{"doi":"10.1172/jci.insight.140532","title":"Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist","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.","journal":"JCI Insight","year":2020,"id":48206,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":501,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":63182,"name":"Jonathan D. Douros","orcid":"0000-0003-2299-6163","position":1,"is_corresponding":false},{"id":226893,"name":"M Gabe","orcid":"0000-0003-2559-862X","position":2,"is_corresponding":false},{"id":229540,"name":"Aaron D. Showalter","orcid":null,"position":3,"is_corresponding":false},{"id":226894,"name":"David B. Wainscott","orcid":"0000-0002-8790-1703","position":4,"is_corresponding":false},{"id":229541,"name":"Todd M. Suter","orcid":null,"position":5,"is_corresponding":false},{"id":226895,"name":"Megan E. Capozzi","orcid":"0000-0002-7587-0663","position":6,"is_corresponding":false},{"id":226896,"name":"Wijnand J. C. van der Velden","orcid":"0000-0003-0785-3762","position":7,"is_corresponding":false},{"id":229542,"name":"Cynthia Stutsman","orcid":null,"position":8,"is_corresponding":false},{"id":229543,"name":"Guemalli R. Cardona","orcid":null,"position":9,"is_corresponding":false},{"id":226897,"name":"Shweta Urva","orcid":"0000-0002-3681-479X","position":10,"is_corresponding":false},{"id":229544,"name":"Paul J. Emmerson","orcid":null,"position":11,"is_corresponding":false},{"id":226898,"name":"Jens J. Holst","orcid":"0000-0001-6853-3805","position":12,"is_corresponding":false},{"id":226899,"name":"David A. D’Alessio","orcid":"0000-0003-4155-4870","position":13,"is_corresponding":false},{"id":226900,"name":"Matthew P. Coghlan","orcid":"0000-0002-0894-1505","position":14,"is_corresponding":false},{"id":226901,"name":"Mette M. Rosenkilde","orcid":"0000-0001-9600-3254","position":15,"is_corresponding":false},{"id":226902,"name":"Jonathan E. Campbell","orcid":"0000-0003-4358-6331","position":16,"is_corresponding":false},{"id":63186,"name":"Kyle W. Sloop","orcid":"0000-0001-6748-9929","position":17,"is_corresponding":false},{"id":226892,"name":"Francis S. Willard","orcid":"0000-0002-4260-2451","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T20:34:12.647743Z","pmid":"32730231","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}