Human GLP1R variants affecting GLP1R cell surface expression contribute to impaired glucose control and increased adiposity

Abstract The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in patients with type 2 diabetes (T2D) and obesity. The impact of genetic variability of the GLP1R gene on receptor function and its association with metabolic traits are unclear. Here, functional profiling of 59 rare and one common GLP1R variant across four signaling pathways reveals an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain- and loss-of-functions. Defective insulin secretion of loss-of-function GLP1R variants was rescued by allosteric GLP1R ligands or high exendin-4 concentrations in INS-1 823/3 cells. Genetic association studies in 200K participants from UK Biobank show that impaired GLP1R cell surface expression contributes to impaired glucose control and increased adiposity with increased HbA1c, BMI and diastolic blood pressure. This study defines impaired GLP-1R cell surface expression as a risk factor for T2D- and obesity-associated traits.