The aim of this dissertation research was to investigate how Glucagon-Like Peptide-1 activates the central nervous system to illicit changes in blood glucose. Understanding how the body regulates blood glucose levels is important for not only understanding the disease diabetes, but also in developing treatments for the disease. Though numerous studies have looked the actions and mechanisms of GLP-1 action, there still is not a concise and agreed upon mechanism of action. Our hypothesis is that it acts in a neural manner by activating the central nervous system to stimulate efferent pathways to regulate glucose homeostasis.
Two likely places for this signaling to take place are the portal vein and the small intestine. By using retrograde tracing and immunohistochemistry techniques, we were able to identify sensory afferent nerves that were capable of accessing circulation that expressed the GLP-1r. After a visiting student demonstrated that when GLP-1 was infused into the portal vein no resulting increase in insulin was observed, we decided to investigate the GLP-1/GLP-1r signaling system in the small intestine. We were able to identify a population of enterocytes that express the GLP-1r in the duodenum, jejunum and ileum. We attempted to identify which enterocytes were expressing the GLP-1r, but were only able to rule out expression on L-cells, D-cells, and enterochromaffin cells. Additionally, we were able to identify GLP-1r on synaptophysin positive cells, in both the enterocytes and myenteric plexi. Further work is required to identify this unique population of enterocytes, and whether or not GLP-1r are present on vagal nerve elements in the small intestine.
In conclusion, we identified that sensory neurons in the portal vein can access circulation, that there is a population of enterocytes in the small intestine that express the GLP-1r and that the GLP-1r is can also be found on some neural elements in the small intestine. These findings are important for the understanding of GLP-1's multiple effects and sites of action to elicit changes in glucose homeostasis, particularly concerning pharmacological manipulation of the GLP-1 system for treatment of diabetes. Further work will continue to expand on our knowledge of this important global glucose homeostasis hormone.