INSULINOTROPIC ACTION OF THE MONOETHYL ESTER OF SUCCINIC ACID

1. Selected esters of succinic acid are currently under investigation as potential insulinotropic tools in the treatment of non-insulin-depe ndent diabetes. At variance with the methyl esters of succinic acid us ed in most of the work so far conducted from this perspective, the mon oethyl ester of succinic acid (EMS) offers the advantage of avoiding t he undesirable generation of methanol by intracellular hydrolysis. In the present study, the metabolism and functional effects of EMS were i nvestigated, therefore, in rat pancreatic islets. 2. At a 10 mM concen tration, EMS enhanced insulin release from islets stimulated by 7-17 m M D-glucose but failed to do so at lower concentrations of the hexose. EMS was efficiently metabolized, as judged from the generation of (CO 2)-C-14 by islets exposed to the monoethyl ester of either [1,4-C-14] or [2, 3-C-14]succinic acid. D-Glucose (6 mM) failed to affect the met abolism of EMS (10 mM), which itself failed to affect the metabolism o f D-[5-H-3]glucose or D-[U-C-14]glucose. EMS also stimulated biosynthe tic activity in the islets. It inhibited Rb-86 and Ca-45 outflow from prelabeled islets perfused in the absence of D-glucose but enhanced th e efflux of the two cationic tracers in the presence of the hexose (7 mM). 3. It is concluded that the insulinotropic action of EMS is attri butable, to a large extent, to its capacity to act as a nutrient in is let cells. GEN PHARMAC 31;3:377-383, 1995. (C) 1998 Elsevier Science I nc.