| First Author | Kumar DP | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 13 | Pages | 6626-40 |
| PubMed ID | 26757816 | Mgi Jnum | J:331862 |
| Mgi Id | MGI:6830327 | Doi | 10.1074/jbc.M115.699504 |
| Citation | Kumar DP, et al. (2016) Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet alpha Cells to Promote Glucose Homeostasis. J Biol Chem 291(13):6626-40 |
| abstractText | The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic beta cells by bile acids induces insulin secretion. Glucagon released from pancreatic alpha 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 alpha cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases beta 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 alpha cells by GS/cAMP/PKA/cAMP-response element-binding protein-dependent activation of PC1. Furthermore, TGR5-induced GLP-1 release from alpha 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 alpha cells and stimulated GLP-1 release from islets of db/db mice compared with control. INT-777 also increased pancreatic beta cell proliferation and insulin synthesis. The effect of TGR5-mediated GLP-1 from alpha cells on insulin release from islets could be blocked by GLP-1 receptor antagonist. These results suggest that TGR5 activation mediates cross-talk between alpha and beta cells by switching from glucagon to GLP-1 to restore beta 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. |
