| Title | Glucagon Potentiates Insulin Secretion Via beta-Cell GCGR at Physiological Concentrations of Glucose |
| Authors | Zhang, Yulin Han, Chengsheng Zhu, Wenzhen Yang, Guoyi Peng, Xiaohong Mehta, Sohum Zhang, Jin Chen, Liangyi Liu, Yanmei |
| Affiliation | Peking Univ, Coll Future Technol, Inst Mol Med, State Key Lab Membrane Biol,Beijing Key Lab Cardi, Beijing 100871, Peoples R China Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA McGovern Inst Brain Res, PKU IDG, Beijing 100871, Peoples R China Beijing Acad Artificial Intelligence, Beijing 100871, Peoples R China South China Normal Univ, Key Lab Brain Cognit & Educ Sci, Minist Educ, Inst Brain Res & Rehabil, Guangzhou 510631, Peoples R China |
| Keywords | GASTRIC-INHIBITORY POLYPEPTIDE PANCREATIC ALPHA-CELLS PEPTIDE-1 7-36 GLP-1 ACTIVATION ISLETS INCRETIN RELEASE OBESITY MOUSE |
| Issue Date | Sep-2021 |
| Publisher | CELLS |
| Abstract | Incretin-potentiated glucose-stimulated insulin secretion (GSIS) is critical to maintaining euglycemia, of which GLP-1 receptor (GLP-1R) on beta-cells plays an indispensable role. Recently, alpha-cell-derived glucagon but not intestine-derived GLP-1 has been proposed as the critical hormone that potentiates GSIS via GLP-1R. However, the function of glucagon receptors (GCGR) on beta-cells remains elusive. Here, using GCGR or GLP-1R antagonists, in combination with glucagon, to treat single beta-cells, alpha-beta cell clusters and isolated islets, we found that glucagon potentiates insulin secretion via beta-cell GCGR at physiological but not high concentrations of glucose. Furthermore, we transfected primary mouse beta-cells with RAB-ICUE (a genetically encoded cAMP fluorescence indicator) to monitor cAMP level after glucose stimulation and GCGR activation. Using specific inhibitors of different adenylyl cyclase (AC) family members, we revealed that high glucose concentration or GCGR activation independently evoked cAMP elevation via AC5 in beta-cells, thus high glucose stimulation bypassed GCGR in promoting insulin secretion. Additionally, we generated beta-cell-specific GCGR knockout mice which glucose intolerance was more severe when fed a high-fat diet (HFD). We further found that beta-cell GCGR activation promoted GSIS more than GLP-1R in HFD, indicating the critical role of GCGR in maintaining glucose homeostasis during nutrient overload. |
| URI | http://hdl.handle.net/20.500.11897/626112 |
| DOI | 10.3390/cells10092495 |
| Indexed | SCI(E) |
| Appears in Collections: | 分子医学研究所 膜生物学国家重点实验室 |
