Correspondence

A Novel Subtype of Type 1 Diabetes Mellitus

N Engl J Med 2000; 342:1835-1837June 15, 2000

Article

To the Editor:

Imagawa and colleagues (Feb. 3 issue)1 provide evidence that an acute insult to the exocrine pancreas, possibly caused by a virus, may trigger type 1 diabetes mellitus. In a subgroup of adult Japanese patients presenting with type 1 diabetes, they found T-lymphocyte infiltration in the exocrine pancreas but no circulating antibodies to islet-cell antigens characteristic of autoimmune diabetes. These patients had an acute onset of hyperglycemia and normal glycosylated hemoglobin values, suggesting that the loss of beta cells was rapid and occurred before the onset of antibody production. However, the authors found no clinical or laboratory evidence of infection.

Pancreatitis and islet-cell antibodies have been associated with rotavirus infection.2 Rotavirus infections cause gastroenteritis in infants but are usually asymptomatic in older children and adults. Among children at risk for type 1 diabetes who were followed from birth, we found a significant and specific association between rotavirus infection and the first appearance of serum antibodies to islet-cell antigens or an increase in these antibodies.3 In a separate study of 10 children with acute rotavirus infection but no family history of type 1 diabetes, we found that 3 had antibodies to the islet-cell antigens glutamic acid decarboxylase and tyrosine phosphatase IA-2. Antibodies to insulin, thyroid peroxidase, and nuclear antigens were not detected. The detection of islet-cell antibodies in 30 percent of these children can be compared with the expected frequency among children of 8 percent for any islet-cell antibody and of 0.1 percent for two islet-cell antibodies.4

Rotavirus is not infectious until it is activated by trypsin,5 a product of the exocrine pancreas, and it can infect islets in tissue culture (unpublished data). Rotavirus infection has also been associated with decreased fecal elastase I activity (Cubitt D: personal communication), and the patients described by Imagawa et al. had high serum elastase I concentrations; both of these characteristics are consistent with the presence of pancreatic exocrine insufficiency. We therefore suggest that rotavirus is a cause of clinically silent pancreatic infection in these adult patients and leads to T-cell–mediated loss of beta cells before islet-cell antibodies can develop.

Margo C. Honeyman, Ph.D.
Walter and Eliza Hall Institute of Medical Research, Melbourne 3050, Australia

Barbara S. Coulson, Ph.D.
University of Melbourne, Melbourne 3050, Australia

Leonard C. Harrison, M.D., D.Sc.
Walter and Eliza Hall Institute of Medical Research, Melbourne 3050, Australia

5 References

1. 1

   Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y. 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;342:301-307
   Full Text | Web of Science | Medline

2. 2

   Nigro G. Pancreatitis with hypoglycemia-associated convulsions following rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr 1991;12:280-282
   CrossRef | Web of Science | Medline

3. 3

   Honeyman MC, Coulson BS, Stone NL, et al. Evidence that rotavirus triggers islet autoimmunity. Diabetes 1999;48:Suppl 1:A65-A65 abstract.
   Web of Science

4. 4

   Bingley PJ, Bonifacio E, Williams AJ, Genovese S, Bottazzo GF, Gale EA. Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes 1997;46:1701-1710
   CrossRef | Web of Science | Medline

5. 5

   Clark SM, Roth JR, Clark ML, Barnett BB, Spendlove RS. Trypsin enhancement of rotavirus infectivity: mechanism of enhancement. J Virol 1981;39:816-822
   Web of Science | Medline

To the Editor:

In their study of patients with acute-onset diabetes, Imagawa et al. reported that pancreatic biopsies revealed the absence of insulitis and the presence of T-cell infiltrates in the exocrine pancreas. However, insulitis disappears within at most a few weeks after the onset of diabetes,1 and the authors say only that the biopsies were performed within five months after the diagnosis of diabetes. Because of the patchy occurrence of insulitis, it may be missed in biopsy specimens.

We have recently examined the pancreas of a 25-year-old man with type 1 diabetes and diabetic ketoacidosis who died 40 minutes after arrival at our hospital. He had had symptoms of nausea and epigastric pain for two days before becoming comatose. His blood glucose concentration was 1540 mg per deciliter, and the glycosylated hemoglobin value was 5.1 percent. Blood gas analysis demonstrated acidosis (pH 6.91), with marked ketonemia. The serum elastase I concentration was 3.4 times the upper limit of the normal range. Tests for serum glutamic acid decarboxylase, IA-2, insulin, and islet-cell and pancreatic exocrine antibodies2 were negative. The patient's HLA-DQA1 and DQB1 genotypes were *0101/*0301 and *0501/*0401, respectively.

Histopathological examination of the patient's pancreas revealed insulitis (Figure 1AFigure 1Insulitis and Cellular Infiltration of Pancreatic Exocrine Tissue in a Patient with Acute-Onset Diabetes Who Died Suddenly.). Some acinar and ductal cells were necrotic and were surrounded by mononuclear cells (Figure 1B). The cells infiltrating the islets and exocrine pancreas consisted mainly of CD8 cells (Figure 1C and Figure 1D), with rare CD4 cells, macrophages, and natural killer cells. The islet cells and exocrine cells did not express major-histocompatibility-complex class II molecules. Immunohistochemical staining for cytomegalovirus and Epstein–Barr virus (EBV) and a test for EBV-encoded small RNA 1 by in situ hybridization were negative.

The CD8 T-cell–dominant insulitis present in this patient is similar to that reported in patients with type 1 diabetes who have serum antibodies to islet-cell antigens,3 suggesting that T-cell–mediated destruction of beta cells is also involved in this subtype of diabetes. Considering our results with those of Imagawa et al., it seems clear that some patients with diabetes have insulitis for only a few days or weeks before the destruction of beta cells supervenes.

Shoichiro Tanaka, M.D.
Tetsuro Kobayashi, M.D., Ph.D.
Toranomon Hospital, Tokyo 105-8470, Japan

Takeshi Momotsu, M.D., Ph.D.
Niigata City General Hospital, Niigata City 950-8739, Japan

3 References

1. 1

   Lernmark A, Kloppel G, Stenger D, et al. Heterogeneity of islet pathology in two infants with recent onset diabetes mellitus. Virchows Arch 1995;425:631-640
   CrossRef | Web of Science | Medline

2. 2

   Kobayashi T, Nakanishi K, Kajio H, et al. Pancreatic cytokeratin: an antigen of pancreatic exocrine cell autoantibodies in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1990;33:363-370
   CrossRef | Web of Science | Medline

3. 3

   Bottazzo GF, Dean BM, McNally JM, MacKay EH, Swift PGF, Gamble DR. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 1985;313:353-360
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Honeyman et al. suggest that rotavirus infection can lead to the development of diabetes-related antibodies and diabetes. However, type 1 diabetes developed in our patients without the formation of any diabetes-related antibodies, and even after the onset of diabetes, some beta cells remained. In addition, rotavirus infections do not seem to cause rapid destruction of beta cells, but instead cause chronic pancreatic injury and the gradual onset of diabetes. Therefore, the patients of Honeyman et al. have autoimmune type 1 diabetes, which is different from the nonautoimmune fulminant type 1 diabetes we described in our patients.

We agree with Tanaka et al. that their patient had the new subtype of type 1 diabetes we described. However, their patient had CD8 T-cell–predominant insulitis, and the pattern of lymphocytic infiltration in the exocrine pancreatic tissue differed from that in our patients. In their patient the beta cells may have been damaged by the CD8 T cells.

The underlying mechanism of beta-cell destruction in this subtype of diabetes is not known. T-cell infiltration of the islets does not always result from autoimmune T-cell activation. We have previously reported CD8 T-cell-predominant insulitis in autoimmune type 1 diabetes,1 and mononuclear-cell infiltration of the islets was noted in a patient with virus-induced type 1 diabetes.2 In addition, the patient described by Tanaka et al. had CD8 T-cell infiltration of both the islets and exocrine pancreas, a finding that differs from the usual findings of insulitis. In both humans and nonobese diabetic mice with autoimmune type 1 diabetes, infiltrating cells usually are concentrated in the islets. Therefore, the cellular infiltration of both the endocrine and the exocrine pancreas in their patient might represent a new type of inflammation associated with this new subtype of diabetes.

Akihisa Imagawa, M.D.
Jun-ichiro Miyagawa, M.D., Ph.D.
Osaka University Graduate School of Medicine, Suita 565-0871, Japan

Toshiaki Hanafusa, M.D., Ph.D.
Osaka Medical College and Hospital, Takatsuki 569-8686, Japan

2 References

1. 1

   Itoh N, Hanafusa T, Miyazaki A, et al. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest 1993;92:2313-2322
   CrossRef | Web of Science | Medline

2. 2

   Yoon J-W, Austin M, Onodera T, Notkins AL. Virus-induced diabetes mellitus: isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 1979;300:1173-1179
   Full Text | Web of Science | Medline

Citing Articles (25)

Citing Articles

1. 1

   Tetsuro Kobayashi, Yoriko Nishida, Shoichiro Tanaka, Kaoru Aida. (2011) Pathological changes in the pancreas of fulminant type 1 diabetes and slowly progressive insulin-dependent diabetes mellitus (SPIDDM): innate immunity in fulminant type 1 diabetes and SPIDDM. Diabetes/Metabolism Research and Reviews 27:8, 965-970
   CrossRef

2. 2

   Fumitaka Haseda, Akihisa Imagawa, Yuko Murase-Mishiba, Hiroyuki Sano, Suzue Hirano-Kuwata, Hironori Ueda, Jungo Terasaki, Toshiaki Hanafusa. (2011) Low CTLA-4 expression in CD4+ helper T-cells in patients with fulminant type 1 diabetes. Immunology Letters 139:1-2, 80-86
   CrossRef

3. 3

   Eiji Kawasaki, Kan Nakamura, Genpei Kuriya, Tsuyoshi Satoh, Masakazu Kobayashi, Hironaga Kuwahara, Norio Abiru, Hironori Yamasaki, Nobuo Matsuura, Junnosuke Miura, Yasuko Uchigata, Katsumi Eguchi. (2011) Differences in the humoral autoreactivity to zinc transporter 8 between childhood- and adult-onset type 1 diabetes in Japanese patients. Clinical Immunology 138:2, 146-153
   CrossRef

4. 4

   Y.-C. Hwang, I.-K. Jeong, S. Chon, S. Oh, K. J. Ahn, H. Y. Chung, J.-T. Woo, S.-W. Kim, J.-W. Kim, Y. S. Kim. (2010) Fulminant Type 1 diabetes mellitus associated with acute hepatitis A. Diabetic Medicine 27:3, 366-367
   CrossRef

5. 5

   Saeko SHIBASAKI, Akihisa IMAGAWA, Sisko TAURIAINEN, Morio IINO, Maarit OIKARINEN, Hitoshi ABIRU, Keiji TAMAKI, Hiroaki SEINO, Katsuhiro NISHI, Izumi TAKASE, Yoshikatsu OKADA, Sae UNO, Yuko MURASE-MISHIBA, Jungo TERASAKI, Hideichi MAKINO, Iichiro SHIMOMURA, Heikki HYöTY, Toshiaki HANAFUSA. (2010) Expression of Toll-like Receptors in the Pancreas of Recent-onset Fulminant Type 1 Diabetes. Endocrine Journal 57:3, 211-219
   CrossRef

6. 6

   Shingo Oya, Kanji Miyata, Norihiro Yuasa, Eiji Takeuchi, Yasutomo Goto, Hideo Miyake, Keiichi Nagasawa, Kenji Omori, Yoichiro Kobayashi. (2010) A Case of Nonocclusive Mesenteric Ischemia induced by Diabetic Ketoacidosis due to Fulminant Type 1 Diabetes. The Japanese Journal of Gastroenterological Surgery 43:9, 970-975
   CrossRef

7. 7

   Tetsuro Kobayashi, Shoichiro Tanaka, Kaoru Aida, Soichi Takizawa, Hiroki Shimura, Toyoshi Endo. (2009) Diabetes associated with autoimmune pancreatitis: new insights into the mechanism of β-cell dysfunction. Expert Review of Endocrinology & Metabolism 4:6, 591-602
   CrossRef

8. 8

   Soichi Takizawa, Toyoshi Endo, Xing Wanjia, Shoichiro Tanaka, Masashi Takahashi, Tetsuro Kobayashi. (2009) HSP 10 is a new autoantigen in both autoimmune pancreatitis and fulminant type 1 diabetes. Biochemical and Biophysical Research Communications 386:1, 192-196
   CrossRef

9. 9

   Se-Won Oh, Ju-Ri Park, Yun-Jeong Lee, Hee-Yeong Kim, Ji-A Seo, Nan-Hee Kim, Kyung-Mook Choi, Sei-Hyun Baik, Dong-Seop Choi, Sin-Gon Kim. (2009) A Case of Fulminant Type 1 Diabetes Mellitus Complicated with Ischemic Ileitis. Journal of Korean Endocrine Society 24:2, 116
   CrossRef

10. 10

    Masao Nagata, Hiroaki Moriyama, Reiko Kotani, Hisafumi Yasuda, Minoru Kishi, Midori Kurohara, Kenta Hara, Koichi Yokono. (2007) Immunological aspects of ‘fulminant type 1 diabetes’. Diabetes Research and Clinical Practice 77:3, S99-S103
    CrossRef

11. 11

    Hwa Young Cho, Young Min Cho, Myoung Hee Park, Mi Yeon Kang, Ki Hwan Kim, Yun Hyi Ku, Eun Kyung Lee, Do Joon Park, Chan Soo Shin, Kyong Soo Park, Seong Yeon Kim, Bo Youn Cho, Hong Kyu Lee. (2007) Two Cases of Autoantibody Negative Fulminant Type 1 Diabetes Mellitus. The Journal of Korean Diabetes Association 31:4, 372
    CrossRef

12. 12

    Toshiaki Hanafusa, Akihisa Imagawa. (2007) Fulminant type 1 diabetes: a novel clinical entity requiring special attention by all medical practitioners. Nature Clinical Practice Endocrinology & Metabolism 3:1, 36-45
    CrossRef

13. 13

    Jung Ho Lee, Gwan Pyo Koh, Jung Kyung Yang, Ki Hong Kim, Dong Mi Im, Keun Yong Park. (2007) A Typical Case of Fulminant Type 1 Diabetes Mellitus. The Journal of Korean Diabetes Association 31:2, 175
    CrossRef

14. 14

    E. Kawasaki, N. Matsuura, K. Eguchi. (2006) Type 1 diabetes in Japan. Diabetologia 49:5, 828-836
    CrossRef

15. 15

    AKIHISA IMAGAWA. (2006) Nihon Naika Gakkai Zasshi 95:6, 1129-1134
    CrossRef

16. 16

    Akihisa IMAGAWA, Toshiaki HANAFUSA. (2006) Fulminant Type 1 Diabetes Mellitus. Endocrine Journal 53:5, 577-584
    CrossRef

17. 17

    Margo Honeyman. (2005) How robust is the evidence for viruses in the induction of type 1 diabetes?. Current Opinion in Immunology 17:6, 616-623
    CrossRef

18. 18

    Takao Taniguchi, Kazuichi Okazaki, Motozumi Okamoto, Shuji Seko, Kazuaki Nagashima, Yuichiro Yamada, Tosio Iwakura, Yutaka Seino. (2005) Autoantibodies Against the Exocrine Pancreas in Fulminant Type 1 Diabetes. Pancreas 30:2, 191-192
    CrossRef

19. 19

    A. Imagawa, T. Hanafusa, Y. Uchigata, A. Kanatsuka, E. Kawasaki, T. Kobayashi, A. Shimada, I. Shimizu, T. Maruyama, H. Makino. (2005) Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus. Diabetologia 48:2, 294-300
    CrossRef

20. 20

    EIJI KAWASAKI, KATSUMI EGUCHI. (2004) Is Type 1 Diabetes in the Japanese Population the Same as among Caucasians?. Annals of the New York Academy of Sciences 1037:1, 96-103
    CrossRef

21. 21

    A. Shimada, T. Maruyama. (2004) Encephalomyocarditis-virus-induced diabetes model resembles ?fulminant? Type 1 diabetes in humans. Diabetologia 47:10, 1854-1855
    CrossRef

22. 22

    Y. Seino, M. Yamauchi, C. Hirai, A. Okumura, K. Kondo, M. Yamamoto, Y. Okazaki. (2004) A case of fulminant Type 1 diabetes associated with mexiletine hypersensitivity syndrome. Diabetic Medicine 21:10, 1156-1157
    CrossRef

23. 23

    I. Shimizu, H. Makino, H. Osawa, E. Kounoue, A. Imagawa, T. Hanafusa, E. Kawasaki, Y. Fujii. (2003) Association of fulminant type 1 diabetes with pregnancy. Diabetes Research and Clinical Practice 62:1, 33-38
    CrossRef

24. 24

    Nobuo YAMADA, Hiroyuki WATANABE, Masahito MIURA, Toshihiro SATO, Yohei HORIKAWA, Masamichi TOSHIMA. (2003) A Case of Fulminant Type 1 Diabetes Mellitus. JOURNAL OF THE JAPANESE ASSOCIATION OF RURAL MEDICINE 52:4, 744-748
    CrossRef

25. 25

    TAISUKE IWAOKA. (2003) A Case of Fulminant Type 1 Diabetes with Transiently Positive Anti-GAD Antibodies. Endocrine Journal 50:2, 225-231
    CrossRef