Francis S. Willard; Jonathan D. Douros; M 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; Jens J. Holst; David A. D’Alessio; Matthew P. Coghlan; Mette M. Rosenkilde; Jonathan E. Campbell; Kyle W. Sloop · 2020 · JCI Insight
Paper
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.
Analysis
This study characterizes tirzepatide, a dual GIP and GLP-1 receptor agonist, revealing its imbalanced GIP receptor engagement and biased signaling at the GLP-1 receptor, which may contribute to its potent metabolic benefits.
Discovery
Sean Wharton; Louis J. Aronne; Adam Stefański; Nasreen Alfaris; Andreea Ciudin; Koutaro Yokote; Bruno Halpern; Alpana P. Shukla; Chunmei Zhou; Lisa Macpherson; Sheryl Allen; Nadia N. Ahmad; Suzanne Klise
Nadia J Abbass; Raya Nahlawi; Jacqueline K. Shaia; Kevin Allan; David C. Kaelber; Katherine E. Talcott; Rishi P. Singh
Roger S. McIntyre; Rodrigo B. Mansur; Joshua D. Rosenblat; Angela T.H. Kwan
A. Michael Lincoff; Kirstine Brown‐Frandsen; Helen M. Colhoun; John Deanfield; Scott S. Emerson; Sille Esbjerg; Søren Hardt‐Lindberg; G. Kees Hovingh; Steven E. Kahn; Robert F. Kushner; Ildiko Lingvay; Tuğçe Kalaycı Oral; Marie Mide Michelsen; Jorge Plutzky; Christoffer W. Tornøe; Donna H. Ryan
Jingyue Wang; Quanwei Wang; Xinyu Yang; Wei Yang; Dong-Rui Li; Jingyu Jin; Hui-Cong Zhang; Xianfeng Zhang
Xin Zhao; Minghe Wang; Zhitong Wen; Zhihong Lu; Lijuan Cui; Chao Fu; Huan Xue; Yunfeng Liu; Yi Zhang
Source record