Characterization of Novel Glucagon Receptor Interactors that Modify Receptor Activity

Glucagon helps maintain blood glucose homeostasis by stimulating gluconeogenesis and glycogenolysis. Elevated glucagon levels have been reported in type 2 diabetics, and may be in part responsible for their abnormally high blood glucose. A comprehensive understanding of glucagon receptor regulators is currently unavailable. Members of my lab performed a mass spectrometry screen to detect glucagon receptor interactors, 5 of which were validated to be true interactors by co-immunoprecipitation and Western blotting. The project outlined in this thesis began with the functional characterization of these interactors. Two interactors, low-density lipoprotein receptor (LDLR) and transmembrane emp24 domain trafficking protein 2 (TMED2) significantly enhanced glucagon stimulated glucose production, while tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta (YWHAB) lowered glucagon stimulated glucose production in primary hepatocytes. Because of YWHAB’s ability to lower glucose production, the underlying mechanism was explored and evidence suggests YWHAB enhances endocytosis of the glucagon receptor into the cell following glucagon stimulation.M.Sc