Proceedings of The Physiological Society
AstraZeneca (2010) Proc Physiol Soc 18, C09 and PC09
TGR5 mediated GLP-1 secretion
1. Cambridge Institute of Medical Research, Cambridge, United Kingdom.
Background: The incretin hormone, GLP-1, is secreted from intestinal L-cells in response to food ingestion, however little is known about how L-cells detect luminal nutrients. Bile acids are also released into the gut lumen in response to nutrients and have been associated with glucose homeostasis and GLP-1 secretion [1, 2]. The aim of this study was to investigate the expression of the bile acid sensitive G-protein coupled TGR5 receptor in primary L-cells and its role in GLP-1 secretion. Material and Methods: mRNA expression was analyzed by qRT-PCR in L-cells purified from transgenic mice with fluorescently labeled proglucagon-expressing cells . GLP-1 secretion was assayed in primary colonic cultures and GLUTag cells. FRET based [cAMP]i and ratiometric [Ca2+]i imaging experiments were performed on GLUTag cells. Results: TGR5 mRNA expression is highly enriched in L-cells compared to control intestinal epithelial cells. The bile acids deoxycholic acid, lithocholic acid and taurolithocholic acid (TLCA) and a TGR5 agonist increased GLP-1 secretion from primary cultures and enhanced the glucose-triggered response. In GLUTag cells, the GLP-1 secretory responses to TLCA and the TGR5 agonist were attenuated by TGR5 siRNA treatment. Consistent with the idea that TGR5 signals via Gs coupled pathways, the TGR5 agonist and TLCA elevated [cAMP]i in GLUTag cells. The TGR5 agonist also elevated [Ca2+]i and enhanced glucose-triggered [Ca2+]i responses, consistent with previously observed responses of GLUTag cells to elevated cAMP. Conclusion: Primary L-cells express the bile acid sensitive TGR5 receptor, which may contribute to the incretin response via the elevation of [cAMP]i and [Ca2+]i. The synergistic stimulation of GLP-1 release may be possible by combined activation of GPCRs and glucose-sensing pathways.
Where applicable, experiments conform with Society ethical requirements