Background and Methods Type 1 diabetes mellitus is now classifiedas autoimmune (type 1A) or idiopathic (type 1B), but littleis known about the latter. We classified 56 consecutive Japaneseadults with type 1 diabetes according to the presence or absenceof glutamic acid decarboxylase antibodies (their presence isa marker of autoimmunity) and compared their clinical, serologic,and pathological characteristics.
Results We divided the patients into three groups: 36 patientswith positive tests for serum glutamic acid decarboxylase antibodies,9 with negative tests for serum glutamic acid decarboxylaseantibodies and glycosylated hemoglobin values higher than 11.5percent, and 11 with negative tests for serum glutamic aciddecarboxylase antibodies and glycosylated hemoglobin valueslower than 8.5 percent. In comparison with the first two groups,the third group had a shorter mean duration of symptoms of hyperglycemia(4.0 days), a higher mean plasma glucose concentration (773mg per deciliter [43 mmol per liter]) in spite of lower glycosylatedhemoglobin values, diminished urinary excretion of C peptide,a more severe metabolic disorder (with ketoacidosis), higherserum pancreatic enzyme concentrations, and an absence of islet-cell,IA-2, and insulin antibodies. Immunohistologic studies of pancreatic-biopsyspecimens from three patients with negative tests for glutamicacid decarboxylase antibodies and low glycosylated hemoglobinvalues revealed T-lymphocyte–predominant infiltrates inthe exocrine pancreas but no insulitis and no evidence of acuteor chronic pancreatitis.
Conclusions Some patients with idiopathic type 1 diabetes havea nonautoimmune, fulminant disorder characterized by the absenceof insulitis and of diabetes-related antibodies, a remarkablyabrupt onset, and high serum pancreatic enzyme concentrations.
Type 1 diabetes mellitus is caused by loss of insulin-secretingcapacity due to selective autoimmune destruction of the pancreaticbeta cells.1,2 Insulitis (i.e., mononuclear-cell infiltrationof the pancreatic islets) is the direct result of the autoimmuneprocess. Antibodies to the cytoplasm of islet cells, glutamicacid decarboxylase, insulin, and tyrosine phosphatase–likeprotein (IA-2 or IA-2ß), which appear before the clinicalonset of diabetes, are good markers of the autoimmune process.1,2
Several lines of evidence have suggested that autoimmunity isnot the only cause of beta-cell destruction. We and others havedescribed young patients who presented with the abrupt onsetof symptoms of hyperglycemia and who were prone to the developmentof ketoacidosis, as is characteristic of patients with type1 diabetes, but who did not have insulitis on either biopsy3,4,5or autopsy.6,7 Furthermore, at least 10 percent of patientswith newly diagnosed type 1 diabetes do not have any diabetes-relatedantibodies.8,9
The American Diabetes Association and the World Health Organizationhave proposed that type 1 diabetes be subdivided into autoimmune(immune-mediated) diabetes (type 1A) and idiopathic diabeteswith beta-cell destruction (type 1B).10,11 However, the specificcharacteristics of the idiopathic subtype are largely unknown.In a previous study,5 we found that the presence of glutamicacid decarboxylase antibodies, but not islet-cell antibodies,was closely correlated with direct evidence of insulitis inpatients with type 1 diabetes. In this report, we describe theresults of detailed clinical and histologic studies of patientswith idiopathic type 1 diabetes.
Methods
Patients
We studied 56 consecutive patients with type 1 diabetes whocame to our hospitals within one year after receiving the diagnosis,during the period from 1994 to 1998. All 56 patients met thecriteria of the American Diabetes Association for type 1 diabetes— that is, pancreatic beta-cell destruction as the primarycause of the disorder and a tendency toward ketoacidosis10,11— as determined by at least two physicians independently.Patients who had a period of remission that lasted for six monthsor more after the diagnosis had been made were excluded.12 Noneof the enrolled patients consumed moderate or large amountsof alcohol. The study was approved by the ethics committee ofOsaka University Medical Hospital, and written informed consentwas obtained from each patient.
Clinical Characteristics and Serum Glutamic Acid Decarboxylase Antibodies
At the time of the onset of overt diabetes, all patients werehospitalized. Their clinical characteristics were recorded,and plasma glucose, serum electrolytes, arterial pH, glycosylatedhemoglobin, and serum total or pancreatic amylase and elastaseI were measured within two days after the initial diagnosis,and an ultrasonographic study of the pancreas was performed.Patients with arterial pH values lower than 7.35 and serum bicarbonateconcentrations lower than 18 mmol per liter received the diagnosisof metabolic acidosis. Urinary C-peptide excretion was measureddaily for at least three days, and the mean value was calculated.Subsequently, all patients underwent clinical examinations andmeasurements of glycosylated hemoglobin at monthly intervals.
The patients were divided into two groups according to the presenceor absence of glutamic acid decarboxylase antibodies in serumsamples obtained within three months after the initial diagnosisof diabetes, with the use of a radioimmunoassay kit (Rip-GAD,Hoechst Japan, Tokyo, or GAD-Ab Cosmic, Cosmic, Tokyo). A valuegreater than 5 units per milliliter (with the first kit) or1.5 units per milliliter (with the second) was considered positive.The specificity and sensitivity of the first kit were 100 percentand 89.5 percent in the Second International GADAb Workshop,respectively,13 and the specificity and sensitivity of the secondkit were both 100 percent in the Second and Third GAD ProficiencyTest Results Evaluations (University of Florida, Gainesville).
Diabetes-Related and Thyroid Antibodies
Serum antibodies were measured within three months after theinitial diagnosis of diabetes. Islet-cell antibodies were measuredby an indirect immunofluorescence method (with an abnormal valuedefined as more than 5 Juvenile Diabetes Foundation units),4IA-2 antibodies with an immunoprecipitation assay kit (withan abnormal value defined as more than 0.75 unit per milliliter)(Cosmic),14 and insulin antibodies with a liquid-phase radioimmunoassay(with an abnormal value defined as higher than the 99th percentilefor 140 normal subjects).15,16 Thyroid antimicrosomal antibodieswere measured by a hemagglutination assay (with an abnormalvalue defined as greater than 1:100).17
HLA Typing and Mitochondrial-DNA Analysis
Genomic and mitochondrial DNA were extracted from peripheral-bloodleukocytes. The HLA class II antigen haplotype and the presenceor absence of a guanine-for-adenine substitution at position3243 in mitochondrial DNA were determined.5,18 No mitochondrialmutations were detected.
Pancreatic Studies
Pancreatic biopsies were performed in six patients within fivemonths after the initial diagnosis of diabetes, as reportedpreviously.3,4,5 The biopsy specimens were examined after stainingwith hematoxylin and eosin and by indirect immunohistochemicalmethods. To detect insulitis, a double immunofluorescence methodwas used with monoclonal antihuman CD3+ T-lymphocyte antibody,B-lymphocyte antibody, or macrophage antibody and anti-insulinor anti-glucagon antibodies. We also examined the expressionof major histocompatibility complex (MHC) class I antigens inislets with the use of antihuman HLA-A, B, and C antibodies.The sources of these antibodies have been reported previously.4
To examine the relation between lymphocytes or macrophages andpancreatic exocrine tissue, we stained the cells with peroxidasesubstrate solution containing diaminobenzidine tetrachloride–nickelchloride (Zymed Laboratories, South San Francisco, Calif.).The sections were then incubated with antihuman alpha-amylaseantibody (Sigma Chemical, St. Louis), and the pancreatic exocrinecells were stained with 3-amino-9-ethylcarbazole (Dakopatts,Glostrup, Denmark).
Statistical Analysis
Statistical analysis was performed with Student's t-test orFisher's exact probability test, as appropriate.
Results
Serum glutamic acid decarboxylase antibodies were detected in36 patients (64 percent) and were not detected in 20 patients(36 percent). The patients without glutamic acid decarboxylaseantibodies were divided into two subgroups according to theinitial glycosylated hemoglobin value: those with values ofless than 8.5 percent, and those with values of more than 11.5percent (Figure 1).
Figure 1. Glycosylated Hemoglobin Values at the Time of the Diagnosis of Diabetes in 56 Patients, According to Whether the Test for Glutamic Acid Decarboxylase (GAD) Antibodies Was Positive or Negative.
The values for glycosylated hemoglobin in the patients with positive antibody tests are scattered, whereas the values in the patients with negative antibody tests are clearly divided into two groups: those below 8.5 percent and those above 11.5 percent. The broken line indicates the upper limit of the normal range for glycosylated hemoglobin.
The clinical characteristics of the patients with positive testsfor glutamic acid decarboxylase antibodies and those of thetwo groups of patients with negative tests are shown in Table 1.The mean duration of hyperglycemic symptoms in the patientswith negative tests for glutamic acid decarboxylase antibodiesand low glycosylated hemoglobin values was only 4.0 days. Thisgroup had a significantly higher mean glucose concentration,despite lower glycosylated hemoglobin values, and a significantlylower mean value for urinary C-peptide excretion than did theother two groups. All the patients with negative antibody testsand low glycosylated hemoglobin values had diabetic ketoacidosis,as compared with 20 percent of the patients with positive antibodytests and 40 percent of the patients with negative tests andhigh glycosylated hemoglobin values. Serum pancreatic enzymeconcentrations were high in all the patients who had negativeantibody tests and low glycosylated hemoglobin values but notin the other two groups (Table 1), and the values fell to thenormal range in 3 to 38 days (median, 17).
Table 1. Characteristics of 56 Patients with Type 1 Diabetes, According to Whether the Test for Glutamic Acid Decarboxylase Antibodies (GAD) Was Positive or Negative.
All patients received multiple insulin injections, with a highermean dose during the first year in the group of patients withnegative antibody tests and low glycosylated hemoglobin valuesthan in the other two groups (Table 1). Diabetes-related antibodieswere not detected in serum samples from any of the patientswith negative tests for glutamic acid decarboxylase antibodiesand low glycosylated hemoglobin values (Table 2).
Table 2. Results of Other Antibody Tests at the Time of Diagnosis, According to Whether the Test for Glutamic Acid Decarboxylase Antibodies (GAD) Was Positive or Negative.
The characteristics of the 11 patients with negative tests forglutamic acid decarboxylase antibodies and low glycosylatedhemoglobin values are shown in Table 3. The HLA class II haplotypewas determined in 10 of the patients. The haplotypes most oftenassociated with type 1 diabetes in Japanese patients,19 HLA-DRB1* 0405, DQA1* 0303, DQB1*0401 and HLA-DRB1* 0901, DQA1*0302, DQB1*0303, were present in five and three patients, respectively.Two haplotypes associated with resistance to type 1 diabetes,HLA-DRB1*1501, DQA1*0102, DQB1*0602 and HLA-DRB1*1502, DQA1*0103, DQB1* 0601, were found in two patients and one patient,respectively.
Table 3. Clinical Characteristics of the 11 Patients with Negative Tests for Glutamic Acid Decarboxylase Antibodies and Low Glycosylated Hemoglobin (HbA1c) Values at the Onset of Diabetes.
Pancreatic biopsies were performed in one patient with a negativetest for glutamic acid decarboxylase antibodies and a low glycosylatedhemoglobin value (Patient 2 in Table 3) and in two other patientswith similar findings (described previously5) who had been hospitalizedbefore we started this study. In all three patients, no islet-cellantibodies were detected, hyperglycemic symptoms lasted forfewer than six days, and at least one serum pancreatic enzymevalue was elevated initially. As a control, pancreatic studieswere also performed in three patients with positive tests forglutamic acid decarboxylase antibodies or islet-cell antibodiesand glycosylated hemoglobin values of 8.5 to 15.1 percent.
Light-microscopical examination of sections of pancreas stainedwith hematoxylin and eosin revealed small, atrophic, distortedislet cells in all six patients. However, none of the patientshad edema, necrosis, hemorrhage, suppuration, cyst formation,fibrosis, or apparent atrophy of the exocrine pancreas. Immunohistochemicalexamination revealed a markedly reduced beta-cell mass in allsix patients, as would be expected in patients with type 1 diabetes.The sections from all three patients with negative tests forglutamic acid decarboxylase antibodies had T-lymphocyte–predominantinfiltration of the exocrine pancreas but no insulitis (Figure 2and Figure 3). On the other hand, insulitis but no cellularinfiltration of the exocrine pancreas was seen in the sectionsfrom all three patients with positive antibody tests (Figure 3).Hyperexpression of MHC class I molecules, another immunologicabnormality in islets, was seen only in the sections from thepatients with insulitis.
Figure 2. Photomicrographs of Double-Stained Pancreatic-Biopsy Specimens Showing Diffuse Infiltration of T Lymphocytes in the Exocrine Pancreas (x140).
Each pair of panels shows CD3+ T lymphocytes (green) and pancreatic alpha cells (red) in a biopsy specimen from one patient. Panels A and B, C and D, and E and F show specimens from three patients with negative tests for glutamic acid decarboxylase and islet-cell antibodies, and Panels G and H show specimens from one patient with positive tests for glutamic acid decarboxylase and islet-cell antibodies.
Figure 3. T-Lymphocyte–Predominant Infiltration of the Exocrine Pancreas in a Patient with a Positive Test for Glutamic Acid Decarboxylase Antibodies (x200).
T lymphocytes (Panel A), B lymphocytes (Panel B), and macrophages (Panel C) were stained with peroxidase substrate solution containing diaminobenzidine tetrahydrochloride–nickel chloride (black), and exocrine pancreas was stained with antihuman alpha-amylase antibody followed by 3-amino-9-ethylcarbazole (pink). Counterstaining was performed with hematoxylin.
Discussion
Among 56 consecutive Japanese patients who had type 1 diabetes,we identified 11 with a subtype of diabetes that differed fromautoimmune diabetes in three respects. First, no autoimmunefeatures were detected. The patients did not have diabetes-relatedserum antibodies, such as islet-cell, glutamic acid decarboxylase,IA-2, or insulin antibodies. Pancreatic biopsies revealed neitherinsulitis nor hyperexpression of MHC class I molecules in islets.
Second, the onset of overt diabetes was rapid, and diabeticketoacidosis occurred soon after the onset of hyperglycemicsymptoms. The mean duration of hyperglycemic symptoms beforethe diagnosis was only four days. The short duration of hyperglycemiawas reflected by the patients' nearly normal glycosylated hemoglobinvalues. Insulin-secretory capacity, estimated on the basis ofurinary C-peptide excretion, was low, and the metabolic derangementat the onset was severe.
Third, the patients had markedly elevated serum pancreatic enzymeconcentrations, a finding in accordance with the lymphocyticinfiltration of the exocrine pancreas seen in the biopsy specimens.In contrast, the other patients had normal serum pancreaticenzyme concentrations and insulitis but did not have lymphocyticinfiltrates in the exocrine pancreas. The edema, necrosis, hemorrhage,suppuration, cyst formation, and fibrosis that characterizeclassic acute or chronic pancreatitis were not present in ourpatients.20 In addition, none of the patients with negativetests for glutamic acid decarboxylase antibodies and low glycosylatedhemoglobin values drank moderate or large amounts of alcohol,only 1 had abdominal pain, and all 11 had normal findings onultrasonography of the pancreas. Therefore, these 11 patientshad a type of diabetes other than that caused by classic pancreatitis.10,11
On the basis of these findings, we believe that diabetes characterizedby the absence of glutamic acid decarboxylase antibodies andlow glycosylated hemoglobin values should be classified as nonautoimmune,fulminant type 1 diabetes, a subtype of idiopathic (type 1B)diabetes. Some similar cases have been reported previously.21,22
The precise mechanism of beta-cell destruction in patients withthis subtype of diabetes is not known. A viral cause is suggestedby the abrupt onset of diabetes, the presence of lymphocyticinfiltrates in the exocrine pancreas, and the affinity of severalviruses for exocrine pancreatic tissue.23,24 In preliminarystudies, however, none of our patients had high titers of antiviralantibodies (data not shown).
Further studies with younger patients and other ethnic groupsmay provide a better understanding of this subtype of diabetes.All our patients were adults, and the clinical features of type1 diabetes differ to some extent in children and adults.25 Diabetes-relatedantibodies are more often detected in white patients than inJapanese patients,26 suggesting that nonautoimmune, fulminanttype 1 diabetes may be rare in whites and that this subtypemay therefore have been overlooked in studies of autoimmunediabetes in whites.
In conclusion, nonautoimmune, fulminant type 1 diabetes mellitusin Japanese adults is a novel subtype of type 1 diabetes characterizedby the absence of both insulitis and diabetes-related antibodies,an abrupt onset, and high serum pancreatic enzyme concentrations.
Supported by grants from the Japanese Ministry of Education,Culture, and Sciences and the Japanese Ministry of Health andWelfare.
We are indebted to Mr. Y. Sato (Yamasa Corporation) for performingtests of insulin autoantibodies.
* Other members of the Osaka IDDM Study Group are listed in theAppendix.
Source Information
From the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
Address reprint requests to Dr. Imagawa at the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan, or at imagawa{at}imed2.med.osaka-u.ac.jp.
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Appendix
Other members of the Osaka IDDM Study Group included M. Namba,H. Nakajima, K. Yamamoto, H. Iwahashi, K. Yamagata, M. Moriwaki,T. Nanmo, S. Kawata, and S. Tamura (Osaka Univeristy); N. Itohand T. Matsuyama (Toyonaka Municipal Hospital); I. Mineo andC. Nakagawa (Otemae Hospital); Y. Yamada (Sumitomo Hospital);H. Itoh (Ikeda Municipal Hospital); M. Kawachi (Izumi-otsu MunicipalHospital); H. Toyoshima (Mino Municipal Hospital); N. Watanabe,M. Hashimoto, and T. Kinoshita (Nishinomiya Prefectural Hospital);and H. Asakawa (Itami Municipal Hospital).
A Novel Subtype of Type 1 Diabetes Mellitus
Honeyman M. C., Coulson B. S., Harrison L. C., Tanaka S., Kobayashi T., Momotsu T., Imagawa A., Miyagawa J.-i., Hanafusa T.
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N Engl J Med 2000;
342:1835-1837, Jun 15, 2000.
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Weets, I., Siraux, V., Daubresse, J.-C., De Leeuw, I. H., Fery, F., Keymeulen, B., Krzentowski, G., Letiexhe, M., Mathieu, C., Nobels, F., Rottiers, R., Scheen, A., Van Gaal, L., Schuit, F. C., Van Der Auwera, B., Rui, M., De Pauw, P., Kaufman, L., Gorus, F. K.
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