Endogenous PYY and GLP-1 mediate l-glutamine responses in intestinal mucosa.

BACKGROUND AND
PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY
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. CONCLUSION AND IMPLICATIONS: 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.