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ResearchIn-Press PreviewTherapeutics Open Access | 10.1172/jci.insight.140532

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

Francis S. Willard,1 Jonathan D. Douros,2 Maria B. N. Gabe,3 Aaron D. Showalter,1 David B. Wainscott,1 Todd M. Suter,1 Megan E. Capozzi,2 Wijnand J. C. van der Velden,3 Cynthia. Stutsman,1 Guemalli R. Cardona,1 Shweta Urva,1 Paul J. Emmerson,1 Jens J. Holst,3 David A. D'Alessio,2 Matthew P. Coghlan,1 Mette M. Rosenkilde,3 Jonathan E. Campbell,4 and Kyle W. Sloop1

1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America

2Duke Molecular Physiology Institute, Duke University, Durham, United States of America

3Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Duke University, Durham, United States of America

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Published July 30, 2020 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.140532.
Copyright © 2020, Willard et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 30, 2020 - Version history
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Abstract

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and non-alcoholic 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 (GIPR) than the GLP-1 receptor (GLP-1R), corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIPR but show bias at the GLP-1R to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1R 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 the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIPR, combined with distinct signaling properties at the GLP-1R, together may account for the promising efficacy of this new investigational agent.

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  • Version 1 (July 30, 2020): In-Press Preview
  • Version 2 (September 3, 2020): Electronic publication
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