MODULATION OF GLIQUIDONE ACTION BY FORSKOLIN IN THE PANCREAS OF NORMAL AND GK RATS

This study aims to investigate whether agents that stimulate adenosine 3',5'-cyclic monophosphate (cAMP) formation could be used to increase insulin release evoked by hypoglycemic sulfonylureas in non-insulin-d ependent diabetes mellitus. For this purpose, the effect of gliquidone (1.0 mu M) on insulin and glucagon release was examined in the perfus ed pancreas of either normal or Goto-Kakizaki (GK) rats at a low conce ntration of D-glucose (2.8 mM) and in the absence or presence of forsk olin (1.3 mu M). In normal rats, the diterpene exerted relatively litt le effect on basal insulin release but markedly augmented the insulino tropic action of gliquidone. In GK rats, forskolin dramatically augmen ted both basal and gliquidone-stimulated insulin output. In mirror ima ge of its effect on insulin release, forskolin augmented basal glucago n output and failed to increase the secretory response of the A cell t o gliquidone, at least in normal rats. On the contrary, in GK rats, fo rskolin, while slightly enhancing basal glucagon output, unmasked the glucagonotropic potential of gliquidone that was otherwise not detecte d in the diabetic animals. These findings are interpreted in light of a dual metabolic and energy-independent response of islet cells to the forskolin-induced generation of cAMP. They document the optimalizatio n by endogenous cAMP of the B cell secretory response to gliquidone in non-insulin-dependent diabetes.