Development and characterization of a humanized GLP-1 receptor mouse model for translational drug development

Background & aim:
Injectable peptide-based GLP-1 receptor (GLP1R) agonists have shown remarkable therapeutic success in the treatment of type 2 diabetes and obesity. In comparison, small-molecule GLP1R agonists may further improve patient compliance and bioavailability through oral administration. In contrast to peptides, non-peptide ligands make fewer receptor contacts and amino acid differences across species may therefore significantly impact receptor binding and functional effects of small molecule GLP1R ligands. Animal models expressing the human GLP1R may therefore better enable in vivo characterization of small-molecule GLP1R agonists and translate preclinical pharmacodynamics to the clinic. We therefore developed a humanized GLP1R (hGLP1R) mouse model using CRISPR-Cas9 gene-editing technology. The present study aimed to phenotype the hGLP1R mouse as compared to wild-type mice.