Screening for insulin-independent pathways that modulate glucose homeostasis identifies androgen receptor antagonists

  1. Sri Teja Mullapudi
  2. Christian SM Helker
  3. Giulia LM Boezio
  4. Hans-Martin Maischein
  5. Anna M Sokol
  6. Stefan Guenther
  7. Hiroki Matsuda
  8. Stefan Kubicek
  9. Johannes Graumann
  10. Yu Hsuan Carol Yang
  11. Didier YR Stainier  Is a corresponding author
  1. Max Planck Institute for Heart and Lung Research, Germany
  2. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria

Abstract

Pathways modulating glucose homeostasis independently of insulin would open new avenues to combat insulin resistance and diabetes. Here, we report the establishment, characterization and use of a vertebrate 'insulin-free' model to identify insulin-independent modulators of glucose metabolism. insulin knockout zebrafish recapitulate core characteristics of diabetes and survive only up to larval stages. Utilizing a highly efficient endoderm transplant technique, we generated viable chimeric adults that provide the large numbers of insulin mutant larvae required for our screening platform. Using glucose as a disease-relevant readout, we screened 2233 molecules and identified 3 that consistently reduced glucose levels in insulin mutants. Most significantly, we uncovered an insulin-independent beneficial role for androgen receptor antagonism in hyperglycemia, mostly by reducing fasting glucose levels. Our study proposes therapeutic roles for androgen signaling in diabetes and, more broadly, offers a novel in vivo model for rapid screening and decoupling of insulin-dependent and -independent mechanisms.

Data availability

Microarray and RNA-Seq data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-7282 and E-MTAB-7283 respectively.

The following data sets were generated

Article and author information

Author details

  1. Sri Teja Mullapudi

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  2. Christian SM Helker

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  3. Giulia LM Boezio

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  4. Hans-Martin Maischein

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  5. Anna M Sokol

    Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  6. Stefan Guenther

    ECCPS Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  7. Hiroki Matsuda

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8639-2719
  8. Stefan Kubicek

    Platform Austria for Chemical Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0855-8343
  9. Johannes Graumann

    Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  10. Yu Hsuan Carol Yang

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  11. Didier YR Stainier

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    For correspondence
    Didier.Stainier@mpi-bn.mpg.de
    Competing interests
    Didier YR Stainier, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0382-0026

Funding

Max-Planck-Gesellschaft (Open-access funding)

  • Sri Teja Mullapudi
  • Christian SM Helker
  • Giulia LM Boezio
  • Hans-Martin Maischein
  • Anna M Sokol
  • Stefan Guenther
  • Hiroki Matsuda
  • Johannes Graumann
  • Yu Hsuan Carol Yang
  • Didier YR Stainier

Deutsches Zentrum für Herz-Kreislaufforschung

  • Anna M Sokol
  • Johannes Graumann

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Zebrafish husbandry was performed under standard conditions in accordance with institutional (MPG) and national ethical and animal welfare guidelines approved by the ethics committee for animal experiments at the Regierungspräsidium Darmstadt, Germany (permit numbers B2/1017, B2/1041, B2/1089, B2/1138 and B2/Anz. 1007).

Reviewing Editor

  1. Richard M White, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: September 20, 2018
  2. Accepted: December 3, 2018
  3. Accepted Manuscript published: December 6, 2018 (version 1)
  4. Version of Record published: December 19, 2018 (version 2)

Copyright

© 2018, Mullapudi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sri Teja Mullapudi
  2. Christian SM Helker
  3. Giulia LM Boezio
  4. Hans-Martin Maischein
  5. Anna M Sokol
  6. Stefan Guenther
  7. Hiroki Matsuda
  8. Stefan Kubicek
  9. Johannes Graumann
  10. Yu Hsuan Carol Yang
  11. Didier YR Stainier
(2018)
Screening for insulin-independent pathways that modulate glucose homeostasis identifies androgen receptor antagonists
eLife 7:e42209.
https://doi.org/10.7554/eLife.42209

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