TGR5 potentiates GLP-1 secretion in response to anionic exchange resins

Sci Rep. 2012;2:430. doi: 10.1038/srep00430. Epub 2012 May 30.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anion Exchange Resins / pharmacology*
  • Bile Acids and Salts / pharmacology
  • Blood Glucose / metabolism
  • CHO Cells
  • Cholic Acids / pharmacology
  • Colon / drug effects*
  • Colon / metabolism
  • Cricetinae
  • Cricetulus
  • Diet, High-Fat / adverse effects
  • Enteroendocrine Cells / drug effects
  • Enteroendocrine Cells / metabolism
  • Glucagon-Like Peptide 1 / blood
  • Glucagon-Like Peptide 1 / genetics
  • Glucagon-Like Peptide 1 / metabolism*
  • Insulin / blood
  • Insulin Resistance / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Obesity / blood
  • Obesity / etiology
  • Obesity / genetics
  • Proglucagon / genetics
  • Proglucagon / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • 6alpha-ethyl-23(S)-methylcholic acid
  • Anion Exchange Resins
  • Bile Acids and Salts
  • Blood Glucose
  • Cholic Acids
  • Gpbar1 protein, mouse
  • Insulin
  • Receptors, G-Protein-Coupled
  • Proglucagon
  • Glucagon-Like Peptide 1
  • cholebine