Glucose-dependent insulinotropic polypeptide stimulates insulin secretion via increased cyclic AMP and [Ca2+]1 and a wortmannin-sensitive signalling pathway.

The effect of wortmannin, a fungal metabolite which is known to inhibit phosphatidylinositol 3-kinase (PI3-kinase) at low concentrations, has been examined for its effect on insulin secretion stimulated by glucose-dependent insulinotropic polypeptide (GIP). Using a hamster derived clonal beta-cell line, the HIT-T15 cell, wortmannin inhibited GIP-stimulated insulin secretion under both static incubation and perfusion conditions. In contrast, wortmannin did not inhibit glucose-stimulated or forskolin-stimulated insulin secretion. The inhibitory effect was of large magnitude, although always partial, and occurred within a few minutes of the onset of stimulation by GIP. Thus GIP, like vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase activating polypeptide (PACAP), exerts some of its stimulatory effect on insulin release via a wortmannin-sensitive signal transduction pathway.