Comparison between the insulinotropic potential of ten new esters of succinic acid.

Selected esters of succinic acid are currently under investigation as insulinotropic tools for the treatment of non-insulin-dependent diabetes mellitus. The aim of the present study was to investigate, in isolated rat pancreatic islets, the insulin secretory response to ten novel esters of succinic acid. According to six different methods of comparison, the following hierarchy in insulinotropic potential was established: 4-tert-butyl-succinate < or = glycerol-1,2-dimethylsuccinate-3-hydrogenosuccinate < or = threitol-3-succinoyl-1,2,4-trimethylsuccinate < or = ethanediol-1,2-diethylsuccinate < or = glycerol-1,2-dimethylsuccinate < or = glycerol-3-hydroxy-1,2-dimethylsuccinate < or = arabitol-5-hydroxy-1,2,3,4-tetramethylsuccinate < or = threitol-1,2,4-trimethylsuccinate < or = ethanediol-1,2-dimethylsuccinate < propanediol-1,2-dimethylsuccinate. There was a close correlation (r = 0.823) between the insulinotropic potential and the minimal effective concentration, which ranged between the extreme values of 10 microM and 2.5 mM. In the presence of the esters, the concentration-response relationship for glucose-stimulated insulin release was changed from its typically sigmoidal shape to a hyperbolic pattern, with most agents enhancing insulin output at a low hexose concentration (2.8 mM) but failing to do so at a high glucose level (16.7 mM). Highly potent insulinotropic esters have several advantages over other antidiabetic agents in clinical use.