Abstract

Insulin secretion from β-cells is reduced at the onset of type-1 and during type-2 diabetes. Although inflammation and metabolic dysfunction of β-cells elicit secretory defects associated with type-1 or type-2 diabetes, accompanying changes to insulin granules have not been established. To address this, we performed detailed functional analyses of insulin granules purified from cells subjected to model treatments that mimic type-1 and type-2 diabetic conditions and discovered striking shifts in calcium affinities and fusion characteristics. We show that this behavior is correlated with two subpopulations of insulin granules whose relative abundance is differentially shifted depending on diabetic model condition. The two types of granules have different release characteristics, distinct lipid and protein compositions, and package different secretory contents alongside insulin. This complexity of β-cell secretory physiology establishes a direct link between granule subpopulation and type of diabetes and leads to a revised model of secretory changes in the diabetogenic process.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

  1. Alex JB Kreutzberger

    Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9774-115X
  2. Volker Kiessling

    Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9388-5703
  3. Catherine A Doyle

    Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Noah Schenk

    Pharmacology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Clint M Upchurch

    Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Margaret Elmer-Dixon

    Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Amanda E Ward

    Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Julia Preobraschenski

    Neurobiology, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Syed S Hussein

    Microbiology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Weronika Tomaka

    Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Patrick Seelheim

    Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Iman Kattan

    Neurobiology, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Megan Harris

    Cell Biology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Binyong Liang

    Cell Biology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Anne K Kenworthy

    Cell Biology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Bimal N Desai

    Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3928-5854
  17. Norbert Leitinger

    Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Arun Anatharam

    Pharmacology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. J David Castle

    Cell Biology, University of Virginia, Charlottesville, United States
    For correspondence
    jdc4r@virginia.edu
    Competing interests
    The authors declare that no competing interests exist.
  20. Lukas K Tamm

    Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
    For correspondence
    lkt2e@virginia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1674-4464

Funding

National Institutes of Health (P01 GM072694)

  • Lukas K Tamm

National Institutes of Health (R01 DK091296)

  • J David Castle

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

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Version history

  1. Received: August 26, 2020
  2. Accepted: November 6, 2020
  3. Accepted Manuscript published: November 9, 2020 (version 1)
  4. Version of Record published: December 15, 2020 (version 2)

Copyright

© 2020, Kreutzberger 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. Alex JB Kreutzberger
  2. Volker Kiessling
  3. Catherine A Doyle
  4. Noah Schenk
  5. Clint M Upchurch
  6. Margaret Elmer-Dixon
  7. Amanda E Ward
  8. Julia Preobraschenski
  9. Syed S Hussein
  10. Weronika Tomaka
  11. Patrick Seelheim
  12. Iman Kattan
  13. Megan Harris
  14. Binyong Liang
  15. Anne K Kenworthy
  16. Bimal N Desai
  17. Norbert Leitinger
  18. Arun Anatharam
  19. J David Castle
  20. Lukas K Tamm
(2020)
Distinct insulin granule subpopulations implicated in the secretory pathology of diabetes types 1 and 2
eLife 9:e62506.
https://doi.org/10.7554/eLife.62506

Share this article

https://doi.org/10.7554/eLife.62506

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