Chloride Modulation of Insulin Release, ⁸⁶Rb⁺ Efflux, and ⁴⁵Ca²⁺ Fluxes in Rat Islets Stimulated by Various Secretagogues

Substitution of extracellular CI⁻ by impermeant isethionate (5 mM residual CI⁻) 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. CI⁻ 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 CI⁻ than at normal CI⁻, but did not restore a normal rate of ⁸⁶Rb⁺ efflux. Lowering the concentration of CI⁻ 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 CI⁻ 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 CI⁻ was substituted by isethionate and the marked decrease of the effect of glucose could be prevented by glutamine. In a glucose-free, low CI⁻ 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 CI⁻ 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 CI⁻ and this inhibition was prevented by glutamine. In conclusion, islet cells possess a CI⁻-activated modality of K efflux, which does not seem to play a role in the stimulus-secretion coupling. Since CI⁻ substitution by an impermeant anion does not inhibit the stimulation of insulin release by all agents, the role of CI⁻ 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 CI⁻ concentration, but it is proposed that some of them could result from modifications of intracellular pH.