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Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes

Author

Listed:
  • A. S. Axelsson

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • T. Mahdi

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
    Medical Research Center, Hawler Medical University)

  • H. A. Nenonen

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • T. Singh

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • S. Hänzelmann

    (Institute of Biomedical Engineering, RWTH Aachen University Hospital)

  • A. Wendt

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • A. Bagge

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • T. M. Reinbothe

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • J. Millstein

    (Sage Bionetworks)

  • X. Yang

    (Sage Bionetworks
    University of California)

  • B. Zhang

    (Sage Bionetworks
    Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • E. G. Gusmao

    (Institute of Biomedical Engineering, RWTH Aachen University Hospital)

  • L. Shu

    (University of California)

  • M. Szabat

    (Diabetes Research Group, Life Sciences Institute, University of British Columbia)

  • Y. Tang

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
    Key Lab of Hormones and Development, Ministry of Health, Metabolic Diseases Hospital, Tianjin Medical University)

  • J. Wang

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
    Zhongshan Hospital, Xiamen University)

  • S. Salö

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • L. Eliasson

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • I. Artner

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • M. Fex

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • J. D. Johnson

    (Diabetes Research Group, Life Sciences Institute, University of British Columbia)

  • C. B. Wollheim

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
    University Medical Center)

  • J.M.J. Derry

    (Sage Bionetworks)

  • B. Mecham

    (Trialomics)

  • P. Spégel

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
    Centre for Analysis and Synthesis, Lund University)

  • H. Mulder

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • I.G. Costa

    (Institute of Biomedical Engineering, RWTH Aachen University Hospital)

  • E. Zhang

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35)

  • A. H. Rosengren

    (Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35
    Sage Bionetworks
    University of Gothenburg)

Abstract

Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and β-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key β-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of β-cell phenotype and function.

Suggested Citation

  • A. S. Axelsson & T. Mahdi & H. A. Nenonen & T. Singh & S. Hänzelmann & A. Wendt & A. Bagge & T. M. Reinbothe & J. Millstein & X. Yang & B. Zhang & E. G. Gusmao & L. Shu & M. Szabat & Y. Tang & J. Wang, 2017. "Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15652
    DOI: 10.1038/ncomms15652
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