Ir directamente a la navegación principal Ir directamente a la búsqueda Ir directamente al contenido principal

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

Producción científica: Article › revisión exhaustiva

173 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)2545-2553
Número de páginas9
PublicaciónDiabetes
Volumen70
N.º11
DOI
EstadoPublished - nov 2021

Nota bibliográfica

Publisher Copyright:
© 2021 by the American Diabetes Association.

Financiación

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.

FinanciadoresNúmero del financiador
Eli Lilly and Company
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK112812, R01DK021397
National Institute of Diabetes and Digestive and Kidney Diseases
Brain and Behavior Research Foundation26634
Brain and Behavior Research Foundation
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung186728, SNF P400PB_186728
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

    ODS de las Naciones Unidas

    Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

    1. Good health and well being
      Good health and well being

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism

    Acceder al documento

    Otros archivos y enlaces

    Huella

    Profundice en los temas de investigación de 'GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models'. En conjunto forman una huella única.
    Ver la huella completa

    Citar esto