Human GLP1R variants affecting GLP1R cell surface expression are associated with 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 individuals with type 2 diabetes and obesity^1,2. The impact of genetic variability of GLP1R on receptor function and its association with metabolic traits are unclear with conflicting reports. Here, we show an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain of function (GoF) and loss of function (LoF), after performing a functional profiling of 60 GLP1R variants across four signalling pathways. The defective insulin secretion of GLP1R LoF variants is rescued by allosteric GLP1R ligands or high concentrations of exendin-4/semaglutide in INS-1 823/3 cells. Genetic association studies in 200,000 particip

SUBMITTER: Gao W 

PROVIDER: S-EPMC11610247 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature