Beta-cell intrinsic dynamics rather than gap junction structure dictates subpopulations in the islet functional network

  1. Jennifer K Briggs
  2. Anne Gresch
  3. Isabella Marinelli
  4. JaeAnn M Dwulet
  5. David J Albers
  6. Vira Kravets
  7. Richard KP Benninger  Is a corresponding author
  1. University of Colorado Anschutz Medical Campus, United States
  2. University of Birmingham, United Kingdom

Abstract

Diabetes is caused by the inability of electrically coupled, functionally heterogeneous -cells within the pancreatic islet to provide adequate insulin secretion. Functional networks have been used to represent synchronized oscillatory [Ca2+] dynamics and to study -cell subpopulations, which play an important role in driving islet function. The mechanism by which highly synchronized -cell subpopulations drive islet function is unclear. We used experimental and computational techniques to investigate the relationship between functional networks, structural (gap-junction) networks, and intrinsic -cell dynamics in slow and fast oscillating islets. Highly synchronized subpopulations in the functional network were differentiated by intrinsic dynamics, including metabolic activity and KATP channel conductance, more than structural coupling. Consistent with this, intrinsic dynamics were more predictive of high synchronization in the islet functional network as compared to high levels of structural coupling. Finally, dysfunction of gap junctions, which can occur in diabetes, caused decreases in the efficiency and clustering of the functional network. These results indicate that intrinsic dynamics rather than structure drive connections in the functional network and highly synchronized subpopulations, but gap junctions are still essential for overall network efficiency. These findings deepen our interpretation of functional networks and the formation of functional sub-populations in dynamic tissues such as the islet.

Data availability

Raw microscopy imaging data is available on the EMBL-EBI-supported BioImage Archive. Analysis code, Model code, and Simulated Data is available via GitHub at https://github.com/jenniferkbriggs/Functional_and_Structural_Networks.git

Article and author information

Author details

  1. Jennifer K Briggs

    Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8737-2215
  2. Anne Gresch

    Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Isabella Marinelli

    Centre for Systems Modelling and Quantitative Biomedicine, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. JaeAnn M Dwulet

    Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2519-5193
  5. David J Albers

    Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Vira Kravets

    Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5147-309X
  7. Richard KP Benninger

    Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, United States
    For correspondence
    richard.benninger@cuanschutz.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5063-6096

Funding

National Institutes of Health (R01 DK102950)

  • Richard KP Benninger

National Institutes of Health (R01 DK106412)

  • Richard KP Benninger

National Science Foundation (Graduate Research Fellowship DGE-1938058_Briggs)

  • Jennifer K Briggs

Juvenile Diabetes Research Foundation United States of America (3-PDF-2019-741-A-N)

  • Vira Kravets

Beckman Research Institute, City of Hope (UC24 DK104162)

  • Vira Kravets

Burroughs Wellcome Fund (25B1756)

  • Vira Kravets

National Institutes of Health (DK126360)

  • JaeAnn M Dwulet

National Institutes of Health (LM012734)

  • David J Albers

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

Ethics

Animal experimentation: All animal procedures were performed in accordance with guidelines established by the Institutional Animal Care and Use Committee of the University of Colorado Anschutz Medical campus (protocol 000024). All surgeries were performed under ketamine/xylazine anesthesia, with minimal discomfort to the animals.

Copyright

© 2023, Briggs 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. Jennifer K Briggs
  2. Anne Gresch
  3. Isabella Marinelli
  4. JaeAnn M Dwulet
  5. David J Albers
  6. Vira Kravets
  7. Richard KP Benninger
(2023)
Beta-cell intrinsic dynamics rather than gap junction structure dictates subpopulations in the islet functional network
eLife 12:e83147.
https://doi.org/10.7554/eLife.83147

Share this article

https://doi.org/10.7554/eLife.83147

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