Exogenous and endogenous ghrelin counteracts GLP-1 action to stimulate cAMP signaling and insulin secretion in islet β-cells

We studied interactive effects of insulinotropic GLP-1 and insulinostatic ghrelinon rat pancreatic islets. GLP-1 potentiated glucose-induced insulin release and cAMP production in isolated isletsand [Ca2+]i increases in single β-cells, and these potentiations were attenuated by ghrelin. Ghrelinsuppressed [Ca2+]i responses to an adenylate cyclase activator forskolin. Moreover, GLP-1-induced insulin release and cAMP production were markedly enhanced by [d-lys3]- GHRP-6, a ghrelinreceptor antagonist, in isolated islets. These results indicate that both exogenous and endogenous islet-derived ghrelincounteracts glucose-dependent GLP-1 action to increase cAMP production, [Ca2+]i and insulin release in isletβ-cells, positioning ghrelinas a modulator of insulinotropic GLP-1.