Fulminant Type 1 Diabetes: A nationwide survey in Japan

Inclusion criteria for fulminant type 1 diabetes in this study were 1) ketosis or ketoacidosis within a week after the onset of hyperglycemic symptoms; 2) urinary C-peptide excretion <10 μg/day, fasting serum C-peptide <0.3 ng/ml (0.1 nmol/l), or serum C-peptide <0.5 ng/ml (0.17 nmol/l) after glucagon injection or meal load soon after disease onset; and 3) HbA_1c <8.5% on the first visit. These criteria were determined based on the data from the first 11 patients diagnosed with fulminant diabetes, as reported by Imagawa et al. (13).

First, using retrospective review of patient records, we identified all patients diagnosed with type 1 diabetes who visited the Internal Medicine section or the Diabetes Center in the participating hospitals from 1991 through 2000. Participating hospitals were Osaka University Medical Hospital, Osaka Medical College Hospital, Hospital of Tokyo Women’s Medical University School of Medicine, Nagasaki University Hospital, Nagasaki Genbaku Hospital, Sasebo-Central Hospital, Kosei-kai Hospital, Nijigaoka Hospital, Toranomon Hospital, Keio University Hospital, Saiseikai Central Hospital, Ehime Prefectural Central Hospital, Saitama Social Insurance Hospital, Ehime University Hospital, South-Matsuyama Hospital, Matsuyama Municipal Hospital, Central Saijo Hospital, and Matsuyama Red-Cross Hospital. Next, we identified all acute-onset type 1 diabetic patients with ketosis or ketoacidosis at onset who met nos. 1–4 or 1–3 plus 5 of the following criteria: 1) presence of ketosis or ketoacidosis at the onset of diabetes, 2) duration of hyperglycemic symptoms before insulin therapy of <3 months, 3) required insulin replacement therapy at both onset and 6 months after onset, 4) presence of at least one islet-related autoantibody (GADAb, ICA, IAA, or IA-2 antibody [IA-2Ab]), and 5) decreased insulin-secreting capacity (urinary C-peptide excretion <20 μg/day, fasting serum C-peptide level <0.4 ng/ml [0.13 nmol/l], or peak serum C-peptide level <1.0 ng/ml [0.33 nmol/l] after glucagon or meal load). Of the 222 patients who were thus identified with acute-onset type 1 diabetes in our hospitals, we determined that 43 had fulminant type 1 diabetes using the criteria described above.

First, we asked all members of the Japan Diabetes Society through direct mail and the Journal of the Japan Diabetes Society if they knew of candidates who fulfilled the criteria of fulminant type 1 diabetes, as described above. To those who responded positively, we sent a questionnaire asking for a description of the patients’ clinical characteristics and autoantibody status, as described herein. The criteria used to determine fulminant type 1 diabetes were the same as those used in Study 1. Through this method, we identified 229 candidates and confirmed 118 patients among them.

The 118 patients from the Japan Diabetes Society survey and the 43 patients identified in study 1 (total 161 patients: 83 male and 78 female patients) were diagnosed with fulminant type 1 diabetes and comprised the subjects of study 2.

Clinical characteristics of all patients (age at onset, sex, BMI, date of onset of hyperglycemic symptoms, date insulin therapy was started, family history of diabetes, symptoms accompanying onset of diabetes, and diabetic complications) were recorded. In addition, dosages of daily insulin injection and the following laboratory data were determined at 0, 3, 6, and 12 months after the onset of diabetes in each hospital: plasma glucose concentration; HbA_1c level; urinary ketone bodies; serum ketone levels; arterial pH; serum concentrations of sodium, potassium, chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, and triglyceride; daily urinary C-peptide excretion; fasting serum C-peptide level; and serum concentrations of amylase, elastase-1, and lipase. Ketosis was determined by ketonuria, elevated serum ketones, or both.

GADAb, ICA, and IA-2Ab were determined at the onset of diabetes. If no data were available, but serum samples stored at the time of diagnosis were available, autoantibodies were examined retrospectively. GADAbs and IA-2Abs were measured by radioimmunoassay or radioligand-binding assay (15) and ICAs were measured by the immunohistochemical methods. Thyroid anti-microsomal and anti-thyroglobulin antibodies were also investigated.

Statistical analysis was performed with Fisher’s exact probability test, the Mann-Whitney U test, and the unpaired or paired t test, as appropriate.

In our 18 hospitals, 222 patients (102 male and 120 female) were diagnosed with acute-onset type 1 diabetes with ketosis at disease onset. Of these 222 patients, 43 (19.4%) were diagnosed as having fulminant type 1 diabetes, including 27 male and 16 female patients. Among the remaining (nonfulminant) 179 patients, 137 (47 male and 90 female patients) were positive for at least one islet-related autoantibody. Of those 137 patients, 117 patients were positive for at least GADAb, another 17 were positive for at least ICA, and the remaining 3 were positive for at least IA-2Ab. We diagnosed these patients as having autoimmune type 1 diabetes. There was a significant difference by sex between fulminant and autoimmune type (P = 0.001); 62.8% of fulminant diabetic patients were male vs. only 34.3% of autoimmune diabetic patients. The final 42 patients (28 male and 14 female) were diagnosed with type 1 diabetes, but were negative for islet-related autoantibodies and did not fulfill the criteria for fulminant type 1 diabetes (Fig. 1). In all, 4.7% of fulminant patients and 72.6% of nonfulminant patients (P < 0.0001) were positive for GADAb. The distribution of HbA_1c level with or without GADAb at the onset of type 1 diabetes in our hospitals is shown in Fig. 2.

In addition to the 43 patients diagnosed with fulminant diabetes in our hospitals, we also identified 118 patients outside our hospitals with this same diagnosis. In all, we identified 161 patients with fulminant type 1 diabetes.

Fulminant type 1 diabetic patients were reported from all over Japan, from Hokkaido Island to Kyushu Island. Fulminant type 1 diabetic patients were accumulated in crowded areas, but not in a specific region by prefecture in Japan.

The annual number of newly diagnosed patients with fulminant diabetes was 0–7 from 1990 to 2000, and has not increased in our hospitals over the past 10 years. As to seasonal changes, 20 patients were diagnosed with fulminant type 1 diabetes in May, whereas 6–13 patients were diagnosed in the other 11 months. In 2000, 39 cases of newly diagnosed fulminant type 1 diabetes were reported, and the average incidence was 3 cases per month all over Japan. In May and July of 2000, eight and six cases of newly diagnosed fulminant diabetes were reported, respectively; one to four cases were reported monthly in the other 10 months.

In the following analysis, two groups of patients were compared: 161 patients with fulminant type 1 diabetes recruited from studies 1 and 2, and the 137 patients with autoimmune type 1 diabetes recruited from study 1.

As shown in Table 1, the mean duration from the onset of hyperglycemic symptoms to the start of insulin therapy was 4.4 days, and the mean value of HbA_1c levels, daily urinary C-peptide excretion, and fasting serum C-peptide concentration was 6.4%, 4.3 μg, and 0.3 ng/ml (0.10 nmol/l), respectively, at the onset of fulminant diabetes. The duration of disease was significantly shorter and HbA_1c levels, urinary C-peptide excretion, and the serum C-peptide concentration were significantly lower in fulminant than in autoimmune type 1 diabetes.

The mean age at onset of type 1 diabetes was 39.1 years in fulminant type 1 diabetic patients and was significantly older than age at onset in autoimmune type 1 diabetic patients. The age at onset of male fulminant patients was 42.8 ± 14.8 years (mean ± SD) and significantly higher than that of female fulminant patients (35.1 ± 15.8) (P = 0.002). The age at onset of fulminant diabetes ranged from 1 year to 80 years. Childhood/adolescent onset of fulminant diabetes (onset before age 20 years) was seen in 14 patients (3 male and 11 female), whereas adult onset was observed in the remaining 147 patients.

The mean BMI at onset of type 1 diabetes was 20.7 in fulminant type 1 diabetic patients, which was significantly higher than that in autoimmune type 1 diabetic patients. There was no significant difference in the presence of family history of type 1 and type 2 diabetes in first-degree relatives between fulminant and autoimmune diabetes, but autoimmune diseases other than type 1 diabetes were more frequently observed in autoimmune diabetes than in fulminant diabetes (Table 1).

Thirst was the most common symptom accompanying the onset of diabetes and was observed in ∼90% of both fulminant and autoimmune type 1 diabetic patients. Lower body weight loss was observed in fulminant diabetes than in autoimmune diabetes.

Flu-like symptoms, abdominal symptoms, and drowsiness were more frequently observed in the fulminant group than in the autoimmune group at disease onset (P < 0.0001) (Table 1). Among the flu-like symptoms, fever was the most common and was observed in 60.0% of patients. Nausea, vomiting, or both were also frequent and were observed in 65.4% of patients.

Of the 14 patients who had type 1 diabetes during or after pregnancy in this study, 13 belonged to fulminant subtype (Table 1). Their onset was the 19th week in one patient, the 22nd week in one patient, the 26th week in one patient, the 29th week in one patient, the 30th week in three patients, the 31st week in one patient, the 35th week in one patient, the 36th week in two patients, and the 2nd week after delivery in two patients.

Compared to autoimmune type 1 patients, fulminant type 1 patients showed markedly higher plasma glucose concentrations and significantly lower arterial pH at the first visit (Table 1). At least one of three serum exocrine pancreatic enzyme levels—amylase, elastase-1, or lipase—was increased over the normal range in 98 patients. In the fulminant diabetes group, only 2 patients had normal levels of all these enzymes, whereas in the autoimmune diabetes group, 17 patients showed elevated serum levels of at least one of these enzymes and 26 patients showed normal levels of all these enzymes.

As shown in Table 1, fulminant patients had significantly lower serum sodium and chloride levels and significantly higher serum potassium levels than autoimmune patients. Serum ALT and AST levels were significantly higher in the fulminant than in the autoimmune group. Serum triglyceride levels were significantly higher in the fulminant than in the autoimmune patients, but the serum cholesterol level was not significantly different between the two groups.

In the fulminant diabetes group, 4.8% were positive for GADAb, but all were negative for IA-2Ab. Thyroid antimicrosomal antibodies were seen significantly more frequently in autoimmune diabetes than in fulminant diabetes patients (Table 1).

A patient with fulminant type 1 diabetes died and another patient suffered from cardiac and respiratory arrest at onset. The former patient had been reported previously (16). None of the autoimmune type 1 diabetic patients suffered from such episodes. The other fulminant and autoimmune type 1 diabetes patients survived the metabolic disorder at onset.

Mean HbA_1c levels were not significantly different between fulminant and autoimmune type 1 diabetic patients at 3, 6, or 12 months after the onset of overt diabetes. Insulin injection dosages were significantly higher in fulminant than in autoimmune diabetic patients 3, 6, and 12 months after the onset (Fig. 3).

Our present study confirmed 161 cases of fulminant type 1 diabetes distributed all over Japan, and clearly showed that fulminant type 1 diabetes is a distinct subtype within type 1 diabetes judging from the clinical characteristics, such as autoantibody status. Several new findings regarding fulminant type 1 diabetes were also confirmed by this nationwide survey: 1) fulminant diabetes accounted for ∼20% of Japanese type 1 diabetes with ketosis or ketoacidosis at onset; 2) few patients were children or adolescents, and >90% of patients were adults; 3) male patients accounted for ∼50% of all cases; 4) flu-like symptoms, especially fever, were frequently observed at onset; and 5) almost all female patients who developed type 1 diabetes during pregnancy had the fulminant type.

This nationwide survey indicated that fulminant type 1 diabetes is a major subtype in Japan. Several cases similar to fulminant type 1 diabetes have been reported in Japan after (16–23) and even before (8–12) Imagawa et al. proposed this novel subtype. However, few cases have been reported from Western countries (24–27). The number of fulminant type 1 diabetes in Caucasians might be relatively small, and therefore this subtype might have been disregarded among the majority of autoimmune type diabetes cases; however, the fulminant subtype does not appear to be rare, at least in the Japanese population.

Second, >90% of fulminant type 1 diabetic patients were adults and no sex difference was observed among cases. The incidence of type 1 diabetes in Japanese children is 0.8 people/10,000 person-years and lower than the incidence in European countries (28); however, type 1 diabetes is not a rare disease. Nonetheless, few cases of fulminant diabetes were reported in the Japanese children or adolescents in this study. These findings suggested that fulminant type 1 diabetes is most likely an adult-onset disease. Female sex was predominant in autoimmune type diabetes.

Third, flu-like symptoms were significantly more frequent in fulminant type than in autoimmune type diabetes. Fever was the most common among such symptoms. In addition to the markedly acute clinical course at onset, this finding suggests that fulminant diabetes may be associated with viral infection. On the other hand, other frequent symptoms such as nausea, vomiting, and drowsiness could be attributable to severe metabolic acidosis in fulminant diabetes at onset. Another important finding was that fulminant diabetes accompanied pregnancy in 21.0% of females ages 13–49 years, and the incidence clearly increased in the third trimester of pregnancy. This finding was compatible with the fact that the incidence of type 1 was tripled in the third trimester (29).

In addition, the present study also confirmed the basic characteristics of fulminant type 1 diabetes proposed by Imagawa et al. (13): 1) markedly acute onset of diabetes, 2) severe metabolic disorder, and 3) elevated levels of serum pancreatic enzymes. The plasma glucose concentration in fulminant patients was 800 mg/dl, higher than that of autoimmune patients, whereas HbA_1c levels of fulminant patients were only slightly higher than the upper limit of normal range. More severe derangement of serum electrolytes was observed in fulminant patients. Loss of consciousness was more frequently observed in fulminant diabetic patients. Lower body weight loss and higher BMI of fulminant patients would indicate shorter duration of hyperglycemic period. The elevation of serum pancreatic enzyme levels was also characteristic of fulminant type 1 diabetes, although these levels can be raised as a consequence of ketoacidosis.

It was also shown that islet-related autoantibodies were seldom positive in fulminant diabetes. In this study, we recruited patients irrespective of the presence or absence of autoantibodies, and it turned out that only 4.8% of fulminant diabetes patients were positive for GADAb and none were positive for ICA and IA-2Ab. Therefore, fulminant type 1 diabetes would be classified as one subtype of idiopathic (type 1B) diabetes, according to the ADA/WHO classification.

Whether or not the pathogenesis of fulminant type 1 diabetes is associated with autoimmunity is still unknown. Tanaka et al. (16) have reported insulitis in an autopsy case of fulminant type 1 diabetes, who died soon after the onset of the disease. Shimada and colleagues reported a fulminant diabetic patient with elevated serum interferon-γ–inducible protein levels (19) and another patient with increased prevalence of GAD-reactive peripheral T-cells (23). These findings suggest that fulminant type 1 diabetes is autoimmune related. However, the prevalence of islet-related autoantibodies in fulminant diabetes was extremely low in the present study. The original report of Imagawa et al. (13) showed neither insulitis nor hyperexpression of MHC class I antigens in islets in all three patients. These findings suggest that fulminant type 1 diabetes is not caused by autoimmunity. Another candidate for the pathogenesis of fulminant diabetes would be viral infection. A frequent flu-like symptom, especially fever at onset in fulminant diabetes, was observed in this study. Two case reports described fulminant diabetes that developed after the reactivation of human herpes virus-6 or the infection of herpes simplex virus (17,22). These findings suggest an association of viral infection to fulminant diabetes.

In conclusion, fulminant type 1 diabetes accounts for ∼20% of the ketosis-onset type 1 diabetic patients in Japan. Flu-like symptoms, especially fever, are characteristic features around the onset of the disease. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes. The mechanism of β-cell death in fulminant type 1 diabetes should be further investigated, with special attention given to viral infection and autoimmunity. Even a single case report of fulminant type 1 diabetes in other countries would help improve the understanding of this subtype. A worldwide survey should be carried out in the future.

This study was supported by a grant-in-aid from the Japanese Ministry of Health, Labor, and Welfare, and a grant-in-aid from the Japan Diabetes Society.

We would like to thank the following doctors who referred the patients to our committee: Yoshitaka Aiso, M.D., Aiso Clinic; Keizo Anzai, M.D., and Ikuyo Hayashi, M.D., First Department of Internal Medicine, Fukuoka University School of Medicine; Takahiko Aoki, M.D., Ogaki Municipal Hospital Internal Medicine; Eiichi Araki, M.D., and Tetsushi Toyonaga, M.D., Department of Metabolic Medicine, Kumamoto University School of Medicine; Kaoru Arii, M.D., Kochi Red Cross Hospital; Yoshihito Atsumi, M.D., Satoru Yamada, M.D., and Kempei Matsuoka. M.D., Saiseikai Central Hospital Tokyo; Takuya Awata, M.D., The Fourth Department of Internal Medicine, Saitama Medical School; Yukihiro Bando, M.D., Fukui-ken Saiseikai Hospital; Masahiro Emoto, M.D., and Yoshitomo Oka, M.D., Third Department of Internal Medicine,Yamaguchi University; Hitomi Fujii, M.D., Nakano Kyoritsu Hospital; Tatsuya Haga, M.D., Kainan Hospital of Aichi Prefectural Welfare Federation of Agricultural Cooperatives; Shigeru Haisa, M.D., Department of Internal Medicine, Okayama Municipal Hospital; Mutsumi Hakamata, M.D., Hakamata Medical Clinic; Yoshihito Hara, M.D.; Oume Municipal General Hospital; Naoko Hara-Nakamura, M.D., Internal Medicine, Nippon Telegraph and Telephone West Corporation Matsuyama Hospital; Naotake Hashimoto, M.D., Department of Applied Translational Research, Graduate School of Medicine, Chiba University; Yoshifumi Suzuki, M.D., Kentaro Kaneko, M.D., and Yasushi Saito, M.D., Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University; Tsutomu Hirano, M.D., First Department of Internal Medicine, Showa University School of Medicine; Rieko Honda-Mizuochi, M.D., and Isamu Wada, M.D., Social Insurance Takaoka Hospital; Choung-I-Houng, M.D., Narita Red Cross Hospital; Kayano Igawa, M.D., Mito National Hospital; Yasuo Imai, M.D., Eiji Omura, M.D., and Shoji Kawazu, M.D., First Dept of Internal Medicine, Saitama Medical Center, Saitama Medical School; Mitsuo Imura, M.D., Yaizu Municipal General Hospital of Metabolism and Endocrine Division; Yasushi Inoue, M.D., Department of Internal Medicine, Yamaguchi Prefecture General Hospital; Yukako Inoue-Ozawa, M.D., Internal Catholic Hospital; Harumi Ishidoh, M.D., and Shuhei Hayashi, M.D., Showa General Hospital; Hidehiro Ishii, M.D., and Kayo Morioka, M.D., Kitakyushu Municipal Medical Center, Diabetes Center; Haruhiko Isotani, M.D., Keizo Furukawa, M.D., and Keiichi Kameoka, M.D., Department of Medicine, Hirakata City Hospital; Yasunori Iwashima, M.D., Sano Hospital; Takuyuki Katabami, M.D., Division of Metabolism and Endocrinology, Department of Internal Medicine, St Marianna University School of Medicine; Shinkuro Kataoka, M.D. Hiroshima City Asa Hospital; Setsuyo Kawakita, M.D., Toki General Hospital; Masahiro Kawanaka, M.D., Sasayama Branch Hospital of Hyogo Medical College; Junji Kobayashi, M.D., Chibaken Saiseikai Narashino Hospital; Masaki Makino, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, Fujita Health University School of Medicine; Norio Matsui, M.D., Toyama Kyoritsu Hospital; Akira Matsumoto, M.D., and Masahiro Nomura, M.D., First Department of Internal Medicine, Sapporo-Kosei General Hospital; Nobuo Matsuura, M.D., Department of Pediatrics, Kitasato University School of Medicine; Yoshitaka Miura, M.D., First Department of Internal Medicine, Nagoya University School of Medicine; Umeo Miwa, M.D., Ishikawa Prefectural Central Hospital; Keiko Miya, M.D., Tokushima Red Cross Hospital; Masakazu Mizutani, M.D., Kozawa Eye Hospital and Diabetes Center; Mizue Mogi, M.D., Shiseikai Daini Hospital, Diabetes Department; Takashige Mochizuki, M.D., Nagano Chuo Hospital; Takeshi Momotsu, M.D., and Noriko Tamura, M.D., Second Department of Internal Medicine, Niigata City General Hospital; Mitsuru Moriya, M.D., Department of Internal Medicine, Memuro Municipal Hospital; Seiho Nagafuchi, M.D., First Department of Internal Medicine, Faculty of Medicine, Kyushu University; Shoichiro Nagasaka, M.D., and Ikuyo Kusaka, M.D., Division of Endocrinology and Metabolism, Jichi Medical School; Kunihiko Nakamura, M.D., Department of Internal Medicine Mazda Hospital, Hiroshima; Koji Nakano, M.D., Yamashiro Public Hospital; Kazuyuki Namai, M.D., Omiya Medical Center, Jichi Medical School; Mitsuyoshi Namba, M.D., Division of Diabetes and Metabolism, Department of Internal Medicine, Hyogo College of Medicine; Kishio Nanjo, M.D., and Masahiro Nishi, M.D., First Department of Medicine, Wakayama University of Medical Science; Hiroshi Ninomiya, M.D., Chikushi Hospital, Fukuoka University; Mitsuo Obana, M.D., Department of Internal Medicine, Kawasaki Municipal Hospital; Koji Oida, M.D., Third Department of Internal Medicine, Faculty of Medicine, Fukui Medical University; Midori Okamura, M.D., Kure Kyosai Hospital; Hiromi Ouchi, M.D., Yamauchi Hospital; Ikue Saito, M.D., Saito Clinic; Tsune Sakai, M.D., Sakai Clinic; Shinsuke Sasaki, M.D., Hitachi General Hospital; Wakano Sato, Fukushima Medical University School of Medicine, Department of Internal Medicine III; Hiroaki Seino, M.D., Department of Internal Medicine, Diabetic Center, Ohta Nishinouchi Hospital; Nobuo Sekine, M.D., Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo; Sakae Sekiya, M.D., Juntendo University School of Medicine, Department of General Medicine; Kenji Shima, M.D., Kawashima Hospital; Makiko Shimodahira, M.D., and Hiroyuki Kurahachi, M.D., Department of Endocrinology, Kobe City General Hospital; Junji Shinoda, M.D., Toyota Memorial Hospital, Department of Endocrinology; Masahiro Shinoda, M.D., Inazawa City Hospital; Shingo Shoji, M.D., Department of Endocrinology and Metabolism, Kurume University School of Medicine; Kazuhiko Sugiyama, M.D., Saiseikai Yamagata Saisei Hospital; Seiichi Sumi, M.D., Suita Municipal Hospital; Norihiro Suzuki, M.D., Mizusawa City Hospital; Kenji Takahashi, M.D., Kurashiki Central Hospital; Tatsuro Takano, M.D., and Tadashi Yamakawa, M.D., Department of Endocrinology and Diabetes Mellitus, Yokohama City Medical Center; Akira Takeda, M.D., Matsue Red Cross Hospital; Tsuyoshi Tanaka, M.D., National Mie Chuo Hospital; Kazuyuki Tobe, M.D., Department of Metabolic Diseases, Graduate School of Medicine Tokyo University; Katsuto Tokunaga, M.D., Itami City Hospital; Akira Tsuruoka, M.D., Funabashi Municipal Medical Center; Tatsuhiko Urakami, M.D., Department of Pediatrics, Nihon University School of Medicine; Ryo Uwamizu, M.D., Uwamizu Diabetes Treatment Institute; Takanobu Wakasugi, M.D., Fukui Prefectural Hospital; Nobuaki Watanabe, M.D., Department of Internal Medicine, Hyogo Prefectural Nishinomiya Hospital; Toshiko Yagi, M.D., Fjieda Municipal General Hospital; Takashi Yamagami, M.D., Ohzu Chuuou Hospital; Kohei Yamaguchi, M.D., Department of Cardiology and Endocrinology, Oita Prefectural Hospital; Takahide Yamaguchi, M.D., Yamaguchi Clinic; Hioryuki Yamamoto, M.D., Tottori Red Cross Hospital; Tsunehiko Yamamoto, M.D., Department of Metabolism and Endocrinology, Osaka City General Hospital; Hiroko Yoneda, M.D., Takeda General Hospital; Yasunao Yoshimasa, M.D., National Cardiovascular Center; Haruhiko Yoshimura, M.D., First Department of Internal Medicine, Hokkaido University Hospital.