Several new non-sulfonylurea hypoglycemic agents such as A-4166, KAD-1229 and repaglinide are structurally related to meglitinide, previously known as the non-sulfonylurea moiety of glibenclamide, or its analog S 3075. There is no parallelism between the ionophoretic and insulinotropic efficiency of these compounds. They are all able, however, to decrease K+ conductance in islet cells as documented by a decrease in 86Rb outlfow from prelabelled pancreatic islets. In terms of concentrations of equal insulinotropic capacity, a difference of at least two orders of magnitude is observed between the weakest (meglitinide) and most potent (S 3075) compound. All these agents exert little effect upon insulin release in nutrient-deprived islets, but markedly augment glucose-stimulated insulin release. The hexose can be replaced, however, by a non-glucidic nutrient such as the methyl ester of succinic acid to support the insulinotropic action of the meglitinide analogs. The question is raised as to the potential advantage of these non-sulfonylurea insulinotropic agents over hypoglycemic sulfonylureas.