Viruses can cause but can also prevent autoimmune disease. The primary efficacy criterion was change from baseline in HbA1C at the 6-month visit. Their experiments have replaced cells in the pancreas damaged by the disease that are unable to make insulin. Fulminant type 1 diabetes has the following clinical characteristics: duration of hyperglycemic symptoms is 4 days on average; there is a high prevalence of preceding common-cold-like and gastrointestinal symptoms; there is a near-normal level of glycated hemoglobin in spite of very high plasma glucose levels associated with ketoacidosis; the disease is sometimes related to pregnancy; and there are increased serum pancreatic enzyme levels, absent C-peptide levels, but virtually no detectable autoantibodies against constituents of pancreatic cells. In both cases, infection with the lymphocytic choriomeningitis virus (LCMV) completely abrogated the diabetic process. Fasting and 120-min postprandial plasma glucose levels were reduced in parallel to HbA1C, in association with miglitol treatment. This has been one of the prime targets of stem cell experiments.
All medical practitioners must remember that this extremely rapidly progressing type of diabetes does exist, and they must pay special attention not to overlook it. Thus, virally induced proinflammatory cytokines and chemokines can influence the ongoing autoaggressive process beneficially at the preclinical stage, if produced at the correct location, time, and levels. Miglitol treatment appears to be at least as efficacious in the African-American type 2 population as in the U.S. Since insulin is the only hormone that lowers blood glucose levels in the human body, depletion of insulin therefore results in marked hyperglycemia. Insulin also has antilipolytic effects, and thus its absence increases lipolysis and causes ketosis followed by ketoacidosis. While several viral infections have been associated with diabetes in northern countries (4–8), the incidence of both T1D and MS is reduced in equatorial countries, where microbial infections are more frequent (1–3, 9). According to the classification made by the American Diabetes Association and the World Health Organization,1,2 type 1 diabetes is further divided into two categories: autoimmune (type 1A) and idiopathic (type 1B) diabetes.
Type 1A diabetes is now believed to result from destruction of cells by autoreactive immunocytes; however, little is known even now about type 1B diabetes. For the last 5 years or so, accumulating evidence has indicated the presence of a new clinical entity—a very rapidly progressing form of type 1 diabetes.3,4,5 This form is now called ‘fulminant type 1 diabetes’, because the disease progresses very rapidly. It is well described that viral infections can enhance autoimmunity via bystander activation (18) or molecular mimicry (4–8, 19, 20). In this review we provide a comprehensive description of our current knowledge about this life-threatening disease. This novel clinical entity is extremely important for all physicians, especially clinical practitioners, because if it is disregarded or not caught, it quickly results in the death of the patient. Fulminant type 1 diabetes is defined as diabetes in which the process of -cell destruction and, therefore, progression of hyperglycemia and ketoacidosis are extremely rapid. First, we wished to examine whether viral infections could negatively influence an ongoing autoimmune process.
Without appropriate therapy, the death of the patient is inevitable, as in all other cases of type 1 diabetes. This rapid aggravation contrasts strikingly with the slow progression of type 1A diabetes, in which it takes at least several years from the initial appearance of autoantibodies in the peripheral blood to the clinical onset of (keto)acidosis (Figure 1). In our original study,3 we collected a group of patients with an extremely rapidly progressing diabetes without anti-GAD (glutamic acid decarboxylase) antibodies; however, when we collected many additional cases of extremely rapidly progressing diabetes in the following nationwide survey in Japan, a small proportion of such patients turned out to have anti-GAD antibodies, though in most of such cases the titer was low and the duration of positivity was short. The line used here offered the unique feature that clinical diabetes (>90% incidence) only develops 2 months after triggering of the autoimmune process with LCMV infection (24). In a hospital-based preliminary study of 5 years duration, the prevalence of fulminant type 1 diabetes was 19.6% (11 out of 56 patients who had type 1 diabetes with ketosis-onset or ketoacidosis-onset).3 A nationwide survey, conducted in Japan, followed and showed that the prevalence of this type of diabetes was 19.4% (43 out of 222 patients who had type 1diabetes with ketosis-onset or ketoacidosis-onset).5 In a regional, hospital-based study for diabetes in the Japanese region of Ehime, the prevalence of fulminant type 1 diabetes among acute-onset type 1 diabetic patients in whom insulin treatment was initiated within 3 months was 14.8% (9 out of 61).6 These lines of epidemiological evidence have confirmed that in Japan fulminant diabetes accounts for 15–20% of type 1 diabetes cases that feature the onset of ketosis or ketoacidosis. The onset age of fulminant type 1 diabetes ranges from 1 to 80 years old (Figure 2). The mean age of the patients at onset of the disease is 39.1 15.7 years (mean SD; Table 1).
In both models, we found that virally induced expression of IFN-γ–inducible protein 10 (IP-10, CXCL10) is higher in the pancreatic draining lymph node (PDLN) than in the islets. The white columns depict males and the gray columns depict females. The light gray bars show pregnant patients or those who recently gave birth. Adapted, with permission, from Hanafusa et al.16 Permission obtained from the Japan Diabetes Society © Hanafusa T et al. Mice were genotyped by PCR and Southern blotting as described by us previously (24). The proportions of male and female patients with fulminant type 1 diabetes are nearly the same: among 161 patients, 78 were female and 83 were male; however, female patients tend to develop fulminant diabetes at significantly younger ages than male patients—the age at onset in female patients is 35.1 15.8 years and that in males is 42.8 14.8 years (P = 0.0015). For the last 10 years, there seems to be a trend of an increase in the number of new-onset fulminant type 1 diabetes cases in Japan (Figure 3);16 however, this trend could be partly attributable to the increasing interest in this disease among doctors in Japan.
The apparent increase, therefore, does not seem to be significant. The viruses were plaque-purified three times on Vero cells, and stocks were prepared by a single passage on BHK-21 cells. Adapted, with permission, from Hanafusa et al.16 Permission obtained from the Japan Diabetes Society © Hanafusa T et al. (2005) J Japan Diab Soc 48 (Suppl 1): A1–A13. Fulminant type 1 diabetes develops most frequently in May, according to a nationwide survey of the disease in Japan (Figure 4). Total RNA was isolated from whole-pancreas homogenates using TRI Reagent (Molecular Research Center Inc., Cincinnati, Ohio, USA). At present the seasonal variation of fulminant diabetes is thus not considered significant.
Human leukocyte antigen (HLA) is a group of molecules encoded by the genes in the HLA complex (also called the MHC) in a region on a short arm of chromosome 6 in humans. Two main classes of HLA molecules are class I (HLA-A, -B, and -C) and class II (HLA-DR, -DQ, and -DP). The resulting analytical acrylamide gel was scanned using a Storm 860 PhosphorImaging system (Molecular Dynamics, Sunnyvale, California, USA), and the intensity of bands corresponding to protected mRNAs was quantified with ImageQuant image-analysis software (Molecular Dynamics) using L32 as a reference gene. HLA molecules play a critical role in immunological specificity; for example, presentation of antigens to the immune system, killing of antigen-bearing target cells by cytotoxic T lymphocytes, and rejection of transplanted tissues. Certain HLA types are known to associate with susceptibility or resistance to various autoimmune diseases including type 1A diabetes. This association is often utilized in exploring the strategies for prediction and prevention of the disease. The number of precursor CTLs (pCTLs) was determined according to the formula: pCTL = [4.6 – ln (% negative wells)]/number of splenocytes per well.
As a part of the nationwide survey, HLA-A, HLA-DR and HLA-DQ serotypes were investigated in 91 patients with fulminant diabetes and 81 patients with type 1A diabetes together with 190 normal controls.22 The distribution of HLA-A was not different between patients with fulminant or type 1A diabetes and controls. Regarding class II HLA, DR4–DQ4 was observed in 41.8% of patients and was significantly more frequent in patients with fulminant diabetes, whereas both DR2–DQ1 and DR8–DQ1 were less frequent. In type 1A diabetes, DR2–DQ1 was extremely rare, whereas DR9–DQ3 was significantly more frequent. (Burlingame, California, USA). These results suggest that the class II HLA genotype also contributes to the development of fulminant type 1 diabetes, but that the susceptibility or resistance of different HLA genotypes to type 1 diabetes is distinct between fulminant and typical type 1A diabetes. The HLA-DR4–DQ4 haplotype is common in Japanese people but rare in Caucasian populations, and this difference might contribute to the different incidence of fulminant diabetes between Japanese and Caucasian people. Insulitis—infiltration of lymphocytes and/or other immunocytes inside and/or around the pancreatic islet—was not a common feature in biopsy specimens of the pancreas in patients with fulminant type 1 diabetes a few months after onset.3,24 This was apparently different to the finding in patients with type 1A diabetes, in which insulitis is frequently seen;25,26 however, we (unpublished observation) and others27 have found insulitis in autopsy samples of the pancreas from patients with fulminant diabetes who died shortly after onset.
Briefly, TUNEL assay detects DNA strand breaks that are characteristic of the DNA fragmentation that occurs during apoptosis. Another interesting pathological feature in the pancreas of patients with fulminant type 1 diabetes is lymphocytic infiltration in the exocrine pancreas tissue.3 The infiltration by lymphocytes is in good accordance with the elevated serum level of exocrine pancreatic enzymes in these patients, as will be described later; however, neither massive infiltration of polymorphonucleocytes nor edema or bleeding in the exocrine pancreatic tissue is observed, indicating that the diagnosis of acute pancreatitis could not be made. There are some characteristic symptoms preceding the onset of fulminant type 1 diabetes. Table 2 shows the symptoms seen at or immediately before onset of the disease. MHC class I tetramers were generated using the immunodominant H-2Db–restricted LCMV peptides NP396-404 (FQPQNGQFI) and GP33-41 (KAVYNFATC) for refolding and biotin-protein ligase BirA (Avidity, Denver, Colorado, USA) for biotinylation of the refolded MHC-peptide complexes using previously described procedures (32, 33). This marked difference suggests the striking rapidity of the disease progression in fulminant type 1 diabetes. The most prevalent symptom around the onset of fulminant type 1 diabetes is thirst (93.7%); however, remarkable symptoms observed just before the onset of the disease are common-cold-like symptoms (71.7%) and abdominal symptoms (72.5%).
Among the common-cold-like symptoms, the most prevalent symptom is fever (60.0%), which is followed by sore throat (25.2%) and cough (12.0%). For assessment of apoptosis, LCMV-specific CD8 lymphocytes were gated for CD8hi and H-2Db-tetramerhi and then analyzed for annexin V binding. Disturbance in consciousness—ranging from slight drowsiness to deep coma—is seen nearly half (45.2%) of the patients with fulminant type 1 diabetes. Cardiopulmonary arrest was seen in one patient with fulminant type 1 diabetes in a series of nationwide surveys. It occurred within 24 h after the patient’s first visit to the general practitioner’s clinic. Hoffmann–La Roche Ltd., Basel, Switzerland) was given at 100 μg (i.v.) on days 1, 3, 6, and 9 after secondary (Past) infection, and neutralizing rat anti–mouse IFN-γ antibody (Pharmingen, San Diego, California, USA) was given at 50 μg (i.v.) on days 1, 3, 6, and 9 after secondary (Past) infection. The correct diagnosis of fulminant diabetes was confirmed after successful cardiopulmonary resuscitation.
The cause of cardiopulmonary arrest remains to be clarified; however, there are some case reports of fulminant type 1 diabetes associated with cardiac disorders, such as T-wave inversion, atrial fibrillation or cardiac arrest of unknown origin.28,29 The presence of such cases indicates the possibility that some patients with fulminant type 1 diabetes die from cardiac arrest during an acute phase, most probably within 24 h, of disease onset and that the death is not suspected to result from this type of diabetes. Table 3 summarizes the laboratory findings at onset of fulminant type 1 diabetes and compares them with those of type 1A diabetes. with 105 PFUs of LCMV-Arm to initiate T1D. Interestingly, in contrast to very high plasma glucose levels, the HbA1c level is almost normal at the onset of fulminant type 1 diabetes—it ranged from 4.7 to 8.4% (6.4 0.9%). This remarkable imbalance between very high plasma glucose level and near-normal HbA1c level could be explained by the very short length of the disease duration in fulminant type 1 diabetes; the HbA1c level reflects the average of plasma glucose levels during the preceding 1 to 2 months, so a very high plasma glucose level for only a few days as seen in fulminant type 1 diabetes is too short a time period for HbA1c to be elevated. The near-normal HbA1c level despite a very high plasma glucose level in patients with ketoacidosis is the key characteristic for diagnosis of fulminant type 1 diabetes, because both HbA1c and plasma glucose levels are almost invariably elevated at the onset of ketoacidosis in type 1A diabetes. injection of 105 PFUs of the autologous LCMV strain Armstrong (LCMV-Arm).
Arterial blood gas had a pH below 7.35 (acidosis) in more than 90% of the patients with this disease. Ketoacidosis is therefore usually seen at onset of this type of diabetes. Serum levels of exocrine pancreas enzymes (pancreas-type amylase, elastase-1 and lipase) are also almost invariably elevated at the onset of fulminant type 1 diabetes. Thus, one would have expected enhancement of disease. In most cases, abdominal CT scans and/or abdominal echograms show no evidence of pancreatic swelling, which is usually seen in acute pancreatitis. In some rare cases, however, swelling of the pancreas could be seen in CT scans and/or echograms before the onset of overt diabetes.30 These abnormalities resemble acute pancreatitis, but symptoms of exocrine dysfunction such as diarrhea or stools with elevated fat content are not long-standing, and increased serum pancreatic enzyme levels and swelling of the pancreas disappear after the treatment for diabetic ketoacidosis alone. Changes in the pancreas of patients with fulminant type 1 diabetes are therefore not like those in acute pancreatitis.
In contrast, infection with an NP escape variant that was described by us previously (36) induced a frequency that was below the detection limit of 1 in 20,000 NP396-specific pCTLs, resulting in no diabetes (Figure b). These changes are more severe than those in autoimmune type 1A diabetes, indicating the more-severe metabolic derangement in fulminant type 1 diabetes. More severe ketonemia, hyponatremia and hyperkalemia in fulminant type 1 diabetes could all be attributable to the greater degree of insulinopenia in this type of diabetes. Serum aspartate transaminase (AST) and alanine transaminase (ALT) levels are elevated in many patients at the onset of fulminant type 1 diabetes. Thus, we extended our observations to another diabetes model, in order to assess whether abrogation of disease could also occur in the absence of antigenic recognition. Autoantibodies against various constituents of pancreatic cells, for example ICA (islet cell antibodies), anti-GAD antibody, IAA (insulin autoantibody), and anti-IA-2 (islet-associated antigen 2), are usually undetectable even at the onset of disease. In exceptional cases of fulminant type 1 diabetes, however, anti-GAD antibodies are detected, usually at a low titer and sometimes transiently.32 The plasma C-peptide level is markedly decreased in patients with fulminant type 1 diabetes.
The C-peptide level is very low not only after fasting but also after stimulation with glucagons, indicating almost complete loss of pancreatic cells. One month after infection, mice were infected i.p. This issue will be discussed later in relation to pathogenesis. Criteria for screening and diagnosing fulminant type 1 diabetes are listed in Box 2.16 The screening criteria must be designed so as not to overlook patients with this disease. The criteria are important because, if they are met, treatment should be started immediately in order to save the patient’s life.