The Role of Gastrointestinal GLP-1R Neurons in Mediating the Glucose-Lowering and Weight Loss Effects of Oral Exendin-4

Current studies demonstrate a strong correlation between obesity and Type 2 Diabetes (T2D). Therefore, therapeutics that are able to reduce weight loss and lower glucose are cornerstone to T2D treatments. To date, the only drugs on the market that are able to claim this success are glucagon like peptide 1 receptor agonists (GLP-1RAs). However, many of these drugs require injections, thus negatively impacting patient compliance. Oral GLP-1RAs have the capacity to increase patient adherence and make T2D therapies affordable. It is important to note that systemic versus oral administration of GLP-1RAs target different GLP-1R populations. Therefore, it is critical that the GLP-1R populations that mediate the glucose lowering and weight loss effects of orally administered GLP-1RAs are assessed. In this proposal, I will eliminate the neuronal GLP-1R populations within the intestine to determine if they are necessary for the enhanced glucose tolerance and weight loss effects of orally administered GLP-1RAs. Data leveraged from this study will enhance our knowledge of GLP-1 biology and lead to the development of more efficacious drugs.