Glucagon Potentiates Insulin Secretion Via β-Cell GCGR at Physiological Concentrations of Glucose.

Yulin Zhang,Guoyi Yang,Chengsheng Han,Xiaohong Peng,Liangyi Chen,Sohum Mehta,Wenzhen Zhu,Yanmei Liu,Jin Zhang

doi:10.3390/cells10092495

Abstract

Incretin-potentiated glucose-stimulated insulin secretion (GSIS) is critical to maintaining euglycemia, of which GLP-1 receptor (GLP-1R) on β-cells plays an indispensable role. Recently, α-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 β-cells remains elusive. Here, using GCGR or GLP-1R antagonists, in combination with glucagon, to treat single β-cells, α-β cell clusters and isolated islets, we found that glucagon potentiates insulin secretion via β-cell GCGR at physiological but not high concentrations of glucose. Furthermore, we transfected primary mouse β-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 β-cells, thus high glucose stimulation bypassed GCGR in promoting insulin secretion. Additionally, we generated β-cell-specific GCGR knockout mice which glucose intolerance was more severe when fed a high-fat diet (HFD). We further found that β-cell GCGR activation promoted GSIS more than GLP-1R in HFD, indicating the critical role of GCGR in maintaining glucose homeostasis during nutrient overload.

Highlights

Insulin released from pancreatic β-cells, which facilitates glucose uptake and utilization in downstream tissues, such as liver, adipocytes, and muscle, is critical in maintaining tight glucose homeostasis [1]
We found that the possible mechanism may be that high glucose and glucagon receptors (GCGR) activate the same pool of adenylyl cyclase (AC) AC5, increasing cAMP to enhance insulin secretion, while glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) seems to recruit other ACs
Reducing the incubating glucose concentration to 5 mM made the glucagon effects susceptible to either GLP-1R or GCGR inhibition (Figure 1B). These results indicate that glucagon stimulates insulin secretion through GLP-1R at 20 mM glucose, but through GLP-1R and GCGR at 5 mM glucose

Summary

Introduction

Insulin released from pancreatic β-cells, which facilitates glucose uptake and utilization in downstream tissues, such as liver, adipocytes, and muscle, is critical in maintaining tight glucose homeostasis [1]. Induced blood glucose elevation triggers two- to threefold more insulin secretion than intravenous glucose injection [2], which is ascribed to the stimulatory effects of intestine-derived incretins, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) [3,4]. GLP-1 is widely accepted as an essential incretin for blood glucose homeostasis, and its receptor (GLP-1R) serves as a therapeutic drug target for T2D. Pancreatic β-cell-specific GLP-1R knockout mice showed normal oral glucose tolerance but impaired intraperitoneal glucose tolerance, indicating an indispensable role of islet-derived rather than intestine-derived ligands in activating GLP-1R in β-cells during glucose stimulation [7]

Methods

Results

Conclusion