Type 1 diabetes in Japan
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Type 1 diabetes is a multifactorial disease which results from a T-cell-mediated autoimmune destruction of the pancreatic beta cells in genetically predisposed individuals. The risk for individuals of developing type 1 diabetes varies remarkably according to country of residence and race. Japan has one of the lowest incidence rates of type 1 diabetes in the world, and recognises at least three subtypes of the condition: acute-onset (‘classical’), slow-onset, and fulminant type 1 diabetes. The incidence rate of type 1 diabetes in children aged 0–14 years in Japan increased over the period from 1973–1992, but remained constant over the last decade, averaging 2.37 cases per 100,000 persons per year; the incidence does not appear to have increased in older age groups. Although there are few reports regarding the incidence and prevalence of type 1 diabetes in adult-onset patients, it appears that the prevalence of type 1 diabetes in adults is more than twice that in childhood-onset patients and that two-thirds of them have a slow-onset form of type 1 diabetes. Differences and similarities in the association of MHC and non-MHC genes with type 1 diabetes are observed in Japan and in countries with Caucasoid populations. Highly susceptible class II HLA haplotypes identified in patients of Caucasoid origin are rarely seen in Japanese patients, whereas protective haplotypes are universal. Non-MHC genes associated with susceptibility to type 1 diabetes in both Japanese and Caucasoid patients include polymorphisms in the insulin gene, the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene, the interleukin-18 (IL18) gene and the major histocompatibility complex class I chain-related gene A (MICA) gene. Fulminant type 1 diabetes is a unique subtype of type 1 diabetes that accounts for about 20% of acute-onset type 1 diabetes, and is seen mainly in adults. The challenge for the future is to investigate the underlying pathogenesis of beta cell destruction, including the genetic or environmental factors that may modify the form of onset for each subtype of Japanese type 1 diabetes.
KeywordsAdult Epidemiology Fulminant Genetics HLA Japanese Non-HLA Type 1 diabetes
cytotoxic T-lymphocyte antigen-4
anti-glutamic acid decarboxylase antibodies
insulinoma associated antigen-2
islet cell antibodies
islet cell antigen 512
protein tyrosine phosphatase, non-receptor type 22
single nucleotide polymorphism
Type 1 diabetes is an organ-specific autoimmune disease characterised by T-cell-mediated destruction of pancreatic beta cells, resulting in absolute dependence on insulin for survival and maintenance of health . Approximately 90% of cases are sporadic, occurring in individuals with no family history of type 1 diabetes. However, first-degree relatives of patients with type 1 diabetes are at increased risk compared to the general population. In Caucasians, the risk of type 1 diabetes in the general population is 0.4% by age 30  and the risk for siblings of affected individuals is about 6% . Thus λs, the ratio of the risk for siblings of type 1 diabetic patients and the risk in the general population, is approximately 15 in Caucasoid populations . In contrast, λs for type 1 diabetes in Japan is estimated to be more than 250 (3.8 vs 0.014%), much higher than that in Caucasoid populations . The reason why the incidence rate of type 1 diabetes is so low in Asian countries, including Japan, is largely unknown.
Type 1 diabetes has traditionally been considered a disease of childhood, but more recent epidemiological studies have indicated that the incidence is comparable in adults . The age-specific incidence rate of type 1 diabetes shows a bimodal distribution. The first peak of incidence rate in patients of Caucasoid origin is at puberty and the second peak after the age of 40 . Furthermore, it has been reported that incidence rates of type 1 diabetes in children are increasing rapidly in many countries . The incidence of type 1 diabetes in the Japanese population peaks twice: once around the age of four (the first peak) and again at puberty (the second peak), both of which are different from peaks in patients of Caucasoid origin . The development of techniques for high-throughput testing of autoantibodies to a series of islet autoantigens has made it possible to diagnose a subgroup of type 1 diabetes in adulthood, termed slowly progressive type 1 diabetes or latent autoimmune diabetes in adults [10, 11]; this subgroup is often misdiagnosed as type 2 diabetes. There may therefore be more patients with type 1 diabetes in adulthood than previously considered. In addition to acute-onset and slow-onset of type 1 diabetes, a new subtype has recently been described in Japan, known as ‘fulminant type 1 diabetes’ . In this paper we review recent research findings on the epidemiology and immunogenetics of type 1 diabetes in Japan, and consider their similarity and differences as compared to those in Caucasoid populations.
Epidemiology of type 1 diabetes in Japan
Several reports have indicated a rapid increase in the incidence of childhood type 1 diabetes worldwide with a rapid rate of increase in children <5 years of age [8, 13]. The most striking increase has been observed in Finland, which has the highest incidence of type 1 diabetes in the world with a rate in excess of 40 cases per year per 100,000 individuals . In the United States and Western Europe, the current incidence rate for type 1 diabetes is second only to that of bronchial asthma in terms of the severe chronic diseases of childhood. Several European countries such as the United Kingdom and Finland have experienced more than a doubling in incidence of ‘classical’ type 1 diabetes over the past three decades [14, 15]. In contrast, Asian countries including Japan, Korea and China have a low incidence. Because the Japanese are a genetically homogeneous population [16, 17], geo-ethnic variation in type 1 diabetes risk probably reflects differences in the frequencies of modifier genes (susceptibility or protective) or environmental factors (causative or protective) or some combination thereof [18, 19]. It was reported that monozygotic twins and first degree relatives of patients with type 1 diabetes in Japan had a similar risk of diabetes to twins and relatives of patients in the United States , suggesting that most of the between-country variation in diabetes risk might relate to genetic differences rather than environmental factors.
Childhood type 1 diabetes
Incidence rates per 100,000 person-years of type 1 diabetes for ages 0–14 in Japanese population
In Japan, there are two population-based systems to detect childhood diabetes which developed during the mid-1970s; a central registry for free medical care for diabetic subjects under 18 years of age, and urine glucose screening for schoolchildren . In 1994, a revision of the school health law made urine glucose screening mandatory for all elementary, middle and high school students in Japan. Although more than two-thirds of cases with positive urine glucose testing prove to have type 2 diabetes, patients with type 1 diabetes whose clinical manifestations are mild and progress slowly to insulin dependence (slow-onset form of type 1 diabetes) can be identified at the stage of mild hyperglycaemia by this screening. An estimated 10% of children with type 1 diabetes fall into this subgroup. In 1996, the overall number of diabetic children registered in this system was 6,509, of whom about 85% were considered to have type 1 diabetes, indicating that the total number and prevalence of type 1 diabetic children can be estimated to be about 5,500 and 22.5 cases per 100,000 individuals, respectively.
Adult onset type 1 diabetes
Although most diabetes registries have studied disease incidence under age 15 years, around half of new-onset patients with ‘classical’ type 1 diabetes are diagnosed in adult life [28, 29]. The heterogeneity of diabetes increases with age, and it becomes more difficult to diagnose type 1 diabetes. A significant number of patients, particularly adults, presenting to their physician with what appears to be non-insulin-requiring diabetes are at an early stage of type 1 diabetes . Currently, there are no reports regarding the incidence of adult type 1 diabetes in Japan, and few prevalence studies have been published, mainly because of the difficulty of distinguishing the slow-onset form of type 1 diabetes from insulin-requiring type 2 diabetes in older individuals. However, better diagnosis is now possible because of the availability of autoantibody assays with high sensitivity and specificity [30, 31]. In our cross-sectional study, autoantibodies to GAD (GADAb) were detected in 3.8% of Japanese diabetic patients who had been treated with diet or oral hypoglycaemic agents for more than half a year after the onset of diabetes. Furthermore, 1.5% were both GADAb-positive and insulin-deficient . Takeda and co-workers found a similar prevalence of GADAb in a larger population-based study, which analysed 4,980 patients with adult-onset diabetes aged >20 years . The prevalence of GADAb in such patients is lower than that in patients of Caucasoid origin and with an initial diagnosis of type 2 diabetes , suggesting that Asian adults have a lower incidence of type 1 diabetes than Caucasoid populations . Results of a survey in 2002  estimated the number of adults with diabetes in Japan at 7.4 million. If our results are applied to this figure, the number of insulin-deficient patients with GADAb who were initially diagnosed as having type 2 diabetes would be about 110,000. However, this could be an overestimate, given that the mean age of insulin-deficient patients with GADAb was about 45 years, and that only 0.9 million patients with type 2 diabetes are under 50 years. Therefore, the number of adults with slow-onset type 1 diabetes can be estimated at about 15,000–20,000, or around two-thirds of adult type 1 diabetic patients. A nationwide registry is needed to evaluate the true incidence and prevalence of adult-onset type 1 diabetes in Japan.
Another subtype of adult type 1 diabetes in Japan is fulminant type 1 diabetes . It is not clear whether this type of diabetes is unique to the Japanese population. A nationwide multicentre study under the auspices of the Japan Diabetes Society has indicated that this subtype accounts for approximately 20% of abrupt-onset type 1 diabetes . The clinical and immunogenetic features of fulminant type 1 diabetes are described later.
Immunogenetic differences between ‘classical’ type 1 diabetes in Japan and in the West
Different contribution of HLA-DRB1*0405 and DRB1* 0901 haplotypes to Japanese or Korean type 1 diabetes
Autoimmune type 1 diabetes is a polygenic disorder, and it seems clear that more than one genetic syndrome can cause autoimmune beta cell destruction. Among the genetic factors associated with type 1 diabetes, approximately 50% of the risk is attributable to the HLA region. The much higher rate of concordance in monozygotic twins of patients than HLA-identical siblings indicates that in addition to genes in the HLA region, other genes are involved in genetic susceptibility to type 1 diabetes. Although more than 20 putative non-MHC chromosomal regions have been implicated in disease risk, only a few with known function have been identified, including IDDM2 (insulin gene) , IDDM5 (small ubiquitin-like modifier 4 [SUMO4] gene) , IDDM12 (cytotoxic T-lymphocyte antigen-4 [CTLA4] gene) , and IDDM18 (IL12B gene) . We and others reported the association between non-MHC genes and susceptibility to or heterogeneity of Japanese type 1 diabetes. The insulin gene hypervariable region (chr. 11p15), CTLA4 gene polymorphism (chr. 2q33), IL18 gene polymorphism (chr. 11q22), and the major histocompatibility complex class I chain-related gene A (MICA) microsatellite polymorphism (chr. 6q21) are associated with type 1 diabetes susceptibility in both Japanese [50, 51, 52, 53] and people of Caucasoid origin [54, 55, 56, 57]. However, several genes have been reported to be susceptibility genes in Japanese, but not in Caucasoid populations, including the genes encoding IFN-γ , NeuroD , vitamin D receptor , and forkhead box 3 . These discrepancies may be caused by differences in the contribution to disease development of each gene, depending on ethnic group, or by the possible presence of another functional variant in linkage disequilibrium with certain polymorphisms.
Recently, a missense SNP at nucleotide 1858 in codon 620 (R620W) of protein tyrosine phosphatase gene (PTPN22), located on chromosome 1p13.3–p13.1, has been reported to be associated with multiple autoimmune diseases including type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, Graves’ disease, and Addison’s disease [62, 63, 64, 65, 66] in Caucasoid populations, implying that the lymphoid phosphatase (Lyp) encoded by PTPN22 is a critical player in multiple autoimmune disorders. Lyp is expressed in lymphocytes and binds to cytoplasmic tyrosine kinase, Cas–Br–M murine ecotopic enteroviral transforming sequence, and growth factor receptor-bound protein 2, which mediate T cell receptor signalling. Furthermore, Lyp is among the most powerful inhibitors of T cell activation, a task accomplished by dephosphorylation of such molecules. However, we found that this locus was monomorphic in the Japanese population, and that the association was stronger in the promoter SNP than in R620W SNP even in multiplex families of white European origin . These ethnic differences may be associated with susceptibility to or clinical outcomes of type 1 diabetes, and it will be necessary to investigate by biological analysis the mechanisms by which the variants produce disease susceptibility, as well as to investigate the origin of the variants by genetic dissection.
Fulminant type 1 diabetes
According to the current classification of diabetes by the American Diabetes Association Expert Committee and the WHO Consultation, type 1 diabetes can be divided into two subtypes, immune-mediated (type 1A) diabetes and idiopathic (type 1B) diabetes [68, 69]. Type 1B diabetes is defined as diabetes not associated with immunological evidence of beta cell autoimmunity but for which insulin therapy is required for survival. We have screened autoantibodies to multiple islet antigens, including GAD, islet cell antigen 512 (ICA512)/insulinoma-associated antigen-2 (IA-2) and insulin, as well as islet cell antibodies (ICA) in Japanese patients at onset of type 1 diabetes. Our study indicated that about 10% of Japanese patients with type 1 diabetes have type 1B diabetes without expression of any autoantibodies . Furthermore, these patients had different clinical characteristics from African American or North American patients with idiopathic type 1 diabetes, some of whom, in fact, have type 2 diabetes [71, 72].
Diagnostic criteria for fulminanat type 1 diabetes
1. Occurrence of diabetic ketosis or keoacidosis soon after (around 7 days) the onset of hyperglycaemic symptoms (elevation of urinary ketone or serum ketone at onset)
2. Plasma glucose > 16.0 mmol/l and HbA1c level < 8.5% at onset
Urinary C-peptide excretion < 10 μg/day
Fasting serum C-peptide < 0.1 nmol/l and serum C-peptide < 0.17 nmol/l after i.v. glucagon or meal load
From the Committee on the Study of Fulminant Type 1 Diabetes, Japan Diabetes Society 
The underlying pathogenesis is largely unknown. Class II HLA may contribute to the development of fulminant type 1 diabetes, but if so, susceptible and resistant HLA subtypes differ from those found in type 1A diabetes . Thus, of the type 1A diabetes susceptibility haplotypes, DRB1*0405–DQB1*0401 and DRB1*0901–DQB1*0303, only the former is a susceptibility haplotype in fulminant type 1 diabetes. In addition, DRB1*1502–DQB1*0601 or DRB1*1501–DQB1*0602, two major protective haplotypes in Japanese type 1A diabetes, are not protective in fulminant type 1 diabetes.
It has recently been reported that GAD-reactive or insulin-B9-23-reactive Th1 cells were identified in peripheral blood lymphocyte from patients with fulminant type 1 diabetes . Furthermore, insulitis has also been reported following autopsy of a fatal case of fulminant type 1 diabetes . These findings suggest that the aetiology of fulminant type 1 diabetes might be heterogeneous and in part autoimmune. The mechanism of beta cell destruction in fulminant type 1 diabetes requires further investigation.
Although the incidence and prevalence of type 1 diabetes are much lower in Japan than in countries with Caucasoid populations, the recurrence risk in siblings of patients with type 1 diabetes is much higher, indicating that in Japanese people type 1 diabetes clusters in families. If genetic factors are responsible for the high λs value for type 1 diabetes in a low-prevalence population such as the Japanese, susceptibility genes whose frequencies are very low in the general population may be segregating in type 1 diabetes families. It is, however, also possible that some environmental factors common to type 1 diabetic families are responsible for the high λs value for type 1 diabetes in Japan.
In has been suggested that, in Asian populations, the protective HLA-DR4 (DRB1*0403 or *0406) is associated with the susceptible DQ allele (DQB1*0302) encountered in Caucasoid populations, while the neutral/protective DQ allele (DQB1*0401) is associated with the susceptible DR4 allele (DRB1*0401, *0402, *0405) . This counterbalancing between susceptible DRB1 and protective DQB1, and vice versa, might be an important contributory factor to the low incidence of type 1 diabetes in the Japanese population.
Clinical features of Japanese type 1 diabetes are heterogeneous in terms of age at onset, mode of onset, and aetiology. However, the prevalence and expression of a series of anti-islet autoantibodies are comparable to those in patients of Caucasoid origin , indicating that the humoral immune responses to islet antigens in Japanese patients are similar to those in patients of Caucasoid origin. There are at least three subtypes of type 1 diabetes in Japan, acute-onset ‘classical’, slow-onset, and fulminant type 1 diabetes. In childhood type 1 diabetes, about 90% have the ‘classical’ form, and the remainder belong to the slow-onset form, with minimal or no clinical symptoms of diabetes at disease onset. The slow-onset form of type 1 diabetes in children is detected by urine glucose screening at school, and affects 1/20,000 school children . It is further estimated that <1% of patients with childhood-onset type 1 diabetes have fulminant type 1 diabetes . In contrast, about two-thirds of adult patients have the slow-onset form, and about 20% of those with acute-onset type 1 diabetes fall into the category of fulminant type 1 diabetes. The different proportions of each subtype in childhood-onset and adult-onset type 1 diabetes may be influenced by MHC and non-MHC genes affecting the age of onset .
Fulminant type 1 diabetes is a subtype that is distinct from type 1A diabetes in terms of clinical features, genetic background, and (probably) mechanisms of beta cell destruction. It is currently unknown how far this is unique to the Japanese population, but a few cases have been reported from Western countries [72, 81]. The underlying pathogenesis remains unclear, although the high frequency of ‘flu-like’ symptoms just before the onset of fulminant type 1 diabetes suggest that it might be associated with viral infection. Two case reports have described fulminant type 1 diabetes developing after the reactivation of human herpes virus-6 or infection with the herpes simplex virus [82, 83]. Elevation of IgA antibodies to enterovirus has also been observed in patients with fulminant type 1 diabetes , suggesting that recurrent enterovirus infection may be one of the triggers for the development of fulminant type 1 diabetes.
The challenge for the future is to identify all the MHC and non-MHC genes or environmental factors involved in the pathogenesis of beta cell destruction for each subtype of Japanese type 1 diabetes. Furthermore, the elucidation of their pathogenic roles should facilitate the development of rational therapies for the prevention of type 1 diabetes.
This work was supported in part by a grant-in-aid from the Ministry of Education, Culture, Science, Sports and Technology of Japan and from the Japan Diabetes Foundation. We thank H. Ikegami, T. Hanafusa, and H. Makino for helpful discussions and suggestions.
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