The β-cell GHSR and downstream cAMP/TRPM2 signaling account for insulinostatic and glycemic effects of ghrelin.

Gastric hormone ghrelinregulates insulin secretion, as well as growth hormone release, feeding behavior and adiposity. Ghrelinis known to exert its biological actions by interacting with the growth hormone secretagogue-receptor (GHSR) coupled to Gq/11-protein signaling. By contrast, ghrelinacts on pancreatic isletβ-cells via Gi-protein-mediated signaling. These observations raise a question whether the ghrelinaction on islet β-cells involves atypical GHSR and/or distinct signal transduction. Furthermore, the role of the β-cell GHSR in the systemic glycemic effect of ghrelinstill remains to be defined. To address these issues, the present study employed the global GHSR-null mice and those re-expressing GHSR selectively in β-cells. We here report that ghrelinattenuates glucose-induced insulin release via direct interaction with ordinary GHSR that is uniquely coupled to novel cAMP/ TRPM2signaling in β-cells, and that this β-cell GHSR with unique insulinostatic signaling largely accounts for the systemic effects of ghrelinon circulating glucose and insulin levels. The novel β-cell specific GHSR-cAMP/ TRPM2signaling provides a potential therapeutic target for the treatment of type 2 diabetes.