Predicting the response to GLP-1 receptor agonists: an unexpected role for β-arrestin-1

Drugs targeting glucagon-like peptide 1 (GLP-1) and its heterotrimeric G protein-coupled receptor (GPCR) are important therapies for type 2 diabetes. 1 Müller TD Finan B Bloom SR et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019; 30: 72-130 Crossref PubMed Scopus (647) Google Scholar GLP-1 is an incretin hormone which potentiates glucose-stimulated insulin secretion after meals. After binding to its receptor on β cells (GLP1R), GLP-1 activates a cascade of intracellular regulators, including the Gαs subunit, which activates adenylyl cyclase and increases intracellular cyclic AMP concentrations; 1 Müller TD Finan B Bloom SR et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019; 30: 72-130 Crossref PubMed Scopus (647) Google Scholar and β-arrestins, which play a more complex role in receptor trafficking and signal transduction. 2 Laporte SA Scott MGH β-Arrestins: multitask scaffolds orchestrating the where and when in cell signalling. Methods Mol Biol. 2019; 1957: 9-55 Crossref PubMed Scopus (21) Google Scholar Different GLP-1 receptor agonists can stabilise different ensembles of active GLP1R conformations, changing the relative coupling and activity of different postreceptor pathways through a process called ligand-biased agonism. 3 Kenakin T New concepts in drug discovery: collateral efficacy and permissive antagonism. Nat Rev Drug Discov. 2005; 4: 919-927 Crossref PubMed Scopus (280) Google Scholar Ligand-biased agonism, along with the ability of different GPCRs to active the same postreceptor pathways, provides the basis for designing new therapies for type 2 diabetes, 4 El Eid L Reynolds CA Tomas A Jones Ben Biased agonism and polymorphic variation at the GLP-1 receptor: implications for the development of personalised therapeutics. Pharmacol Res. 2022; 184106411 Crossref PubMed Scopus (7) Google Scholar , 5 Jones B Bloom SR Buenaventura T Tomas A Rutter GA Control of insulin secretion by GLP-1. Peptides. 2018; 100: 75-84 Crossref PubMed Scopus (52) Google Scholar such as tirzepatide, a biased agonist of GLP1R that also targets the gastric inhibitory polypeptide receptor, a second incretin receptor on β cells. 6 Willard FS Douros JD Gabe MB et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020; 5e140532 Crossref Scopus (128) Google Scholar Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trialsThis genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. Full-Text PDF Open Access