MODULATION OF THE INSULINOTROPIC ACTION OF GLIBENCLAMIDE AND GLIMEPIRIDE BY NUTRIENT SECRETAGOGUES IN PANCREATIC-ISLETS FROM NORMOGLYCEMIC AND HYPERGLYCEMIC RATS

In perifused pancreatic islets from euglycemic rats, the secretory response to either glibenclamide or glimepiride (1.0 muM each) increases as a function of the concentration of D-glucose (2.8-16.7 mM) present in the perifusion medium. On the contrary, the sulfonylurea-induced increment in Ca-45 efflux from prelabeled islets decreases at increasing concentrations of the hexose. Neither glibenclamide nor glimepiride affect D-glucose metabolism in isolated islets, as judged from the production of (HOH)H-3 from D-[5-H-3]glucose or the generation of (CO2)-C-14, as well as C-14-labeled amino acids and acidic metabolites, from D-[3,4-C-14]glucose, D-12-[C-14]glucose and D-[6-C-14]glucose. The insulinotropic action of the hypoglycemic sulfonylureas is not impaired in islets prepared from rats infused for 48 hr with a hypertonic solution of D-glucose. The dimethyl ester of succinic acid is more efficient than D-glucose in supporting the insulin-releasing effect of glibenclamide or glimepiride. Thus, although the insulinotropic action of hypoglycemic sulfonylureas appears unaffected in a model of B-cell glucotoxicity, a potentiation of their secretory effects might be expected, in non-insulin-dependent diabetes, from the combined administration of succinic acid methyl ester.