title: Molecular mechanisms underlying bile acid-stimulated glucagon-like peptide-1 secretion.
abstract: OBJECTIVE
  The glucagon-like peptides GLP-1 and GLP-2 are secreted from enteroendocrine L-cells following nutrient ingestion. Drugs that increase activity of the GLP-1 axis are highly successful therapies for type 2 diabetes, and boosting L-cell secretion is a potential strategy for future diabetes treatment. The aim of the present study was to further our understanding of the bile acid receptor GPBA (TGR5), an L-cell target currently under therapeutic exploration.
  
  
  METHODS
  GLUTag cells and mixed primary murine intestinal cultures were exposed to bile acids and a specific agonist, GPBAR-A. Secretion was measured using hormone assays and intracellular calcium and cAMP responses were monitored using real-time imaging techniques.
  
  
  RESULTS
  Bile acid-triggered GLP-1 secretion from GLUTag cells was GPBA-dependent, as demonstrated by its abolition following tgr5 siRNA transfection. Bile acids and GPBAR-A increased GLP-1 secretion from intestinal cultures, with evidence for synergy between the effects of glucose and GPBA activation. Elevation of cAMP was observed following GPBA activation in individual GLUTag cells. Direct calcium responses to GPBAR-A were small, but in the presence of the agonist, a subpopulation of cells that was previously poorly glucose-responsive exhibited robust glucose responses. In vivo, increased delivery of bile to more distal regions of the ileum augmented L-cell stimulation.
  
  
  CONCLUSIONS
  GPBA signalling in L-cells involves rapid elevation of cAMP, and enhanced calcium and secretory responses to glucose. Modulation of this receptor therapeutically may be an attractive strategy to enhance GLP-1 secretion and achieve better glycaemic control in diabetic patients.
authors: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, UK.
authors: H E
authors: HE
authors: Parker
authors: K
authors: K
authors: Wallis
authors: C W
authors: CW
authors: le Roux
authors: K Y
authors: KY
authors: Wong
authors: F
authors: F
authors: Reimann
authors: F M
authors: FM
authors: Gribble
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology*; D002460:Cell Line; D003106:Colon / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism* / Q000502:physiology; D053767:Glucagon-Like Peptide 2 / Q000097:blood / Q000378:metabolism / Q000502:physiology; D007421:Intestine, Small / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology*
chemical_list: D001647:Bile Acids and Salts; D053767:Glucagon-Like Peptide 2; C513561:Gpbar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP