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Unique pathological changes in the pancreas of fulminant type 1 diabetes

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Abstract

Distinct features of the pancreas of fulminant type 1 diabetes (FT1DM) include (1) enterovirus infection of the islets and exocrine acinar tissue. (2) Activated innate immune responses: MDA5 and RIG-I expression and TLR4 and TLR9 expression in the islets of FT1DM. (3) Combined activation of the STAT/JNK and NFkB pathways, resulting in Type I interferon (IFN) and proinflammatory cytokine (i.e., IFNγ) expression in islet beta cells and MHC class I hyper-expression. (4) Activation of dendritic cells followed by effector cell infiltration of CD8+ T cells and CD68+ macrophages, resulting in apoptosis and neurosis of islet cells and exocrine acinar cells. (5) Many chemo-attractants (i.e., CXCL10) and chemotactic activators (i.e., l-plastin) were induced by a viral infection. (6) Mutual stimulating effect of cytokines expressed in beta cells in autocrine and paracrine mechanisms may enhance beta-cell destruction through the STA1-caspase pathway. (7) Proteomics analysis using laser capture microdissection followed by mass spectrometry found 38 molecules in inflamed islets of FT1DM, which were not highlighted before. Our pathologically verified model of beta-cell destruction in FT1DM will contribute to anti-virus therapy of type 1 diabetes in the near future.

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Acknowledgements

The authors would like to thank the late Taro Maruyama, Saitama Social Insurance Hospital, for his generous assistance in obtaining the study samples, Erika Jimbo, Okinaka Memorial Institute for Medical Research, for her excellent technical assistance with immunostaining of samples, and Fumie Takano, Okinaka Memorial Institute for Medical Research, for her excellent secretarial assistance.

Funding

This work was supported by a research grant from Japan Society for the Promotion of Science KAKENHI (Grant 2459319).

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Authors and Affiliations

  1. Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Tetsuro Kobayashi

  2. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan

    Tetsuro Kobayashi

  3. Ai Home Clinic Toshima, 4th Floor, INS Building, 2-32-2 Minamiotsuka, Toshima-ku, Tokyo, 170-0005, Japan

    Shoichiro Tanaka

  4. Department of Diabetes Medicine, Kanoiwa Hospital, Kamijinnai River 1309, Yamanashi, Yamanashi, Japan

    Kaoru Aida

Authors
  1. Tetsuro Kobayashi
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  2. Shoichiro Tanaka
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  3. Kaoru Aida
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Contributions

TK, KA and ST conducted the immunohistochemical staining and discussed, reviewed, and edited the manuscript. TK contributed to the planning and discussions and edited the manuscript.

Corresponding author

Correspondence to Tetsuro Kobayashi.

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Conflict of interest

The authors report no conflict of interest in this work.

Ethical approval

All procedures used in this study were approved by the ethics committees of the University of Yamanashi and Toranomon Hospital.

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Written, informed consent was obtained from the next of kin on behalf of the autopsied patients.

Statement on human research

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation of Toranomon Hospital and University of Yamanashi and with the Helsinki Declaration of 1964 and later versions.

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Kobayashi, T., Tanaka, S. & Aida, K. Unique pathological changes in the pancreas of fulminant type 1 diabetes. Diabetol Int 11, 323–328 (2020). https://doi.org/10.1007/s13340-020-00462-6

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  • DOI: https://doi.org/10.1007/s13340-020-00462-6

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