Evidence for guanosine 3′, 5′-monophosphate as a putative mediator of insulin secretion from isolated rat islets

Cyclic nucleotides are proposed mediators of insulin secretion from islets, although their role has not been defined. Sodium nitroprusside (SNP) and ascorbic acid are agents which increase tissue cGMP levels by dissimilar mechanisms. In these studies, both drugs enhanced rat islet cGMP, but not cAMP, levels. Islet cGMP levels not only increased with time in response to the drugs and reflected drug concentration, but increased cGMP release also accompanied elevated islet levels of the nucleotide. Glucose (17 HIM) stimulated both cAMP and cGMP formation in islets. Glucose-stimulated islet cGMP levels were lower than those generated in response to SNP (0.01-10 mM) but approximated the levels in islets treated with 5 mM ascorbate. At a submaximal concentration of SNP (0.1 mM), glucose stimulation produced additive increases in islet cGMP levels. Islets in static incubations responded to SNP and ascorbic acid stimulations with an enhanced release of insulin which was dose related; glucose also enhanced insulin secretion in this system. In addition, perifused islet insulin secretion responded to these three agents. Perifused islets exposed to glucose (17 mM) exhibited a characteristic early, abrupt phase of insulin release and a later, second phase of progressively increasing rates of insulin secretion. SNP and ascorbic acid mimicked the glucose-stimulated early phase of insulin secretion in perifused islets, causing similar amounts of total insulin to be released. The peak rates of insulin secretion for the three agents during the early release phase were also similar. The later phase of insulin secretion in response to SNP or ascorbate contrasted sharply with the glucose-stimulated phase, since it was characterized by a low rate and short duration of release. SNP and ascorbate both inhibited the late phase of glucose-stimulated insulin release but were without effect on the early phase. It is proposed that islet cGMP may be a putative mediator of insulin secretion. On the other hand, the inhibitory actions of SNP and ascorbic acid suggest that high intracellular levels of the nucleotide or unidentified drug effects may antagonize certain aspects of the release phenomenon.