STIMULATION OF INSULIN RELEASE BY REPAGLINIDE AND GLIBENCLAMIDE INVOLVES BOTH COMMON AND DISTINCT PROCESSES

The action of repaglinide, a novel insulin secretagogue, was compared with the sulfonylurea glibenclamide with regard to the hypoglycemic ac tion in vivo, binding to beta TC-3 cells, insulin secretion from perif used mouse islets, and capacity to stimulate exocytosis by direct inte raction with the secretory machinery in single voltage-clamped mouse b eta-cells. Two binding sites were identified: a high-affinity repaglin ide (K-D, = 3.6 nmol/l) site having lower affinity for glibenclamide ( 14.4 nmol/l) and one high-affinity glibenclamide (25 nmol/l) site havi ng lower affinity for repaglinide (550 nmol/l), In contrast to glibenc lamide, repaglinide (in concentrations as high as 5 mu mol/l) lacked t he ability to enhance exocytosis in voltage-clamped beta-cells, Repagl inide was more potent than glibenclamide in stimulating insulin releas e from perifused mouse islets (EC50 29 vs, 80 nmol/l), The greater pot ency of repaglinide in vitro was paralleled by similar actions in vivo , The ED50 values for the hypoglycemic action were determined to be 10 .4 and 15.6 mu g/kg after intravenous and oral administration, respect ively, The corresponding values for glibenclamide were 70.3 mu g/kg (i ntravenous) and 203.2 mu g/kg (oral), Further, repaglinide (1 mg/kg p. o.) was effective (P < 0.001) as an insulin-releasing agent in a rat m odel (low-dose streptozotocin) of type 2 diabetes, These observations suggest that the insulinotropic actions of repaglinide and glibenclami de in vitro and in vivo are secondary to their binding to the high-aff inity repaglinide site and that the insulinotropic action of repaglini de involves both distinct and common cellular mechanisms.