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.
Keywords:
G protein-coupled receptor; bile acid; cell signaling; metabolic syndrome; pancreatic islet; reprogramming.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Benzene Derivatives / pharmacology
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Benzenesulfonates / pharmacology
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Cell Line
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Cholic Acids / pharmacology*
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Cyclic AMP-Dependent Protein Kinases / genetics
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Diabetes Mellitus, Experimental / drug therapy
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Diabetes Mellitus, Experimental / genetics*
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / pathology
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Estrenes / pharmacology
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Gene Expression Regulation
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Glucagon-Like Peptide 1 / biosynthesis
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Glucagon-Like Peptide 1 / genetics
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Glucagon-Like Peptide 1 / metabolism*
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Glucagon-Secreting Cells / drug effects
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Glucagon-Secreting Cells / metabolism
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Glucagon-Secreting Cells / pathology
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Glucose / metabolism*
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Homeostasis / drug effects
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Humans
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Insulin Resistance
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism
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Insulin-Secreting Cells / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Paracrine Communication / genetics*
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Proprotein Convertase 1 / genetics
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Proprotein Convertase 1 / metabolism
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Proprotein Convertase 2 / genetics
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Proprotein Convertase 2 / metabolism
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Pyrrolidinones / pharmacology
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction
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Sulfones / pharmacology
Substances
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4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate)
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6alpha-ethyl-23(S)-methylcholic acid
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Benzene Derivatives
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Benzenesulfonates
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Cholic Acids
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ESI-05
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Estrenes
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Gpbar1 protein, mouse
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Pyrrolidinones
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Receptors, G-Protein-Coupled
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Sulfones
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1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
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Glucagon-Like Peptide 1
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Cyclic AMP-Dependent Protein Kinases
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Proprotein Convertase 1
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Proprotein Convertase 2
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Glucose