Phenytoin inhibition of insulin release. Studies on the involvement of Ca2+ fluxes in rat pancreatic islets.

The mechanism by which phenytoin inhibits insulin release was studied. Insulin release and 45Ca2+ efflux were measured during perifusion of collagenase isolated rat islets after 2-day maintenance in tissue culture in the presence of a trace amount of 45Ca2+. Islets maintained in the absence of the isotope were used to measure 45Ca2+ uptake over 5 min. Glucose (16.7 mM) induced a biphasic release of insulin, which was accompanied by a biphasic increase in the rate of 45Ca2+ efflux above basal. Phenytoin (80 microM) added during second phase rapidly inhibited insulin release. In contrast, phenytoin added together with glucose failed to affect first phase, but reduced second phase release by 64%. Phenytoin failed to affect basal 45Ca2+ efflux in the presence or absence of Ca2+, nor did it interfere with the inhibitory effect of high glucose on Ca2+ efflux. The drug did not affect basal Ca2+ uptake, but significantly reduced glucose-induced Ca2+ uptake. Glucose utilization was not inhibited by phenytoin. It is suggested that phenytoin inhibits glucose-stimulated insulin release by interfering with Ca2+ uptake via voltage-dependent Ca2+ channels. The pattern of inhibition of insulin release appears to favor this conclusion as the second phase is more dependent on the stimulation of Ca2+ uptake than is the first phase.