title: Endogenous PYY and GLP-1 mediate l-glutamine responses in intestinal mucosa.
abstract: OBJECTIVE
  l-glutamine (Gln) is an energy source for gastrointestinal (GI) epithelia and can stimulate glucagon-like peptide 1 (GLP-1) release from isolated enteroendocrine L-cells. GLP-1 and peptide YY (PYY) are co-secreted postprandially and both peptides have functional roles in glucose homeostasis and energy balance. The primary aim of this project was to establish the endogenous mechanisms underpinning Gln responses within intact GI mucosae using selective receptor antagonists.
  
  
  METHODS
  Mouse mucosae from different GI regions were voltage-clamped and short-circuit current (Isc) was recorded to Gln added to either surface in the absence or presence of antagonists, using wild-type (WT) or PYY-/- tissues. The glucose sensitivity of Gln responses was also investigated by replacement with mannitol.
  
  
  RESULTS
  Colonic apical and basolateral Gln responses (at 0.1 and 1 mM) were biphasic; initial increases in Isc were predominantly GLP-1 mediated. GLP-1 receptor antagonism significantly reduced the initial Gln response in the PYY-/- colon. The slower reductions in Isc to Gln were PYY-Y1 mediated as they were absent from the PYY-/- colon and were blocked selectively in WT tissue by a Y1 receptor antagonist. In jejunum mucosa, Gln stimulated monophasic Isc reductions that were PYY-Y1 receptor mediated. Gln effects were partially glucose sensitive, and Calhex 231 inhibition indicated that the calcium-sensing receptor (CaSR) was involved.
  
  
  CONCLUSIONS
  Gln stimulates the co-release of endogenous GLP-1 and PYY from mucosal L-cells resulting in paracrine GLP-1 and Y1 receptor-mediated electrogenic epithelial responses. This glucose-sensitive mechanism appears to be CaSR mediated and could provide a significant therapeutic strategy releasing two endogenous peptides better known for their glucose-lowering and satiating effects.
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Joshi
authors.forename: I R
authors.initials: IR
authors.lastname: Tough
authors.forename: H M
authors.initials: HM
authors.lastname: Cox
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019899:Paracrine Communication; D019894:Peptide YY / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C577923:CASR protein, mouse; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D006727:Hormone Antagonists; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D005973:Glutamine; D019894:Peptide YY; D052216:Glucagon-Like Peptide 1; D005947:Glucose
keywords: PYY-/- mice; Y1 receptor; calcium-sensing receptor; endogenous peptide YY; enteroendocrine L-cell; mucosal ion transport