TGR5 potentiates GLP-1 secretion in response to anionic exchange resins.
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.
Laboratory of Integrative and Systems Physiology-LISP, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Taoufiq
T
Harach
Thijs W H
TW
Pols
Mitsunori
M
Nomura
Adriano
A
Maida
Mitsuhiro
M
Watanabe
Johan
J
Auwerx
Kristina
K
Schoonjans
D000818:Animals; D000837:Anion Exchange Resins / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D002793:Cholic Acids / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D059305:Diet, High-Fat / Q000009:adverse effects; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000235:genetics; D052336:Proglucagon / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C545501:6alpha-ethyl-23(S)-methylcholic acid; D000837:Anion Exchange Resins; D001647:Bile Acids and Salts; D001786:Blood Glucose; D002793:Cholic Acids; C513561:Gpbar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; C106574:cholebine