INSULINOTROPIC EFFECT OF THE TUMOR PROMOTER 12-O-TETRADECANOYLPHORBOL-13-ACETATE IN RAT PANCREATIC-ISLETS

Abstract

In isolated rat pancreatic islets, the tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA), when used in the 2.10-9 to 2.10-7 M range, stimulated insulin release in the absence and presence of glucose. The non-tumor-promoting agent 4-methylphorbol-12, 13-didecanoate failed to stimulate insulin release. The insulinotropic capacity of TPA was enhanced by glucose in a dose-related fashion. In the absence of glucose, the TPA-stimulated release of insulin was a slowly induced and not rapidly reversible phenomenon. It was inhibited by antimycin A, by epinephrine at low temperatures, and in the absence of extracellular Ca2+ or the presence of cytochalasin B, was unaffected by the organic calcium antagonist D600 or indomethacin, and was potentiated by theophylline. No obvious effect of TPA upon 86Rb or 32P efflux and 45Ca net uptake was detected in the isolated islets. TPA caused a progressive increase in 45Ca fractional outflow rate and cAMP content in the islets. The insulinotropic action of TPA may be due, in part at least, to interference with the transport of calcium by native ionophores.