Biased agonism of GLP-1R and GIPR enhances glucose lowering and weight loss, with dual GLP-1R/GIPR biased agonism yielding greater efficacy.

ABSTRACT: Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have recently been shown to play a significant role in the treatment of diabetes and obesity. Better understanding of their signaling and mechanism of action could further improve their therapeutic effects. In the current study, we investigate the impact of biased cyclic AMP (cAMP) signaling of GLP-1R and GIPR, individually, as well as the combined effects of a unimolecular dually biased GLP-1R/GIPR agonist, CT-859, on glucose, food consumption, and body weight regulation. Our data demonstrate that biased agonism of either GLP-1R or GIPR leads to better glycemic regulation, greater food intake suppression, and weight loss. In addition, concerted biased activation of both GLP-

SUBMITTER: Rodriguez R 

PROVIDER: S-EPMC12208311 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature