Insulinotropic action of meglitinide analogues: modulation by an activator of ATP-sensitive K+ channels and high extracellular K+ concentrations.

At normal extracellular K+ concentration (5 mM), the meglitinide analogues A-4166, KAD-1229, repaglinide and S3075, all tested at a 10 mu M concentration, markedly enhanced insulin release evoked by 6 mM D-glucose in isolated rat pancreatic islets. They failed, however, to augment the much higher rate of insulin release evoked by D-glucose in islets exposed to a high K+ concentration (30 mM). Under the latter conditions, the potent diazoxide analogue BPDZ-44 (50 mu M) did not exert any sizeable effect upon insulin release. Even at normal K+ concentration, BPDZ-44 (50 mu M), which suppressed glucose-stimulated insulin release, only caused a partial inhibition of the insulinotropic action of A-4166 and failed to affect significantly insulin secretion in the presence of KAD-1229, repaglinide or S3075. These findings argue against the view that meglitinide analogues could affect cytosolic Ca2+ activity independently of the closing of ATP-sensitive K+ channels. The present results also indicate that, with the possible exception of A-4166 which in the least potent secretagogue in this series, meglitinide analogues are able, like hypoglycemic sulphonylureas, to fully protect ATP-sensitive K+ channels against their activation by BPDZ-44.