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

Publication ,  Journal Article
Willard, FS; Douros, JD; Gabe, MB; Showalter, AD; Wainscott, DB; Suter, TM; Capozzi, ME; van der Velden, WJ; Stutsman, C; Cardona, GR; Urva, S ...
Published in: JCI Insight
September 3, 2020

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.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

September 3, 2020

Volume

5

Issue

17

Location

United States

Related Subject Headings

  • beta-Arrestin 1
  • Receptors, Gastrointestinal Hormone
  • Mice, Knockout
  • Mice
  • Male
  • Islets of Langerhans
  • Insulin
  • Hypoglycemic Agents
  • Glucagon-Like Peptide-1 Receptor
  • Gastric Inhibitory Polypeptide
 

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Willard, F. S., Douros, J. D., Gabe, M. B., Showalter, A. D., Wainscott, D. B., Suter, T. M., … Sloop, K. W. (2020). Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight, 5(17). https://doi.org/10.1172/jci.insight.140532
Willard, Francis S., Jonathan D. Douros, Maria Bn Gabe, Aaron D. Showalter, David B. Wainscott, Todd M. Suter, Megan E. Capozzi, et al. “Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.JCI Insight 5, no. 17 (September 3, 2020). https://doi.org/10.1172/jci.insight.140532.
Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020 Sep 3;5(17).
Willard, Francis S., et al. “Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.JCI Insight, vol. 5, no. 17, Sept. 2020. Pubmed, doi:10.1172/jci.insight.140532.
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. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020 Sep 3;5(17).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

September 3, 2020

Volume

5

Issue

17

Location

United States

Related Subject Headings

  • beta-Arrestin 1
  • Receptors, Gastrointestinal Hormone
  • Mice, Knockout
  • Mice
  • Male
  • Islets of Langerhans
  • Insulin
  • Hypoglycemic Agents
  • Glucagon-Like Peptide-1 Receptor
  • Gastric Inhibitory Polypeptide