Abstract
Anionic exchange resins are bona fide cholesterol-lowering agents with glycemia lowering actions in diabetic patients. Potentiation of intestinal GLP-1 secretion has been proposed to contribute to the glycemia lowering effect of these non-systemic drugs. Here, we show that resin exposure enhances GLP-1 secretion and improves glycemic control in diet-induced animal models of "diabesity", effects which are critically dependent on TGR5, a G protein-coupled receptor that is activated by bile acids. We identified the colon as a major source of GLP-1 secretion after resin treatment. Furthermore, we demonstrate that the boost in GLP-1 release by resins is due to both enhanced TGR5-dependent production of the precursor transcript of GLP-1 as well as to the local enrichment of TGR5 agonists in the colon. Thus, TGR5 represents an essential component in the pathway mediating the enhanced GLP-1 release in response to anionic exchange resins.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anion Exchange Resins / pharmacology*
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Bile Acids and Salts / pharmacology
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Blood Glucose / metabolism
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CHO Cells
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Cholic Acids / pharmacology
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Colon / drug effects*
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Colon / metabolism
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Cricetinae
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Cricetulus
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Diet, High-Fat / adverse effects
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Enteroendocrine Cells / drug effects
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Enteroendocrine Cells / metabolism
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Glucagon-Like Peptide 1 / blood
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Glucagon-Like Peptide 1 / genetics
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Glucagon-Like Peptide 1 / metabolism*
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Insulin / blood
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Insulin Resistance / genetics
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Male
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Mice
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Mice, Knockout
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Obesity / blood
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Obesity / etiology
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Obesity / genetics
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Proglucagon / genetics
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Proglucagon / metabolism
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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6alpha-ethyl-23(S)-methylcholic acid
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Anion Exchange Resins
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Bile Acids and Salts
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Blood Glucose
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Cholic Acids
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Gpbar1 protein, mouse
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Insulin
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Receptors, G-Protein-Coupled
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Proglucagon
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Glucagon-Like Peptide 1
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cholebine