagon-like peptide 1 (GLP-1) because PACAP-(6---27) enhanced the GLP-1 response to gastric glucose. Furthermore, the GLP-1 antagonist exendin-3-(9---39) (30 nmol/kg) exerted additive inhibitory effect on the insulin response when combined with PACAP-(6---27). The PACAP antagonism was specific because intravenous PACAP-(6---27) inhibited the insulin response to intravenous PACAP-27 plus glucose without affecting the insulin response to intravenous glucose alone (1 g/kg) or glucose together with other insulin secretagogues of potential incretin relevance of intestinal (GLP-1, gastric inhibitory polypeptide, cholecystokinin) and neural (vasoactive intestinal peptide, gastrin-releasing peptide, cholinergic agonism) origin. We conclude that PACAP contributes to the insulin response to gastric glucose in mice and suggest that PACAP is involved in the regulation of prandial insulin secretion.