title: Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis.
abstract: The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic β cells by bile acids induces insulin secretion. Glucagon released from pancreatic α 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 α cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases β 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 α cells by GS/cAMP/PKA/cAMP-response element-binding protein-dependent activation of PC1. Furthermore, TGR5-induced GLP-1 release from α 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 α cells and stimulated GLP-1 release from islets of db/db mice compared with control. INT-777 also increased pancreatic β cell proliferation and insulin synthesis. The effect of TGR5-mediated GLP-1 from α cells on insulin release from islets could be blocked by GLP-1 receptor antagonist. These results suggest that TGR5 activation mediates cross-talk between α and β cells by switching from glucagon to GLP-1 to restore β 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.
authors.affiliation: Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 and.
authors.forename: Divya P
authors.initials: DP
authors.lastname: Kumar
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Amon
authors.initials: A
authors.lastname: Asgharpour
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Faridoddin
authors.initials: F
authors.lastname: Mirshahi
authors.affiliation: the Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23507.
authors.forename: So Hyun
authors.initials: SH
authors.lastname: Park
authors.affiliation: the Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23507.
authors.forename: Sichen
authors.initials: S
authors.lastname: Liu
authors.affiliation: the Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23507.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Imai
authors.affiliation: the Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23507.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.affiliation: Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 and.
authors.forename: John R
authors.initials: JR
authors.lastname: Grider
authors.affiliation: Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 and srinivasa.karnam@vcuhealth.org.
authors.forename: Karnam S
authors.initials: KS
authors.lastname: Murthy
authors.affiliation: From the Departments of Internal Medicine and arun.sanyal@vcuhealth.org.
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D002460:Cell Line; D002793:Cholic Acids / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004963:Estrenes / Q000494:pharmacology; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019899:Paracrine Communication / Q000235:genetics*; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000235:genetics / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology
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; D001555:Benzene Derivatives; D001557:Benzenesulfonates; D002793:Cholic Acids; C000589230:ESI-05; D004963:Estrenes; C513561:Gpbar1 protein, mouse; D011760:Pyrrolidinones; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D052216:Glucagon-Like Peptide 1; D017868:Cyclic AMP-Dependent Protein Kinases; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2; D005947:Glucose
keywords: G protein-coupled receptor; bile acid; cell signaling; metabolic syndrome; pancreatic islet; reprogramming