Expression and function of bile acid receptor TGR5 in glucagon secreting pancreatic α cells: hyperglycemia induced expression of PC1 and release of GLP‐1 in response to activation of TGR5 by bile acids (1108.6)

Abstract

We have recently shown that TGR5, a novel G protein coupled receptor, expressed in the pancreatic β cells induces insulin secretion in response to bile acids. Secretion of glucagon from the pancreatic α cells and glucagon‐like peptide 1 (GLP‐1) from the intestinal enteroendocrine cells also regulate insulin secretion. Glucagon and GLP‐1 are processed from the proglucagon by the cell‐specific expression of proconvertase 2 (PC2) and PC1, respectively. AIM. To determine expression and function of TGR5 in pancreatic α cells in normal and hyperglycemia. RESULTS. mRNA and protein expression of TGR5 was demonstrated in α cell line αTC1‐6 and mouse islets. Addition of INT‐777, a selective TGR5 ligand or lithocholic acid (LCA) increased glucagon secretion at low glucose (3 mM) in a concentration dependent manner in αTC1‐6 cells and mouse islets. PC2, but not PC1 was expressed in control αTC1‐6 cells. Treatment of α cells or mice islets with 25 mM glucose for 7 days induced expression of PC1 leading to secretion of GLP‐1 in response to INT‐777 and LCA. Similar release of GLP‐1 was obtained from diabetic db/db mice islets. CONCLUSION. Pancreatic α cells express TGR5 and PC2, and release glucagon in response to bile acids. Hyperglycemia induces expression of PC1 and causes release of GLP‐1. The importance of GLP‐1 in the regulation of insulin secretion underscores the significance of TGR5 as a potential therapeutic target in diabetes.