Endocrine Abstracts

Background: Glucagon-like peptide 1 (GLP-1) is an incretin hormone released from enteroendocrine L-cells in the gut. GLP-1 analogues and dipeptidyl-peptidase-4 inhibitors are currently used to treat type-2 diabetes. A greater understanding of the mechanisms underlying the release of GLP-1 may facilitate the development of therapeutics to stimulate the release of endogenous GLP-1. Bile acids have been shown to induce GLP-1 release via the G protein-coupled bile acid receptor 1 (GPBAR1/TGR5) and increased cAMP. The apical sodium-dependent bile acid transporter (ASBT) and nuclear farnesoid X receptor (FXR) may also be involved.

Aim: To identify pathways of bile acid-stimulated GLP-1 secretion and whether these are activated by bile acids from the apical or basolateral direction.

Methods: Intracellular cAMP and Ca2+ were monitored in cultured primary murine L-cells using transgenic mice expressing fluorescent sensors (Epac2camps or GCaMP3) specifically in L-cells. GLP-1 release was measured from primary murine intestinal cultures, tissue segments mounted in Ussing chambers and perfused rat intestine.

Results: Bile acids increased intracellular cAMP and Ca2+ in L-cells and stimulated GLP-1 secretion from intestinal cultures. GPBAR-A, a specific GPBAR1 agonist, also stimulated GLP-1 secretion but GW4064, a specific FXR agonist, did not. Bile acids stimulated GLP-1 secretion from intestinal tissue segments mounted in Ussing chambers when applied to either the apical or basolateral side. However, stimulation by apically applied bile acids was blocked by an ASBT inhibitor. GPBAR-A was only effective when applied basolaterally. Furthermore, in perfused rat intestine, vascular application of TDCA elicited a greater secretory response than when luminally applied.

Conclusion: Bile acids stimulate GLP-1 secretion primarily via activation of GPBAR1 on the basolateral surface of intestinal L-cells. This has implications for the design of therapeutics to target GPBAR1 and suggests the stimulation of gut hormone secretion may include post-absorptive mechanisms.