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Fulminant type 1 diabetes: recent research progress and future prospects

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Abstract

To clarify the clinical and etiological characteristics of fulminant type 1 diabetes, we reviewed data from patients who had developed type 1 diabetes following anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) therapy, and research on pancreatic beta cells derived from induced pluripotent stem (iPS) cells from patients with fulminant type 1 diabetes. As determined from the disease classifications and clinical and genetic characteristics, anti-PD-1/PD-L1 therapy-related type 1 diabetes includes both fulminant type 1 diabetes and acute-onset type 1 diabetes. Using insulin-positive cells derived from iPS cells, beta-cell fragility to inflammatory cytokines, but not its regeneration failure, was observed in fulminant type 1 diabetes. Moreover, severe hyperglycemia was reported as a risk factor of sudden death or cardiac arrest at disease onset, diffusion-weighted magnetic resonance imaging was suggested as an additional tool for making a diagnosis, and the CSAD/lnc-ITGB7-1 locus was genetically associated with fulminant type 1 diabetes. To fully understand fulminant type 1 diabetes, it is important to clarify the molecular mechanisms step by step through multifaceted approaches such as through analyses of the genetic factors, clinical features, histological findings, and cell biology. The careful and detailed study of patients is a great means for clarifying the etiology and pathophysiology of the disease.

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References

  1. Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y, Osaka IDDM Study Group. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. N Engl J Med. 2000;342:301–7.

    CAS  PubMed  Google Scholar 

  2. Imagawa A, Hanafusa T, Uchigata Y, Kanatsuka A, Kawasaki E, Kobayashi T, Shimada A, Shimizu I, Toyoda T, Maruyama T, Makino H. Fulminant type 1 diabetes: a nationwide survey in Japan. Diabetes Care. 2003;26:2345–52.

    PubMed  Google Scholar 

  3. Hanafusa T, Imagawa A. Fulminant type 1 diabetes: a novel clinical entity requiring special attention by all medical practitioners. Nat Clin Pract Endocrinol Metab. 2007;3:36–45.

    CAS  PubMed  Google Scholar 

  4. Imagawa A, Hanafusa T, Awata T, Ikegami H, Uchigata Y, Osawa H, Kawasaki E, Kawabata Y, Kobayashi T, Shimada A, Shimizu I, Takahashi K, Nagata M, Makino H, Maruyama T. Report of the committee of the Japan Diabetes Society on the Research of Fulminant and Acute-onset Type 1 Diabetes Mellitus: new diagnostic criteria of fulminant type 1 diabetes mellitus. Diabetol Int. 2012;3:179–83.

    Google Scholar 

  5. Hosokawa Y, Imagawa A, Hanafusa T. Pathogenesis of fulminant type 1 diabetes: genes, viruses and the immune mechanism, and usefulness of patient-derived induced pluripotent stem cells for future research. J Diabetes Investig. 2019;10:1158–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kawabata Y, Ikegami H, Awata T, Imagawa A, Maruyama T, Kawasaki E, Tanaka S, Shimada A, Osawa H, Kobayashi T, Hanafusa T, Tokunaga K, The Committee on Type 1 Diabetes, Japan Diabetes Society. Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset. Diabetologia. 2009;52:2513–21.

    CAS  PubMed  Google Scholar 

  7. Tsutsumi C, Imagawa A, Ikegami H, Makino H, Kobayashi T, Hanafusa T, The Japan Diabetes Society Committee on Type 1 Diabetes Mellitus Research. Class II HLA genotype in fulminant type 1 diabetes—a nationwide survey with reference to glutamic acid decarboxylase antibodies. J Diabetes Invest. 2012;3:62–9.

    CAS  Google Scholar 

  8. Kawabata Y, Nishida N, Awata T, Kawasaki E, Imagawa A, Shimada A, Osawa H, Tanaka S, Takahashi K, Nagata M, Yasuda H, Uchigata Y, Kajio H, Makino H, Yasuda K, Kobayashi T, Hanafusa T, Tokunaga K, Ikegami H. Genome-wide association study confirming a Strong Effect of HLA and identifying variants in CSAD/lnc-ITGB7–1 on chromosome 12q13.13 associated with susceptibility to fulminant type 1 diabetes. Diabetes. 2019;68:665–75.

    CAS  PubMed  Google Scholar 

  9. Tanaka S, Nishida Y, Aida K, Maruyama T, Shimada A, Suzuki M, Shimura H, Takizawa S, Takahashi M, Akiyama D, Arai-Yamashita S, Furuya F, Kawaguchi A, Kaneshige M, Katoh R, Endo T, Kobayashi T. Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated b-cell failure in fulminant type 1 diabetes. Diabetes. 2009;58:2285–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shibasaki S, Imagawa A, Tauriainen S, Iino M, Oikarinen M, Abiru H, Tamaki K, Seino H, Nishi K, Takase I, Okada Y, Uno S, Murase-Mishiba Y, Terasaki J, Makino H, Shimomura I, Hyöty H, Hanafusa T. Expression of toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes. Endocr J. 2010;57:211–9.

    CAS  PubMed  Google Scholar 

  11. Yoneda S, Imagawa A, Fukui K, Uno S, Kozawa J, Sakai M, Yumioka T, Iwahashi H, Shimomura I. A histological study of fulminant type 1 diabetes mellitus related to human cytomegalovirus reactivation. J Clin Endocrinol Metab. 2017;102:2394–400.

    PubMed  Google Scholar 

  12. Haseda F, Imagawa A, Murase-Mishiba Y, Sano H, Hirano-Kuwata S, Ueda H, Terasaki J, Hanafusa T. Low CTLA-4 expression in CD4+helper T cells in patients with fulminant type 1 diabetes. Immunol Lett. 2011;139:80–6.

    CAS  PubMed  Google Scholar 

  13. Fujisawa R, Haseda F, Tsutsumi C, Hiromine Y, Noso S, Kawabata Y, Mitsui S, Terasaki J, Ikegami H, Imagawa A, Hanafusa T. Low programmed cell death-1 (PD-1) expression in peripheral CD4(+) T cells in Japanese patients with autoimmune type 1 diabetes. Clin Exp Immunol. 2015;180:452–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Baden MY, Imagawa A, Abiru N, Awata T, Ikegami H, Uchigata Y, Oikawa Y, Osawa H, Kajio H, Kawasaki E, Kawabata Y, Kozawa J, Shimada A, Takahashi K, Tanaka S, Chujo D, Fukui T, Miura J, Yasuda K, Yasuda H, Kobayashi T, Hanafusa T, for the consultation of the Japan Diabetes Society Committee on Type 1 Diabetes Mellitus Research. Characteristics and clinical course of type 1 diabetes mellitus related to anti-programmed cell death-1 therapy. Diabetol Int. 2019;10:58–66.

    PubMed  Google Scholar 

  15. Hosokawa Y, Toyoda T, Fukui K, Baden MY, Funato M, Kondo Y, Sudo T, Iwahashi H, Kishida M, Okada C, Watanabe A, Asaka I, Osafune K, Imagawa A, Shimomura I. Insulin-producing cells derived from 'induced pluripotent stem cells' of patients with fulminant type 1 diabetes: vulnerability to cytokine insults and increased expression of apoptosis-related genes. J Diabetes Investig. 2018;9:481–93.

    CAS  Google Scholar 

  16. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Boussiotis VA. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med. 2016;375:1767–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Gaudy C, Clévy C, Monestier S, Dubois N, Préau Y, Mallet S, Richard MA, Grob JJ, Valéro R, Béliard S. Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care. 2015;38:e182–3.

    PubMed  Google Scholar 

  19. Yoneda S, Imagawa A, Hosokawa Y, Baden MY, Kimura T, Uno S, Fukui K, Goto K, Uemura M, Eguchi H, Iwahashi H, Kozawa J, Shimomura I. T lymphocyte Infiltration to Islets in the pancreas of a patient who developed type 1 diabetes after administration of immune checkpoint inhibitors. Diabetes Care. 2019;42(7):e116–e118.

    CAS  PubMed  Google Scholar 

  20. Tachibana M, Imagawa A. Drug-related type 1 diabetes. Practice. 2018;35:389–94 (in Japanese).

    Google Scholar 

  21. Miyoshi Y, Ogawa O, Oyama Y. Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes. Tohoku J Exp Med. 2016;239:155–8.

    CAS  PubMed  Google Scholar 

  22. Okamoto M, Okamoto M, Gotoh K, Masaki T, Ozeki Y, Ando H, Anai M, Sato A, Yoshida Y, Ueda S, Kakuma T, Shibata H. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig. 2016;7:915–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Usui Y, Udagawa H, Matsumoto S, Imai K, Ohashi K, Ishibashi M, Kirita K, Umemura S, Yoh K, Niho S, Osame K, Goto K. Association of serum anti-GAD antibody and HLA haplotypes with type 1 diabetes mellitus triggered by nivolumab in patients with non-small cell lung cancer. J Thor Oncol. 2017;12:e41–43.

    Google Scholar 

  24. Asai S, Katabami T, Kawanabe S, Igarashi K, Fukuda H, Yasushi T. A case of fulminant type 1 diabetes mellitus developed after the administration of nivolumab, an immune checkpoint inhibitor. J Japan Diab Soc. 2017;60:237–43.

    Google Scholar 

  25. Kumagai R, Muramatsu A, Nakajima R, Fujii M, Kaino K, Katakura Y, Okumura N, Ohara G, Kagohashi K, Satoh H, Yagyu H. Acute-onset type 1 diabetes mellitus caused by nivolumab in a patient with advanced pulmonary adenocarcinoma. J Diabetes Investig. 2017;8:798–9.

    PubMed  PubMed Central  Google Scholar 

  26. Sakurai K, Niitsuma S, Sato R, Takahashi K, Arihara Z. Painless thyroiditis and fulminant type 1 diabetes mellitus in a patient treated with an immune checkpoint inhibitor, nivolumab. Tohoku J Exp Med. 2018;244:33–40.

    PubMed  Google Scholar 

  27. Shiba M, Inaba H, Ariyasu H, Kawai S, Inagaki Y, Matsuno S, Iwakura H, Yamamoto Y, Nishi M, Akamizu T. A case of fulminant type 1 diabetes mellitus accompanied by positive conversion of anti-insulin antibody after the administration of anti-CTLA-4 antibody following the discontinuation of anti-PD-1 antibody. Intern Med. 2018;57:2029–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Matsumura K, Nagasawa K, Oshima Y, Kikuno S, Hayashi K, Nishimura A, Okubo M, Uruga H, Kishi K, Kobayashi T, Mori Y. Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes-resistant human leukocyte antigen DRB1*15:02 treated with nivolumab. J Diabetes Investig. 2018;9:438–41.

    CAS  PubMed  Google Scholar 

  29. Sakai G, Saito D, Nakajima R, Hatano M, Noguchi Y, Kurihara S, Katayama S, Inoue I, Noda M, Shimada A. Intrinsic insulin secretion capacity might be preserved by discontinuing anti-programmed cell death protein 1 antibody treatment in ‘anti-programmed cell death protein 1 antibody-induced’ fulminant type 1 diabetes. J Diabetes Investig. 2018;9:448–9.

    PubMed  PubMed Central  Google Scholar 

  30. Saito D, Oikawa Y, Yano Y, Ikegami Y, Satomura A, Isshiki M, Kurihara S, Inoue I, Noda M, Shimada A. Detailed time course of decline in serum C-peptide levels in anti-programmed cell death-1 therapy-induced fulminant type 1 diabetes. Diabetes Care. 2019;42:e40–e41.

    CAS  PubMed  Google Scholar 

  31. Yamamoto N, Tsurutani Y, Katsuragawa S, Kubo H, Sunouchi T, Hirose R, Hoshino Y, Ichikawa M, Takiguchi T, Yukawa H, Arioka H, Saitou J, Nishikawa T. A Patient with nivolumab-related fulminant type 1 diabetes mellitus whose serum C-peptide level was preserved at the initial detection of hyperglycemia. Intern Med. 2019;58:2825–30.

    PubMed  PubMed Central  Google Scholar 

  32. Miyauchi M, Toyoda M, Zhang J, Hamada N, Yamawaki T, Tanaka J, Harada K, Kashizaki F, Fukagawa M. Nivolumab-induced fulminant type 1 diabetes with precipitous fall in C-peptide level. J Diabetes Investig. 2020;11:748–9.

    CAS  PubMed  Google Scholar 

  33. Kurihara S, Oikawa Y, Nakajima R, Satomura A, Tanaka R, Kagamu H, Shimada A. Simultaneous development of Graves' disease and type 1 diabetes during anti-programmed cell death-1 therapy: a case report. J Diabetes Investig. 2020;11:1006–9.

    PubMed Central  Google Scholar 

  34. Kusuki K, Suzuki S, Mizuno Y. Pembrolizumab-induced fulminant type 1 diabetes with C-peptide persistence at first referral. Endocrinl Diabetes Metab Case Rep. 2020;29(2020):19–0152.

    Google Scholar 

  35. Ueda E, Doi H, Kurihara A, Tabeya T, Saito T, Tanaka S. A case of type 1 diabetes mellitus developed hypopituitarism at around the same time after treatment with pembrolizumab. J Japan Diab Soc. 2020;63:521–7.

    Google Scholar 

  36. Okahata S, Sakamoto K, Mitsumatsu T, Kondo Y, Noso S, Ikegami H, Shiba T. Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody-insight into the pathogenesis of autoimmune endocrinopathy. Endocr J. 2019;66:295–300.

    CAS  PubMed  Google Scholar 

  37. Sakaguchi C, Ashida K, Yano S, Ohe K, Wada N, Hasuzawa N, Matsuda Y, Sakamoto S, Sakamoto R, Uchi H, Furue M, Nomura M, Ogawa Y. A case of nivolumab-induced acute-onset type 1 diabetes mellitus in melanoma. Curr Oncol. 2019;26:e115–e118.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Baden MY, Imagawa A, Iwahashi H, Shimomura I, Awata T, Ikegami H, Uchigata Y, Osawa H, Kajio H, Kawasaki E, Kawabata Y, Shimada A, Takahashi K, Tanaka S, Yasuda K, Yasuda H, Kobayashi T, Hanafusa T. Risk factors for sudden death and cardiac arrest at the onset of fulminant type 1 diabetes mellitus. Diabetol Int. 2015;7:281–8.

    PubMed  PubMed Central  Google Scholar 

  39. Tokunaga A, Imagawa A, Nishio H, Hayata S, Shimomura I, Abiru N, Awata T, Ikegami H, Uchigata Y, Oikawa Y, Osawa H, Kajio H, Kawasaki E, Kawabata Y, Kozawa J, Shimada A, Takahashi K, Tanaka S, Chujo D, Fukui T, Miura J, Yasuda K, Yasuda H, Kobayashi T, Hanafusa T, consultation of Japan Diabetes Society Committee on Fulminant Type 1 Diabetes Mellitus Research. Diffusion-weighted magnetic resonance imaging in the pancreas of fulminant type 1 diabetes. Diabetol Int. 2018;9:257–65.

    PubMed  PubMed Central  Google Scholar 

  40. WHO. Classification of diabetes mellitus. Geneva: WHO; 2019. p. p14.

    Google Scholar 

  41. Araújo M, Ligeiro D, Costa L, Marques F, Trindade H, Correia JM, Fonseca C. A case of fulminant type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient. Immunotherapy. 2017;9:531–5.

    PubMed  Google Scholar 

  42. Keskin M, Savaş-Erdeve Ş, Çetinkaya S, Aycan Z. Low hemoglobin A1c levels in a patient with diabetic ketoacidosis: fulminanttype 1 diabetes mellitus. Turk J Pediatr. 2018;60:201–5.

    PubMed  Google Scholar 

  43. Chokr N, Farooq H, Guadalupe E. Fulminant diabetes in a patient with advanced melanoma on nivolumab. Case Rep Oncol Med. 2018;28(2018):8981375.

    Google Scholar 

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Acknowledgements

We would like to express our sincere thanks to the doctors, Hanafusa T (Sakai City Medical Center), Terasaki J, Murase-Mishiba Y, Matsumoto H, Sano H, Haseda F, Tsutsumi C, Shibasaki S, Fujisawa R (Dept. of Internal Medicine (I),Osaka Medical College), Shimomura I, Iwahashi H, Okita K, Kozawa J, Fukui K, Uno S, Sayama K, Nakata S, Tokunaga A, Yoshikawa A, Yoneda S, Hosokawa Y, Baden MY, Ishibashi C. (Dept. of Metabolic Medicine, Osaka Univ, Graduate School of Medicine), Osafune K, Toyoda T (Center for iPS Cell Research and Application (CiRA), and Kyoto University), for the collaboration. We would also like to thank the members of the Committee on Type 1 Diabetes, the Japan Diabetes Society, including Abiru N (Nagasaki University), Awata T (Saitama Prefectural University), Ikegami H, Kawabata Y (Kindai, University), Oikawa Y, Shimada A (Saitama Medical University), Osawa H (Ehime University), Kajio H (National Center for Global Health and Medicine), Kawasaki E (Shin-Koga Hospital), Takahashi K (Iwate Prefectural University), Chujo D (University of Toyama), Fukui T (Showa University), Miura J (Tokyo Women’s Medical University), Yasuda K (Kyorin University), Yasuda H (Kobe University), and Kobayashi T (Okinaka Memorial Institute for Medical Research), and the diabetes specialists affiliated with the Japan Diabetes Society for answering the questionnaire. We also thank Editage for editing a draft of this manuscript. This work was supported in part by JSPS KAKENHI Grant Number 18K08529 received by AI.

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  1. Department of Internal Medicine (I), Osaka Medical College, 2-7 Daigaku-cho, Takatsuki, 569-8686, Japan

    Akihisa Imagawa & Megumi Tachibana

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  1. Akihisa Imagawa
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Correspondence to Akihisa Imagawa.

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In connection with this manuscript, we disclose COI with the following companies/organizations: honoraria for lectures: Eli Lilly Japan K.K., Ono Pharmaceutical Co. Ltd., and Astellas Pharma Inc.; research funding: Astellas Pharma Inc., Astra-Zeneca K. K., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co. Ltd., Soiken Holdings Inc., and Taiho Pharmaceutical Co. Ltd.; scholarship donations: Takeda Pharmaceutical Company Limited, Astellas Pharma Inc., Kyowa Hakko Kirin Co. Ltd., and Ono Pharmaceutical Co. Ltd.

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Imagawa, A., Tachibana, M. Fulminant type 1 diabetes: recent research progress and future prospects. Diabetol Int 11, 336–341 (2020). https://doi.org/10.1007/s13340-020-00466-2

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