Variants of Glucagon-like Peptide 1 Receptor Modify Intracellular Signaling

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Dagnachew, Mesgana
Printz, Richard
Niswender, Kevin
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Scholarship Sewanee 2020 , Diabetes , GLP1 , GLP1R , Obesity , Cellular stress , Inflammation , Receptor variants , Phosphomimetics
Glucagon-like peptide-1 (GLP-1) is a peptide hormone that is mostly produced in the intestinal epithelial endocrine cells and released in response to food intake. The actions of this hormone include stimulating insulin secretion, inhibiting glucagon secretion and gastrointestinal motility, regulating appetite and providing protection from inflammation and other forms of cellular stress. Due to these functions, its receptor, known as the GLP-1 receptor (GLP1R), has gained attention as an effective therapeutic target for obesity and type 2 diabetes. Recent studies have shown that a low-frequency missense variant of the GLP1R gene encoding a receptor with an amino acid change, A316T, is associated with reduced risk of obesity comorbidities, coronary artery disease and type 2 diabetes. We will determine if the GLP1R variant with an A316T-substitution has an intracellular signaling bias, coupling uniquely to downstream signaling pathways to promote the associated beneficial health outcomes. We will express GLP1R or the A316T variant in a specialized form of HEK-293 cells derived from human embryonic kidney and treat these GLP1R expressing cells with GLP-1R agonists to study differences between the GLP1R receptor and its variant. Through Western blot analysis, we plan to assess the activation of downstream transcription factors to develop the mechanism of action of the GLP1R variant, A316T. These findings will enable us to understand the cytoprotective pathways associated with GLP-1R, which may lead to reduced risk of coronary artery disease and type 2 diabetes.