Endocrine Abstracts

Rationale – Obesity is a major global health challenge in the face of accessible nutrient-rich meals and increasing sedentary lifestyles. While glucagon-like peptide-1 receptor (GLP-1R) agonists are therapeutically effective, high rates of nausea and vomiting (up to 40%) often cause treatment discontinuation. Certain G protein-biased GLP-1R agonists may offer a promising therapeutic strategy by favouring beneficial G protein signalling over β-arrestin pathways, potentially enhancing efficacy while minimising internalisation-mediated side effects. Rationale – To isolate the functional consequences of bias independently of ligand pharmacology, we employed a hGLP-1R mutant sequence modifications that inhibit its phosphorylation to recapitulate G protein-biased activation. We compared the mutant and wild-type receptors in HEK293 cells using the native ligand GLP-1 and two oppositely biased agonists (Exendin-F1 and Exendin-D3), measuring internalisation, β-arrestin recruitment, Gas activation and signalling readouts in HEK293 cells.

Key findings and Conclusion – The “phosphodeficient” receptor mutant exhibited reduced arrestin recruitment and internalisation upon stimulation with GLP-1 and β-arrestin-biased Ex-D3, to similar levels achieved with G protein-biased Ex-F1 in wild-type receptor. Consequently, this “arrestin-away” cellular phenotype of the mutant receptor results in markedly enhanced ligand-induced kinase activation and cAMP signalling. These findings support the potential of receptor-mediated G protein-bias to improve drug responses for GLP-1-based obesity treatments.