Objective: Ghrelin is a 28 amino acid residue peptide identified in both human and rat stomach and which acts as an endogenous ligand for the GH secretagogue receptor (GHS-R) and stimulates GH release. GHS-Rs are expressed in a number of tissues, including the pancreas, and ghrelin-like immunoreactivity is present in peripheral plasma, where its levels increase during fasting and decrease after food intake. The relationship between nutritional status and circulating ghrelin concentrations prompted us to investigate the effect of this peptide on pancreatic hormone secretion. Methods: The study was performed in the isolated rat pancreas perfused in situ. Insulin, glucagon and somatostatin were measured by radioimmunoassay. Results: Addition of 10 nM ghrelin to the perfusate significantly reduced the insulin response to the secretagogues glucose, arginine and carbachol, which act on the B-cell via different mechanisms, as well as the somatostatin response to arginine. Ghrelin was without effect on the glucagon output induced by this amino acid. At a lower concentration (2 nM) ghrelin was also found to inhibit glucose-induced insulin release. Conclusion: These findings support the proposal that the inhibitory effect of ghrelin on insulin release constitutes a tonic regulation of the B-cell, contributing to restrain its secretory activity in the state of food deprivation. On the other hand, the inhibition of pancreatic somatostatin release by ghrelin suggests a blocking effect of this hormone on the widely distributed D-cell population.

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Amylin, a peptide hormone from pancreatic beta-cells, is reported to inhibit insulin secretion in vitro and in vivo and to inhibit nutrient-stimulated glucagon secretion in vivo. However, it has been reported not to affect arginine-stimulated glucagon secretion in vitro. To resolve if the latter resulted from inactive peptide (a problem in the early literature), those experiments were repeated here with well-characterized peptide and found to be valid. In isolated perfused rat pancreas preparations, coperfusion with 1 nM amylin had no effect on arginine-, carbachol-, or vasoactive intestinal peptide-stimulated glucagon secretion. Amylin also had no effect on glucagon output stimulated by decreasing glucose concentration from 11 to 3.2 mM or on glucagon suppression caused by increasing glucose from 3.2 to 7 mM. Amylin at 100 nM had no effect in isolated islets in which glucagon secretion was stimulated by exposure to 10 mM arginine, even though glucagon secretion in the same preparation was inhibited by somatostatin. In anesthetized rats, amylin coinfusion had no effect on glucagon secretion stimulated by insulin-induced hypoglycemia. To reconcile reports of glucagon inhibition with the absence of effect in the experiments just described, anesthetized rats coinfused with rat amylin or with saline were exposed sequentially to intravenous L-arginine (during a euglycemic clamp) and then to hypoglycemia. Amylin inhibited arginine-induced, but not hypoglycemia-induced, glucagon secretion in the same animal. In conclusion, we newly identify a selective glucagonostatic effect of amylin that appears to be extrinsic to the isolated pancreas and may be centrally mediated.

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