SPECIES-DIFFERENCES IN THE INDUCTION OF TIME-DEPENDENT POTENTIATION OF INSULIN-SECRETION

The secretory responsiveness of the pancreatic beta-cell can be marked ly improved by prior short term exposure to a stimulatory glucose leve l. Termed time-dependent potentiation (TDP), priming, or sensitization , this phenomenon has been documented to occur in both human and rat i slets and may involve, at least in part, information flow in the phosp holipase C and protein kinase C (PKC) signal transduction pathway. In contrast to human and rat islets, however, mouse islets fail to exhibi t TDP in response to priming with high glucose. In the present series of studies, we explored in more detail the conditions and stimulants n ecessary for the induction of TDP in mouse islets and compared these r esponses with those obtained in rat islets. In agreement with previous reports, high (15 mM) glucose alone primed the rat beta-cell, but not the mouse beta-cell, to subsequent restimulation with 15 mM glucose. However, muscarinic stimulation of mouse islets with carbachol (100 mu M) in the presence of 15 mM glucose primed the beta-cell to a subsequ ent 15-mM glucose stimulus. In addition, prior exposure to 50 nM of th e PKC activator tetradecanoyl phorbol acetate dramatically amplified t he subsequent insulin secretory responses of mouse islets to 15 mM glu cose. In contrast to its significant inhibitory effect on glucose-indu ced insulin release from rat islets, the PKC inhibitor staurosporine ( 50 nM) had no effect on 15 mM glucose-induced release from control or prior glucose-exposed mouse islets. However, staurosporine significant ly reduced the priming effect of tetradecanoyl phorbol acetate or carb achol on 15 mn glucose-induced insulin secretion from mouse islets. Th ese findings emphasize the dramatic species differences that exist in the capacity of prior high glucose stimulation to induce TDP in rat an d, presumably, human islets, on the one hand, and mouse islets, on the other. They also serve to emphasize the role of phosphoinositide hydr olysis and PKC activation in the induction of TDP.