title: Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells.
abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic β cells. In the present study, we have identified the expression of TGR5 in pancreatic β cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated Gα(s) and caused an increase in intracellular cAMP and Ca(2+). OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective Gα(s) inhibitor) or U73122 (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, U73122 or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G(s)/cAMP/Ca(2+) pathway. 8-pCPT-2'-O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic β cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Divya P
authors.initials: DP
authors.lastname: Kumar
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Rajagopal
authors.forename: Sunila
authors.initials: S
authors.lastname: Mahavadi
authors.forename: Faridoddin
authors.initials: F
authors.lastname: Mirshahi
authors.forename: John R
authors.initials: JR
authors.lastname: Grider
authors.forename: Karnam S
authors.initials: KS
authors.lastname: Murthy
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002793:Cholic Acids / Q000378:metabolism / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009828:Oleanolic Acid / Q000378:metabolism / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); C545501:6alpha-ethyl-23(S)-methylcholic acid; D001557:Benzenesulfonates; D001647:Bile Acids and Salts; D002793:Cholic Acids; D004963:Estrenes; C473772:GPBAR1 protein, human; C513561:Gpbar1 protein, mouse; D007328:Insulin; D010716:Phosphatidylinositols; D011760:Pyrrolidinones; D043562:Receptors, G-Protein-Coupled; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D009828:Oleanolic Acid; D005947:Glucose; D002118:Calcium