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

Gastric hormone ghrelin regulates insulin secretion, as well as growth hormone release, feeding behavior and adiposity. Ghrelin is known to exert its biological actions by interacting with the growth hormone secretagogue-receptor (GHSR) coupled to G(q/11)-protein signaling. By contrast, ghrelin acts on pancreatic islet beta-cells via G(i)-protein-mediated signaling. These observations raise a question whether the ghrelin action on islet beta-cells involves atypical GHSR and/or distinct signal transduction. Furthermore, the role of the beta-cell GHSR in the systemic glycemic effect of ghrelin still remains to be defined. To address these issues, the present study employed the global GHSR-null mice and those re-expressing GHSR selectively in beta-cells. We here report that ghrelin attenuates glucose-induced insulin release via direct interaction with ordinary GHSR that is uniquely coupled to novel cAMP/TRPM2 signaling in beta-cells, and that this beta-cell GHSR with unique insulinostatic signaling largely accounts for the systemic effects of ghrelin on circulating glucose and insulin levels. The novel beta-cell specific GHSR-cAMP/TRPM2 signaling provides a potential therapeutic target for the treatment of type 2 diabetes.