Effect of a new xanthine derivative on the release of insulin from rat pancreatic islets

Abstract

S 9795 (1-methyl-3-isobutyl-8-[2-ethyl 1-(4-diphenylmethylpiperazinyl)]-3,7-dihydro (1H) purine-2,6-dione) is a new xanthine derivative displaying antiasthmatic properties in animals. The drug might exert its pharmacological actions either by inhibiting phosphodiesterases, or by inhibiting cellular Ca2+ movements or antagonizing purinoreceptors. Since the process of glucose-induced insulin release is markedly influenced by xanthine derivatives, the effect of S 9759 was compared to that of two other xanthine derivatives (theophylline and 3-isobutyl-1-methylxanthine (IBMX) on glucose-induced insulin release and ionic fluxes in rat pancreatic islets. Theophylline and IBMX potentiated glucose-induced insulin release, as expected, while S 9795 inhibited the insulinotropic effect of glucose. The effect of S 9795 was observed at a concentration of 10-5 mol/l, lower concentrations (10-6 to 10-9 mol/l) failing to affect glucose-induced insulin release. At 10-5 mol/l, the drug also inhibited the secondary rise in 45Ca efflux evoked by glucose from preloaded islets and the uptake of 45Ca by incubated islets stimulated either by glucose or potassium. The drug failed to alter 86Rb fluxes in stimulated and unstimulated islets labelled with the radioisotope. These data show that S 9795 inhibits glucose-induced insulin release, possibly by blocking glucose-stimulated Ca2+ inflow into the B-cell.