A wortmannin-sensitive signal transduction pathway is involved in the stimulation of insulin release by vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide.

Vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide-27 (PACAP-27), and PACAP-38 stimulated insulin release with EC50 values of 0.15, 0.15, and 0.06 nM respectively, as expected for the VIP2/PACAP3 receptor subtype. Secretion was stimulated promptly and peaked at 6-10 min. At 30 min, the secretion rate was still 2-3-fold higher than the control rate. The peptides increased cyclic AMP and [Ca2+]i transiently so that at 30 min they had returned to control values. Therefore, an additional signal is required to explain the prolonged stimulation of release. The prolonged effects, but not the acute effects of VIP and PACAP on insulin release were inhibited by low concentrations of wortmannin, a phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor. While wortmannin inhibited PI 3-kinase activity in cell lysates, no activation by the peptides was seen. Therefore, the wortmannin-sensitive pathway is either dependent on basal PI 3-kinase activity, or another target for wortmanin is responsible for inhibition of the peptide-stimulated secretion. It is concluded that the acute stimulation of insulin release by VIP and PACAP is mediated by increased cyclic AMP and [Ca2+]i, whereas the sustained release is mediated by a novel wortmannin-sensitive pathway.