CAMP enhances insulin secretion by an action on the ATP-sensitive K+ channel-independent pathway of glucose signaling in rat pancreatic islets

Cyclic AMP potentiates glucose-stimulated insulin release by actions predom inantly at a site, or sites, distal to the elevation of the cytosolic free Ca2+ concentration ([Ca2+](i)). Glucose also acts at a site, or sites, dist al to the elevation of [Ca2+](i) via the ATP-sensitive K+ channel (K-ATP(+) channel)-independent signaling pathway. Accordingly, using rat pancreatic islets, me studied the location of the action of cAMP and its interaction w ith the glucose pathway. Forskolin, an activator of adenylyl cyclase, raise d intracellular cAMP levels and enhanced KCl-induced (Ca2+-stimulated) insu lin release in the presence, but not in the absence, of glucose. Thus, cAMP has no direct effect on Ca2+-stimulated insulin release. The interaction b etween cAMP and glucose occurs at a step distal to the elevation of [Ca2+]( i) because forskolin enhancement of KCl-induced insulin release, in the pre sence of glucose, was demonstrated in the islets treated with diazoxide, a K-ATP(+) channel opener. The enhancement of insulin release was not associa ted with any increase in [Ca2+](i). Furthermore, the interaction between cA MP and glucose was unequivocally observed even under stringent Ca2+-free co nditions, indicating the Ca2+-independent action of cAMP. This action of cA MP is physiologically relevant, because not only forskolin but also glucago n-like peptide 1, glucose-dependent insulinotropic polypeptide, and pituita ry adenylyl cyclase activating polypeptide exerted similar actions. In conc lusion, the cAMP/protein kinase A pathway has no direct effect on Ca2+-stim ulated insulin exocytosis. Rather, it strongly potentiates insulin release by increasing the effectiveness of the K-ATP(+) channel-independent action of glucose.