Abstract

Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.

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Acknowledgements

The authors thank P. Jeggo, C. Mathieu, D. Gray and A. Goris for critical insights and D. Pombal, J. Sreenivasan, A. Bullman, M. Koina and T. Dagpo for technical assistance. We acknowledge the Human Tissue Laboratory (HTL) of the Lund University Diabetes Centre (LUDC) for providing high-quality data from human pancreatic islets. This work was supported by the VIB, European Research Council (ERC) and a Juvenile Diabetes Research Foundation (JDRF) Career Development Award (A.L.) and by the National Health and Medical Research Council of Australia (project grant 1028108; C.J.N.). N.O. and V. Lyssenko acknowledge support by a Strategic Research Grant from the Swedish Research Council (2009-1039).

Author information

Author notes

    • James Dooley
    • , Lei Tian
    • , Susann Schonefeldt
    •  & Viviane Delghingaro-Augusto

    These authors contributed equally to this work.

    • Susan M Schlenner
    •  & Adrian Liston

    These authors jointly supervised this work.

Affiliations

  1. Center for the Biology of Disease, VIB, Leuven, Belgium.

    • James Dooley
    • , Lei Tian
    • , Susann Schonefeldt
    • , Josselyn E Garcia-Perez
    • , Emanuela Pasciuto
    • , Dean Franckaert
    • , Vasiliki Lagou
    • , Susan M Schlenner
    •  & Adrian Liston
  2. Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.

    • James Dooley
    • , Lei Tian
    • , Susann Schonefeldt
    • , Josselyn E Garcia-Perez
    • , Emanuela Pasciuto
    • , Dean Franckaert
    • , Vasiliki Lagou
    • , Susan M Schlenner
    •  & Adrian Liston
  3. Australian National University Medical School, Canberra, Australian Capital Territory, Australia.

    • Viviane Delghingaro-Augusto
    • , Jane E Dahlstrom
    •  & Christopher J Nolan
  4. Department of Informatics, Università della Svizzera Italiana, Lugano, Switzerland.

    • Daniele Di Marino
  5. Lymphocyte Signaling and Development Institute Strategic Programme, Babraham Institute, Cambridge, UK.

    • Edward J Carr
    •  & Michelle A Linterman
  6. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.

    • Nikolay Oskolkov
    •  & Valeriya Lyssenko
  7. Department of Translational Pathophysiology, Steno Diabetes Center, Gentofte, Denmark.

    • Valeriya Lyssenko
  8. Department of Neurosciences, University of Leuven, Leuven, Belgium.

    • Vasiliki Lagou
  9. Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium.

    • Lut Overbergh
  10. Department of Medical Protein Research, VIB, Ghent, Belgium.

    • Jonathan Vandenbussche
    •  & Kris Gevaert
  11. Department of Biochemistry, Ghent University, Ghent, Belgium.

    • Jonathan Vandenbussche
    •  & Kris Gevaert
  12. VIB Nucleomics Core, University of Leuven, Leuven, Belgium.

    • Joke Allemeersch
  13. Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.

    • Genevieve Chabot-Roy
    •  & Sylvie Lesage
  14. Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.

    • Genevieve Chabot-Roy
    •  & Sylvie Lesage
  15. Department of Anatomical Pathology, Canberra Hospital, Garran, Australian Capital Territory, Australia.

    • Jane E Dahlstrom
  16. Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia.

    • D Ross Laybutt
    •  & Chris C Goodnow
  17. Department of Endocrinology, Flinders University, Adelaide, South Australia, Australia.

    • Nikolai Petrovsky
  18. John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.

    • Luis Socha
  19. Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.

    • Anton M Jetten
  20. Vesalius Research Center, VIB, Leuven, Belgium.

    • Diether Lambrechts
  21. Department of Oncology, University of Leuven, Leuven, Belgium.

    • Diether Lambrechts
  22. Department of Endocrinology, Canberra Hospital, Garran, Australian Capital Territory, Australia.

    • Christopher J Nolan

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Contributions

A.L., S.M.S., S.L., N.P., C.J.N., D.R.L. and C.C.G. designed the study. J.D., L.T., S.S., V.D.-A., J.E.G.-P., E.P., D.D.M., D.F., L.O., J.V., G.C.-R., J.D., L.S., S.M.S., J.E.D. and A.L. performed the experiments. E.J.C., N.O., V. Lyssenko, V. Lagou, J.A., K.G., D.L., M.A.L. and A.L. analyzed results. A.M.J. provided reagents. A.L. wrote the manuscript. All authors discussed results and read and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Adrian Liston.

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    Supplementary Text and Figures

    Supplementary Figures 1–13 and Supplementary Tables 1 and 2.

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    Supplementary Data Set 1

    Transcriptional analysis of the effect of insHEL on the B10 and NOD backgrounds.

  2. 2.

    Supplementary Data Set 2

    Network analysis of the effect of insHEL on the B10 and NOD backgrounds.

  3. 3.

    Supplementary Data Set 3

    Proteomics analysis of the effect of insHEL on the B10 and NOD backgrounds.

  4. 4.

    Supplementary Data Set 4

    Genomic variation analysis of islet-expressed genes on the B10 and NOD backgrounds.

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https://doi.org/10.1038/ng.3531

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