Abstract
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 Gq/11-protein signaling. By contrast, ghrelin acts on pancreatic islet β-cells via Gi-protein-mediated signaling. These observations raise a question whether the ghrelin action 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 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 β-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 β-cells, and that this β-cell GHSR with unique insulinostatic signaling largely accounts for the systemic effects of ghrelin on circulating glucose and insulin levels. The novel β-cell specific GHSR-cAMP/TRPM2 signaling provides a potential therapeutic target for the treatment of type 2 diabetes.
Highlights
Gastric hormone ghrelin regulates insulin secretion, as well as growth hormone release, feeding behavior and adiposity
We found that ghrelin failed to affect glucose (8.3 mM)-induced insulin release in islets from growth hormone secretagogue-receptor (GHSR)-null mice, while ghrelin inhibited it in islets of wild-type mice
Glucose-induced insulin release in GHSR-null islets was greater than those in wild-type islets, while insulin content per islet was unaltered in GHSR-null mice. These results in islets of GHSR-null mice are similar to those reported in ghrelin-KO mice[21]
Summary
Gastric hormone ghrelin regulates insulin secretion, as well as growth hormone release, feeding behavior and adiposity. 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 β-cells, and that this β-cell GHSR with unique insulinostatic signaling largely accounts for the systemic effects of ghrelin on circulating glucose and insulin levels. In consistent with the pharmacological studies, mice lacking gene of ghrelin[21] and those of GOAT26 showed improved glucose tolerance and enhanced plasma insulin release under normal chow condition. Ablation of ghrelin improved glucose tolerance and enhances insulin secretion in leptin-deficient ob/ob mice[27] These findings suggest that the insulinostatic function of ghrelin would affect blood glucose levels, and manipulation of the β -cell ghrelin action could provide a novel tool to optimize insulin release for achieving normoglycemia. The study explored the role of the β -cell GHSR in the glycemic effects of ghrelin administration and endogenous ghrelin as assessed by the effect of ghrelin antagonists
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