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

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Dokumenter

  • Francis S. Willard
  • Jonathan D. Douros
  • Maria Gabe
  • Aaron D. Showalter
  • David B. Wainscott
  • Todd M. Suter
  • Megan E. Capozzi
  • Wijnand J. C. van der Velden
  • Cynthia Stutsman
  • Guemalli R. Cardona
  • Shweta Urva
  • Paul J. Emmerson
  • Holst, Jens Juul
  • David A. D'Alessio
  • Matthew P. Coghlan
  • Rosenkilde, Mette
  • Jonathan E. Campbell
  • Kyle W. Sloop

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 beta-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal beta-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.

OriginalsprogEngelsk
Artikelnummer140532
TidsskriftJCI insight
Vol/bind5
Udgave nummer17
Antal sider16
ISSN2379-3708
DOI
StatusUdgivet - 2020

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