STIMULATION OF BIOSYNTHETIC ACTIVITY BY NOVEL SUCCINATE ESTERS IN RATPANCREATIC-ISLETS

Selected esters of succinic acid are currently under investigation as possible insulinotropic agents for the treatment of noninsulin-depende nt diabetes mellitus. The aim of the present study was to investigate the effects of ten novel esters of succinic acid upon biosynthetic act ivity in rat pancreatic islets. In the absence of any other exogenous nutrient, glycerol-3-hydroxy-1,2-dimethyl succinate (0.5 mM), D-arabit ol-5-hydroxy-1,2,3,4-tetramethylsuccinate (0.5 mM), and 4-tert-butylsu ccinate (2.5 mM) exerted little or no effect upon L-[4-H-3]phenylalani ne incorporation into trichloroacetic acid-precipitable material. A mo dest but significant increase in biosynthetic activity to approximatel y 150% of basal value was found in the presence of L-threitol-1,2,4-tr imethylsuccinate (2.0 mM) and ethanediol-1,2-diethylsuccinate (2.5 mM) . A two-to five-fold increase in protein biosynthesis was observed in islets exposed to propanediol-1,2-dimethylsuccinate, glycerol-1 ,2-dim ethylsuccinate-3-hydrogenosuccinate, L-threitol-3-succinoyl-1,2,4-trim ethylsuccinate, glycerol-1,2-dimethylsuccinate or ethanediol-1,2-dimet hylsuccinate (2.5 mM each), these esters being mentioned in order of i ncreasing biological efficiency. There was a significant correlation b etween these results and the insulinotropic action of the same eaters. The present findings thus reinforce the view that such esters act as nutrients in islet cells and, therefore, offer the advantage over phar macological agents currently used for the treatment of type-2 diabetes in stimulating both the biosynthetic and secretory activity of insuli n-producing B-cells. (C) 1998 Elsevier Science Inc.