GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models

Tito Borner; Caroline E. Geisler; Samantha M. Fortin; Richard Cosgrove; Jorge Alsina-Fernandez; Mridula Dogra; Sarah Doebley; Marcos J. Sanchez-Navarro; Rosa M. Leon; Jane Gaisinsky; Arianna White; Ankur Bamezai; Misgana Y. Ghidewon; Harvey J. Grill; Richard C. Crist; Benjamin C. Reiner; Minrong Ai; Ricardo J. Samms; Bart C.De Jonghe; Matthew R. Hayes

doi:10.2337/DB21-0459

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models

Tito Borner
, Caroline E. Geisler
, Samantha M. Fortin
, Richard Cosgrove
, Jorge Alsina-Fernandez
, Mridula Dogra
, Sarah Doebley
, Marcos J. Sanchez-Navarro
, Rosa M. Leon
, Jane Gaisinsky
, Arianna White
, Ankur Bamezai
, Misgana Y. Ghidewon
, Harvey J. Grill
, Richard C. Crist
, Benjamin C. Reiner
, Minrong Ai
, Ricardo J. Samms
, Bart C.De Jonghe
, Matthew R. Hayes

Research output: Contribution to journal › Article › peer-review

170 Scopus citations

Abstract

Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypep-tide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activa-tion, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in g-aminobutyric acid-ergic neu-rons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.

Original language	English
Pages (from-to)	2545-2553
Number of pages	9
Journal	Diabetes
Volume	70
Issue number	11
DOIs	https://doi.org/10.2337/DB21-0459
State	Published - Nov 2021

Bibliographical note

Publisher Copyright:
© 2021 by the American Diabetes Association.

Funding

Acknowledgments. The authors would like to thank Lauren Stein and Jack Chen (Department of Psychiatry, University of Pennsylvania, Philadelphia, PA) for technical assistance. Funding. This work was supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grants DK021397 (M.R.H., H.J.G.) and DK112812 (B.C.D.J.), and by the Swiss National Science Foundation (Grant SNF P400PB_186728 to T.B.). B.C.R. is supported, in part, by a 2017 National Association for Research on Schizophrenia and Depression Young Investigator Grant (No. 26634) from the Brain and Behavior Research Foundation as the Patrick A. Coffer Investigator, funding for which was generously provided by Ronald and Kathy Chandonais. Duality of Interest. This work was supported by an investigator-initiated sponsored agreement from Eli Lilly & Co. (M.R.H., B.C.D.J.). M.R.H. receives research funding from Boehringer Ingelheim that was not used in support of these studies. M.R.H. and B.C.D.J. are chief executive officer and chief scientific officer of Cantius Therapeutics, LLC, that pursues biological work unrelated to the current study. R.C., J.A.-F., M.D., M.A., and R.J.S. are employees of Eli Lilly & Co. No other potential conflicts of interest relevant to this article were reported. Author Contributions. T.B., C.E.G., S.M.F., R.C., J.A.-F., M.D., S.D., M.J.S.-N., R.M.L., J.G., A.W., A.B., M.Y.G., H.J.G., R.C.C., and B.C.R. performed experiments. TB, H.J.G., R.C.C., B.C.R., M.A., R.J.S., B.C.D.J., and M.R.H. analyzed the data. T.B., M.A., R.J.S., B.C.D.J., and M.R.H. conceived and designed the experimental approach. T.B., M.A., R.J.S., B.C.D.J., and M.R.H. prepared the manuscript. All authors edited the manuscript. M.R.H. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This work was supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grants DK021397 (M.R.H., H.J.G.) and DK112812 (B.C.D.J.), and by the Swiss National Science Foundation (Grant SNF P400PB_186728 to T.B.). B.C.R. is supported, in part, by a 2017 National Association for Research on Schizophrenia and Depression Young Investigator Grant (No. 26634) from the Brain and Behavior Research Foundation as the Patrick A. Coffer Investigator, funding for which was generously provided by Ronald and Kathy Chandonais.

Funders	Funder number
Eli Lilly and Company
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK112812, R01DK021397
National Institute of Diabetes and Digestive and Kidney Diseases
Brain and Behavior Research Foundation	26634
Brain and Behavior Research Foundation
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	186728, SNF P400PB_186728
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

Access to Document

10.2337/DB21-0459

Cite this

Borner, T., Geisler, C. E., Fortin, S. M., Cosgrove, R., Alsina-Fernandez, J., Dogra, M., Doebley, S., Sanchez-Navarro, M. J., Leon, R. M., Gaisinsky, J., White, A., Bamezai, A., Ghidewon, M. Y., Grill, H. J., Crist, R. C., Reiner, B. C., Ai, M., Samms, R. J., Jonghe, B. C. D., & Hayes, M. R. (2021). GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models. Diabetes, 70(11), 2545-2553. https://doi.org/10.2337/DB21-0459

@article{a5f14d56cba245548dc695cd60bf43ee,

title = "GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models",

abstract = "Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypep-tide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activa-tion, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in g-aminobutyric acid-ergic neu-rons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.",

author = "Tito Borner and Geisler, \{Caroline E.\} and Fortin, \{Samantha M.\} and Richard Cosgrove and Jorge Alsina-Fernandez and Mridula Dogra and Sarah Doebley and Sanchez-Navarro, \{Marcos J.\} and Leon, \{Rosa M.\} and Jane Gaisinsky and Arianna White and Ankur Bamezai and Ghidewon, \{Misgana Y.\} and Grill, \{Harvey J.\} and Crist, \{Richard C.\} and Reiner, \{Benjamin C.\} and Minrong Ai and Samms, \{Ricardo J.\} and Jonghe, \{Bart C.De\} and Hayes, \{Matthew R.\}",

note = "Publisher Copyright: {\textcopyright} 2021 by the American Diabetes Association.",

year = "2021",

month = nov,

doi = "10.2337/DB21-0459",

language = "English",

volume = "70",

pages = "2545--2553",

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Borner, T, Geisler, CE, Fortin, SM, Cosgrove, R, Alsina-Fernandez, J, Dogra, M, Doebley, S, Sanchez-Navarro, MJ, Leon, RM, Gaisinsky, J, White, A, Bamezai, A, Ghidewon, MY, Grill, HJ, Crist, RC, Reiner, BC, Ai, M, Samms, RJ, Jonghe, BCD & Hayes, MR 2021, 'GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models', Diabetes, vol. 70, no. 11, pp. 2545-2553. https://doi.org/10.2337/DB21-0459

TY - JOUR

T1 - GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models

AU - Borner, Tito

AU - Geisler, Caroline E.

AU - Fortin, Samantha M.

AU - Cosgrove, Richard

AU - Alsina-Fernandez, Jorge

AU - Dogra, Mridula

AU - Doebley, Sarah

AU - Sanchez-Navarro, Marcos J.

AU - Leon, Rosa M.

AU - Gaisinsky, Jane

AU - White, Arianna

AU - Bamezai, Ankur

AU - Ghidewon, Misgana Y.

AU - Grill, Harvey J.

AU - Crist, Richard C.

AU - Reiner, Benjamin C.

AU - Ai, Minrong

AU - Samms, Ricardo J.

AU - Jonghe, Bart C.De

AU - Hayes, Matthew R.

PY - 2021/11

Y1 - 2021/11

N2 - Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypep-tide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activa-tion, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in g-aminobutyric acid-ergic neu-rons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.

AB - Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypep-tide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activa-tion, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in g-aminobutyric acid-ergic neu-rons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.

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JO - Diabetes

JF - Diabetes

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ER -

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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