Stimulation of insulin release by an organic calcium agonist.

The calcium-agonist 4-[2-(difluoromethoxy)phenyl]-1,4,5,7-tetrahydro-2-methyl-5-oxo-fu ro[ 3,4-b]pyridine-3-carboxylic acid ethylester provoked, in the 1.0-100 mumol/l range, a dose-related increase of glucose-stimulated insulin release by rat pancreatic islets. A fixed concentration of the drug (50 mumol/l) caused a shift to the left of the sigmoidal curve relating insulin output to glucose concentration. The drug failed to affect insulin release evoked, in the absence of Ca2+, by the combination of Ba2+ and theophylline. The enhancing action of the calcium-agonist upon insulin release was rapid and sustained, and coincided with stimulation of both 45Ca net uptake and 45Ca efflux, the latter phenomenon being abolished in the absence of extracellular Ca2+. It is concluded that the gating of Ca-channels, as presumably provoked by the calcium-agonist, simulates the stimulant action of glucose upon both Ca influx into and insulin release from the pancreatic islets.