{"id":"doi:10.1172/jci.insight.140532","kind":"article","title":"Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist","authors":["Willard FS","Douros JD","Gabe MB","Showalter AD","Wainscott DB","Suter TM","Capozzi ME","van der Velden WJ","Stutsman C","Cardona GR","Urva S","Emmerson PJ","Holst JJ","D'Alessio DA","Coghlan MP","Rosenkilde MM","Campbell JE","Sloop KW"],"author_count":18,"year":2020,"published":"2020-09-03","venue":"JCI insight","cited_by":414,"doi":"10.1172/jci.insight.140532","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1172/jci.insight.140532","archive_url":"https://space-kitty.com/papers/doi:10.1172/jci.insight.140532","updated":null,"pmid":"32730231","pmcid":"PMC7526454","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC7526454/pdf","abstract":"Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist\" by Willard FS, Douros JD, Gabe MB et al., https://doi.org/10.1172/jci.insight.140532, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"glp1-metabolic","name":"GLP-1 & Incretin Therapies","domain_slug":"medicine"}],"cited_in_dossiers":[{"slug":"glp1-metabolic","title":"GLP-1 & Incretin Therapies: State of the Field (October 2026)","url":"https://space-kitty.com/dossiers/glp1-metabolic"}]}