COMPARISON BETWEEN THE INSULINOTROPIC POTENTIAL OF 10 NEW ESTERS OF SUCCINIC ACID

Selected esters of succinic acid are currently under investigation as insulinotropic tools for the treatment of non-insulin-dependent diabet es mellitus. The aim of the present study was to investigate, in isola ted rat pancreatic islets, the insulin secretory response to ten novel esters of succinic acid. According to six different methods of compar ison, the following hierarchy in insulinotropic potential was establis hed: 4-tert-butyl-succinate less than or equal to lycerol-1,2-dimethyl succinate-3-hydrogenosuccinate less than or equal to threitol-3-succin oyl-1,2,4-trimethylsuccinate less than or equal to ethanediol-1,2-diet hylsuccinate less than or equal to glycerol-1,2-dimethylsuccinate less than or equal to glycerol-3-hydroxy-1,2-dimethylsuccinate less than o r equal to arabitol-5-hydroxy-1,2,3,4-tetramethylsuccinate less than o r equal to threitol-1,2,4-trimethylsuccinate less than or equal to met hylsuccinate<propanediol-1,2-dimethylsuccinate. There was a close corr elation(r = 0.823) between the insulinotropic potential and the minima l effective concentration, which ranged between the extreme values of 10 mu M and 2.5 mM. Ln the presence of the esters, the concentration-r esponse relationship for glucose-stimulated insulin release was change d from its typically sigmoidal shape to a hyperbolic pattern, with mos t agents enhancing insulin output at a low hexose concentration (2.8 m M) but failing to do so at a high glucose level(16.7 mM). Highly poten t insulinotropic esters have several advantages over other antidiabeti c agents in clinical use. (C) 1998 Elsevier Science B.V.