12506 Vagal Glp-1 Receptors Are Essential In The Efficacy Of Orally Administered Exendin-4

Disclosure: M.M. Bethea: None. S. da Silva Teixeira: None. T.M. Cook: None. J. Hendrix: None. D. Sandoval: None. Oral formulations, such as the first and only FDA-approved oral GLP-1 analog (semaglutide), have the advantage of improving patient adherence and quality of life. Yet, how these oral GLP-1 receptor (GLP-1R) agonists mediate their glucose-lowering effects is unknown. Because systemic administration of GLP-1R analogs likely targets different GLP-1R populations than that of oral administration, it is imperative that we advance our understanding of the key GLP-1Rs needed for the metabolic benefits of orally administered GLP-1 therapies. We have preliminary data demonstrating that the oral administration of free Ex-4 significantly enhances glucose tolerance in fasted non-diabetic mice, strongly suggesting that oral Ex-4 is bioactive after transit through the GI system. Importantly, we have additional evidence that shows the oral administration of either Ex-4 or GLP-1 does not lead to detectable circulating levels of either peptide, suggesting that a local source is mediating this effect. Furthermore, using a GLP-1R Cre mouse crossed with a tdTomato reporter mouse, we see that the GLP-1R is expressed on epithelial cells within the intestine, yet oral Ex-4 administration in mice lacking GLP-1R in intestinal enterocytes elicited glycemic improvements. We hypothesized that neuronal GLP-1R populations within the gastrointestinal tract mediate the glycemic improvements of orally administered GLP-1 agonists. To test this hypothesis, we used various genetic mouse models lacking GLP-1Rs subjected to an oral gavage of Exendin-4, a GLP-1RA. We found that vagal GLP-1Rs are necessary for the glucose-lowering effects of orally administered Exendin-4. These findings will ultimately facilitate the development of more efficacious tailored compounds for the treatment of T2D and enhance our knowledge of GLP-1 biology. Presentation: 6/1/2024