Synergistic effect of a tumor-promoting phorbol ester and a hypoglycemic sulfonylurea upon insulin release

The tumor-promoting phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and the hypoglycemic sulfonylurea gliclazide both stimulate insulin release from rat pancreatic islets incubated at a low concentration of glucose (2.8 mM). The increment in secretion rate evoked by the combination of these two secretagogues was at least 7 times higher than the sum of increments evoked by each agent alone. TPA augmented insulin release evoked by gliclazide more efficiently than that induced by glucose. The enhancing action of TPA could not be attributed solely to changes in the capacity of gliclazide to inhibit 86Rb outflow, to provoke an exchange between influent 40Ca and effluent 45Ca, or to stimulate the net uptake of 45Ca by the islets. Nevertheless, the facilitation by TPA of gliclazide-induced insulin release suggests that a biophysical interference with the handling of cations at the plasma membrane level represents the primary site of action of hypoglycemic sulfonylureas in the pancreatic B cell.