Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist
| العنوان: | Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist |
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| المؤلفون: | Francis S. Willard, Mette M. Rosenkilde, David B. Wainscott, Guemalli R. Cardona, Shweta Urva, Jens J. Holst, Matthew P. Coghlan, Todd M. Suter, Megan E. Capozzi, Kyle W. Sloop, Jonathan D. Douros, Cynthia Stutsman, David A. D'Alessio, Aaron D. Showalter, Jonathan E. Campbell, Maria Buur Nordskov Gabe, Wijnand J.C. van der Velden, Paul J. Emmerson |
| المصدر: | JCI Insight, Vol 5, Iss 17 (2020) Willard, F S, Douros, J D, Gabe, M, Showalter, A D, Wainscott, D B, Suter, T M, Capozzi, M E, van der Velden, W J C, Stutsman, C, Cardona, G R, Urva, S, Emmerson, P J, Holst, J J, D'Alessio, D A, Coghlan, M P, Rosenkilde, M M, Campbell, J E & Sloop, K W 2020, ' Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist ', JCI insight, vol. 5, no. 17, 140532 . https://doi.org/10.1172/jci.insight.140532Test JCI Insight |
| بيانات النشر: | American Society for Clinical investigation, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Blood Glucose, Male, 0301 basic medicine, Pharmacology, ACTIVATION, Mice, 0302 clinical medicine, Functional selectivity, Insulin, Receptor, PHARMACOLOGY, AFFINITY, Mice, Knockout, geography.geographical_feature_category, GLUCAGON-LIKE PEPTIDE-1, Chemistry, Diabetes, General Medicine, Islet, beta-Arrestin 1, 030220 oncology & carcinogenesis, Medicine, medicine.symptom, hormones, hormone substitutes, and hormone antagonists, Research Article, Agonist, endocrine system, medicine.drug_class, DEPENDENT INSULINOTROPIC POLYPEPTIDE, Gastric Inhibitory Polypeptide, Therapeutics, Glucagon-Like Peptide-1 Receptor, Receptors, Gastrointestinal Hormone, Islets of Langerhans, 03 medical and health sciences, Diabetes mellitus, medicine, SERUM-PROTEIN BINDING, Animals, Hypoglycemic Agents, Glucagon-like peptide 1 receptor, geography, DULAGLUTIDE, IN-VITRO, medicine.disease, 030104 developmental biology, Mechanism of action, Metabolic control analysis, INHIBITORS, SEMAGLUTIDE |
| الوصف: | 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. Studies of the dual GIP and GLP-1 receptor agonist tirzepatide reveal occupancy favoring the GIP receptor and biased cAMP signaling at the GLP-1 receptor. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2379-3708 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::624e5796daeef879f0b6faed814fb99cTest https://doaj.org/article/03002ae150b14972b6d0c404574ecbbdTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....624e5796daeef879f0b6faed814fb99c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23793708 |
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