Ionic mechanism of diphenylhydantoin action on glucose-induced insulin release

Diphenylhydantoin inhibits glucose-stimulated insulin release. The mode of action of diphenylhydantoin was investigated by characterizing its effect on 86Rb and 45Ca fluxes in isolated pancreatic islets. The inhibition of glucose-stimulated insulin release by diphenylhydantoin was apparently not attributable to activation of a Na+ + K+ATPase as diphenylhydantoin failed to affect 86Rb net uptake, at least in glucose-stimulated islets. Diphenylhydantoin decreased 45Ca net uptake by the islets, an effect possibly due to inhibition of Ca2+ entry into the islet cells. Diphenylhydantoin indeed markedly inhibited the glucose-induced increase in 45Ca outflow and decreased the process of 40Ca-45 exchange evoked by a rise in extracellular Ca2+ concentration. Diphenylhydantoin failed to affect the inhibitory action of glucose upon 45Ca outflow whether in the presence or absence of extracellular Ca2+, and did not impair the antimycin A-induced release of 45Ca from intracellular organelles. These findings suggest that the inhibitory effect of diphenylhydantoin upon glucose-stimulated insulin release is attributable mainly to a blockade of Ca2+ inflow into the beta-cell.