Chloride modulation of insulin release, 86Rb+ efflux, and 45Ca2+ fluxes in rat islets stimulated by various secretagogues.

Substitution of extracellular Cl- by impermeant isethionate (5 mM residual Cl-) caused a monophasic inhibition of glucose-stimulated insulin release, accompanied by an initial transient increase and a secondary lasting decrease in 86Rb+ efflux from perifused islets. Cl- reintroduction restored insulin release with an overshoot above control values and successively produced a small decrease and a large increase in efflux. Theophylline potentiated the insulinotropic effect of glucose more markedly at low Cl- than at normal Cl-, but did not restore a normal rate of 86Rb+ efflux. Lowering the concentration of Cl- did not alter the effect of glucose, tolbutamide, or arginine on 86Rb+ efflux, but simply shifted the efflux rates to lower values. The first phase of glucose-stimulated insulin release was not modified, but the second phase was inhibited. The insulinotropic effect of tolbutamide was augmented at low Cl- and that of arginine (at 7 mM glucose) was not affected. In incubated islets, the stimulation of insulin release by glyceraldehyde was barely inhibited when Cl- was substituted by isethionate and the marked decrease of the effect of glucose could be prevented by glutamine. In a glucose-free, low Cl- medium, the insulinotropic effect of leucine, arginine, and lysine was inhibited; this inhibition was reversed by glutamine, but not by theophylline. Lowering the concentration of Cl- had no effect on 45Ca2+ influx or efflux in the absence of glucose, did not alter the increase in influx and efflux during the first 5 min of glucose stimulation, but impaired both influx and efflux during the second phase. Leucine-induced 45Ca2+ uptake was inhibited at low Cl- and this inhibition was prevented by glutamine. In conclusion, islet cells possess a Cl- -activated modality of K efflux, which does not seem to play a role in the stimulus-secretion coupling. Since Cl- substitution by an impermeant anion does not inhibit the stimulation of insulin release by all agents, the role of Cl- ions does not appear to be restricted to a chemiosmotic mechanism of exocytosis. No single mechanism explains the multiple changes in B-cell function resulting from the decrease in Cl- concentration, but it is proposed that some of them could result from modifications of intracellular pH.