Sodium requirement for insulin release: putative role in regulation of intracellular pH.

The effects on insulin release of Na+ removal, alteration of extracellular pH, and inhibition of acid extrusion processes were examined using freshly isolated and 46-h cultured islets of Langerhans. Na+ removal inhibited the secretory response to 16.7 mM glucose specifically in fresh islets but stimulated the low-glucose response in cultured islets. These divergent effects of Na+ depletion were perfectly mimicked by amiloride, an inhibitor of Na+-H+ exchange, and could be overcome in a raised HCO-3, pH 8.0 medium. Simply raising extracellular pH at constant HCO-3 had no effect. Na+ removal also inhibited the secretory responses to other nutrient secretagogues such as D-glyceraldehyde and L-leucine but not to agents like 3-isobutyl-1-methylxanthine or 12-O-tetradecanoylphorbol-13-acetate. The results show that Na+ is not itself essential for the secretory process but rather suggest that it plays a permissive role in the regulation of intracellular pH via Na+-H+ exchange. Such a regulation appears important mainly for nutrient-stimulated insulin release, which is associated with the generation of acidic metabolites.