Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

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...

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Veröffentlicht in:JCI insight Jg. 5; H. 17
Hauptverfasser: Willard, Francis S., Douros, Jonathan D., Gabe, Maria B.N., Showalter, Aaron D., Wainscott, David B., Suter, Todd M., Capozzi, Megan E., van der Velden, Wijnand J.C., Stutsman, Cynthia, Cardona, Guemalli R., Urva, Shweta, Emmerson, Paul J., Holst, Jens J., D’Alessio, David A., Coghlan, Matthew P., Rosenkilde, Mette M., Campbell, Jonathan E., Sloop, Kyle W.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States American Society for Clinical Investigation 03.09.2020
American Society for Clinical investigation
Schlagworte:
Agonists
Animals
Arrestin
beta-Arrestin 1 - physiology
Blood Glucose - metabolism
Clinical trials
Diabetes
Diabetes mellitus (non-insulin dependent)
Drug dosages
Fatty liver
Gastric Inhibitory Polypeptide - pharmacology
GLP-1 receptor agonists
Glucagon
Glucagon-Like Peptide-1 Receptor - agonists
Glucose
Hypoglycemic Agents - pharmacology
Insulin
Insulin - metabolism
Insulin secretion
Internalization
Islets of Langerhans - drug effects
Islets of Langerhans - metabolism
Islets of Langerhans - pathology
Ligands
Male
Metabolism
Mice
Mice, Knockout
Obesity
Peptides
Pharmacokinetics
Pharmacology
Receptors, Gastrointestinal Hormone - agonists
Therapeutics
Weight control
Therapeutics
Diabetes
ISSN:2379-3708, 2379-3708
Online-Zugang:Volltext
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.140532