Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet Cells to Promote Glucose Homeostasis

The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic cells by bile acids induces insulin secretion. Glucagon released from pancreatic cells and glucagon-like peptide 1 (GLP-1) released from intestinal L cells regulate insulin secretion. Both glucagon and GLP-1 are derived from alternate splicing of a common precursor, proglucagon by PC2 and PC1, respectively. We investigated whether TGR5 activation in pancreatic cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases cell mass and function in a paracrine manner. TGR5 activation augmented a hyperglycemia-induced switch from glucagon to GLP-1 synthesis in human and mouse islet cells by G(S)/cAMP/PKA/cAMP-response element-binding protein-dependent activation of PC1. Furthermore, TGR5-induced GLP-1 release from cells was via an Epac-mediated PKA-independent mechanism. Administration of the TGR5 agonist, INT-777, to db/db mice attenuated the increase in body weight and improved glucose tolerance and insulin sensitivity. INT-777 augmented PC1 expression in cells and stimulated GLP-1 release from islets of db/db mice compared with control. INT-777 also increased pancreatic cell proliferation and insulin synthesis. The effect of TGR5-mediated GLP-1 from cells on insulin release from islets could be blocked by GLP-1 receptor antagonist. These results suggest that TGR5 activation mediates cross-talk between and cells by switching from glucagon to GLP-1 to restore cell mass and function under hyperglycemic conditions. Thus, INT-777-mediated TGR5 activation could be leveraged as a novel way to treat type 2 diabetes mellitus.