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.
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
The population-based, long-term epidemiological study of childhood type 1 diabetes in Japan, conducted by the Childhood IDDM Hokkaido Registry Study Group , reported that the incidence rates of ‘classic’ type 1 diabetes under 15 years ranged from 0.98 to 2.53 cases per 100,000 persons per year, and that the annual trend obviously increased over the 20-year period between 1973 and 1992, with an overall annual increase of 5.9%  (Table 1). The incidence was greatest among children of 10–14 years of age at onset (Table 1), as in most populations studied worldwide . The increase in Japan was mainly due to a rapid increase in the number of children aged 10–14 years, in contrast to countries with populations of Caucasoid origin (Fig. 1a). Accordingly, age at onset increased overall from a mean of 8.72 to 9.92 (Fig. 1b). A significant sex difference (female preponderance; F/M=1.4–1.5) and lack of geographical variation were also noted in Japan [22, 23]. The increase in the incidence of type 1 diabetes from 1973 to 1992 is almost certainly due to environmental factors. Matsuura and co-workers suggested that the year 1985, which had a high incidence of diabetes in their study, coincided with the 10-year time lag from the lowest breast-feeding rate in Japan, as reported in epidemiological studies from Norway and Sweden . In addition, there was an epidemic of Echo 7 in 1986 and of Coxsackie B3 in 1987, both of which could be linked to the higher incidence in that period . Recent data from the Ministry of Health, Labor, and Welfare, Government of Japan [25, 26] indicate that the incidence rate of ‘classic’ type 1 diabetes in patients aged 0–14 years appears to have remained constant over the past decade (1993–2001), averaging 2.37 cases per 100,000 persons per year (Table 1). The current estimate suggests that about 450 children under the age of 15 develop type 1 diabetes in Japan each year.
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
It has been reported that the genetic background of Japanese type 1 diabetes differs from that of Caucasians (Fig. 2). The high-risk class II HLA haplotype, HLA-DRB1*0301–DQA1*0501–DQB1*0201, found in patients of Caucasoid origin with type 1 diabetes, is extremely rare in the Japanese general population. However, DQB1*0201 is almost universally found in excess among patients with type 1 diabetes when compared to control subjects, even in Japan . The major susceptible haplotypes in Japanese ‘classical’ type 1 diabetes are DRB1*0405–DQA1*0301–DQB1*0401 and DRB1*0901–DQA1*0301–DQB1*0303. It has been reported that DQB1*0402, which differs by only one amino acid from the DQB1*0401 molecule and is relatively rare in the general population of Caucasoid origin, is a highly susceptible DQ allele in that ethnic group according to the transmission disequilibrium test . Furthermore, the HLA-DR2 haplotypes, DRB1*1501–DQA1*0102–DQB1*0602 and DRB1*1502–DQA1*0103–DQB1*0601, are negatively associated with type 1 diabetes in Japanese people. Although the latter haplotype is rare in people of Caucasoid origin and in Blacks, DRB1*1501–DQA1*0102–DQB1*0602 is also associated with disease protection in the former, and the similar DRB1*1503–DQA1*0102–DQB1*0602 is associated with resistance in Blacks , suggesting that DQA1*0102–DQB1*0602 is a primary protective molecule. This HLA-linked protection from type 1 diabetes is dominant over susceptibility, consistent with observations in the NOD mouse, in which one dose of non-NOD MHC provides strong protection against diabetes . Among Japanese patients with type 1 diabetes both DRB1*0405–DQB1*0401 and DRB1*0901–DQB1*0303 confer susceptibility to childhood–onset type 1 diabetes, whereas DRB1*0405– DQB1*0401 is the only susceptibility class II HLA haplotype in adult-onset type 1 diabetes , suggesting that DRB1*0901–DQB1*0303 may uniquely predispose to early clinical presentation. In contrast to the highest risk seen with the DRB1*0301/ *0401 or *0402 (with DQB1*0302) heterozygote in Caucasoid populations, the DRB1*0405/ *0901 heterozygote has no synergetic effect in the Japanese population, which can be explained by the trans complementation of the DQαβ heterodimer [43, 44].
Kawabata and co-workers recently reported an interesting association of genotypic combinations of Asian DRB1–DQB1 haplotypes with susceptibility to type 1 diabetes in Japanese and Koreans . Among the susceptible class II HLA in Japanese ‘classical’ type 1 diabetes, the odds ratios of homozygotes and heterozygotes with the DRB1*0405–DQB1*0401 haplotype were similar. In contrast, homozygotes, but not heterozygotes, with the DRB1*0901–DQB1*0303 haplotype were more frequent in people with type 1 diabetes. The genetic contribution of the DR4 and DR9 haplotypes thus differs depending on the genotypic combination of the haplotypes: the DRB1*0405–DQB1*0401 haplotype predisposes to type 1 diabetes in a dominant fashion, whereas DRB1*0901–DQB1*0303 predisposes in a recessive fashion. Interestingly, susceptibility to type 1 diabetes in DRB1*0901–DQB1*0303 homozygotes was also observed in the Korean population, where the HLA-DRB1*0301–DQB1*0201 haplotype is present in addition to Asian-specific DRB1*0405–DQB1*0401 and DRB1*0901–DQB1*0303 haplotypes (Fig. 2), indicating that the DRB1*0901–DQB1*0303 haplotype in itself confers susceptibility to type 1 diabetes in the absence of other susceptibility haplotypes (Table 2). These findings indicate that the Japanese population lacks the highly susceptible class II HLA haplotype of type 1 diabetes, and that the moderately susceptible DR–DQ haplotype may then surface as a major haplotype of the disease, consistent with the low incidence of type 1 diabetes in Japan.
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 [50–53] and people of Caucasoid origin [54–57]. 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 [62–66] 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].
Type 1B diabetes is probably a heterogeneous insulin-deficient form of diabetes not mediated by autoimmunity. It is well-known that several disorders other than type 1A diabetes lead to extensive pancreatic islet beta cell destruction including MODY1, MODY3, Wolfram’s syndrome, and mitochondrial diabetes . Indeed, we found that about 7% of Japanese patients with type 1B diabetes have mutations in the gene encoding hepatocyte nuclear factor 1α, which are the cause of MODY3 . These disorders often have characteristic inheritance patterns or extra-pancreatic disease manifestations. Imagawa and co-workers proposed that a group of Japanese patients that presented with diabetic ketoacidosis and a low HbA1c level had fulminant type 1 diabetes . Cases resembling fulminant type 1 diabetes were described in Japan as early as 1987 . Fulminant type 1 diabetes exhibits distinct clinical features from type 1A diabetes, and is characterised by: (1) remarkably rapid onset with diabetic ketoacidosis; (2) very short duration of diabetic symptoms; (3) male predominance; (4) onset mainly in adult life; (5) high frequency of ‘flu-like’ symptoms prior to onset; (6) permanent insulin dependence from diagnosis; (7) negative for islet-related autoantibodies; (8) elevated serum pancreatic enzyme levels; (9) lymphocytic infiltration in the exocrine pancreas; and (10) destruction of pancreatic alpha cells and beta cells. In women, pregnancy may also be a risk factor for fulminant type 1 diabetes. The nationwide multicentre study under the auspices of the Japan Diabetes Society suggested that this subtype accounts for approximately 20% of acute-onset type 1 diabetes presenting with ketosis or ketoacidosis . The text box shows the diagnostic criteria for fulminant type 1 diabetes currently established by the Committee for the study of fulminant type 1 diabetes.
|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.
- CTLA4 :
cytotoxic T-lymphocyte antigen-4
anti-glutamic acid decarboxylase antibodies
insulinoma associated antigen-2
islet cell antibodies
islet cell antigen 512
- PTPN22 :
protein tyrosine phosphatase, non-receptor type 22
single nucleotide polymorphism
Kawasaki E, Gill RG, Eisenbarth GS (1999) Type 1 diabetes mellitus. In: Eisenbarth GS (ed) Molecular mechanisms of endocrine and organ-specific autoimmunity. R.G. Landes, Austin, Texas, 149–182
Spielman RS, Baker L, Zmijewski CM (1980) Gene dosage and susceptibility to insulin dependent diabetes. Ann Hum Genet 44:135–150
Thomson G, Robinson WP, Kuhner MK et al (1988) Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet 43:799–816
Risch N (1987) Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet 40:1–14
Ikegami H, Ogihara T (1996) Genetics of insulin-dpendent diabetes mellitus. Endocr J 43:605–613
Molbak AG, Christau B, Marner B, Borch-Johnsen K, Nerup J (1994) Incidence of insulin-dependent diabetes mellitus in age groups over 30 years in Denmark. Diabet Med 11:650–655
Krolewski AS, Warram JH, Rand LI, Kahn CR (1987) Epidemiologic approach to the etiology of type I diabetes mellitus and its complications. N Engl J Med 317:1390–1398
Onkamo P, Vaananen S, Karvonen M, Tuomilehto J (1999) Worldwide increase in incidence of type I diabetes—the analysis of the data on published incidence trends. Diabetologia 42:1395–1403
Otani T, Yokoyama H, Higami Y, Kasahara T, Uchigata Y, Hirata Y (1990) Age of onset and type of Japanese younger diabetics in Tokyo. Diabetes Res Clin Pract 10:241–244
Kobayashi T, Itoh T, Kosaka K, Sato K, Tsuji K (1987) Time course of islet cell antibodies and b cell function in non-insulin dependent stage of type 1 diabetes. Diabetes 36:510–517
Tuomi T, Carlsson A, Li H et al (1999) Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48:150–157
Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y (2000) A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM study group. N Engl J Med 342:301–307
EURODIAB ACE Study Group (2000) Variation and trends in incidence of childhood diabetes in Europe. Lancet 355:873–876
Drykoningen CEM, Mulder ALM, Vaandrager GJ, LaPorte RE, Bruining GJ (1992) The incidence of male childhood type 1 (insulin-dependent) diabetes mellitus is rising rapidly in the Netherlands. Diabetologia 35:139–142
Gardner SG, Bingley PJ, Sawtell PA, Weeks S, Gale EA (1997) Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis. The Bart’s–Oxford study group. BMJ 315:713–717
Matsumoto H (1984) On the origin of the Japanese race: studies of genetic markers of the immunoglobulins. Proc Jpn Acad 60:211–226
Matsumoto H (1988) Characteristics of Mongoloid and neighboring populations based on the genetic markers of human immunoglobulins. Hum Genet 80:207–218
Matsuura N, Ko KW, Park YS, Elliott R (1996) Molecular epidemiology of IDDM in the Western Pacific Rim Region. WHO diamond molecular epidemiology sub-project group. Diabetes Res Clin Pract 34(Suppl):S117–S123
Dorman JS, McCarthy B, McCanlies E et al (1996) Molecular IDDM epidemiology: international studies. WHO diamond molecular epidemiology sub-project group. Diabetes Res Clin Pract 34(Suppl):S107–S116
Matsuura N, Fukuda K, Okuno A et al (1998) Descriptive epidemiology of IDDM in Hokkaido, Japan: the Childhood IDDM Hokkaido registry. Diabetes Care 21:1632–1636
Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J (2000) Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) project group. Diabetes Care 23:1516–1526
Japan IDDM Epidemiology Study Group (1993) Lack of regional variation in IDDM risk in Japan. Diabetes Care 16:796–800
Kida K, Mimura G, Ito T, Murakami K, Ashkenazi I, Laron Z (2000) Incidence of type 1 diabetes mellitus in children aged 0–14 in Japan, 1986–1990, including an analysis for seasonality of onset and month of birth: JDS study. The data committee for childhood diabetes of the Japan Diabetes Society (JDS). Diabet Med 17:59–63
Anonymous (1991) Annual report on findings of infectious agents in Japan. Jpn J Med Sci Biol 44:49–67
Okuno A (1998) Epidemiological study on child-onset diabetes in Hokkaido. In: Kosaka K (ed) Annual report of diabetes study group. Ministry of Health and Welfare, Government of Japan, Tokyo, pp 60–63
Matsuura N (2004) Study on epidemiology of diabetes. In: Kato T (ed) Report of study on registry, management, and evaluation of therapeutical research project on chronic and specific disease in childhood. Ministry of health, labour and welfare, government of Japan, Tokyo, pp 100–102
Tajima N, LaPorte RE, Hibi I, Kitagawa T, Fujita H, Drash AL (1985) A comparison of the epidemiology of youth-onset insulin-dependent diabetes mellitus between Japan and the United States (Allegheny County, Pennsylvania). Diabetes Care 8(Suppl 1):17–23
Feltbower RG, McKinney PA, Parslow RC, Stephenson CR, Bodansky HJ (2003) Type 1 diabetes in Yorkshire, UK: time trends in 0–14 and 15–29-year-olds, age at onset and age-period-cohort modelling. Diabet Med 20:437–441
Weets I, De Leeuw IH, Du Caju MV et al (2002) The incidence of type 1 diabetes in the age group 0–39 years has not increased in Antwerp (Belgium) between 1989 and 2000: evidence for earlier disease manifestation. Diabetes Care 25:840–846
Zimmet PZ, Tuomi T, Mackay IR et al (1994) Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med 11:299–303
Kawasaki E, Eisenbarth GS (2000) High-throughput radioassays for autoantibodies to recombinant autoantigens. Front Biosci 5:E181–E190
Abiru N, Takino H, Yano M et al (1996) Clinical evaluation of non-insulin-dependent diabetes mellitus patients with autoantibodies to glutamic acid decarboxylase. J Autoimmun 9:683–688
Takeda H, Kawasaki E, Shimizu I et al (2002) Clinical, autoimmune, and genetic characteristics of adult-onset diabetic patients with GAD autoantibodies in Japan (Ehime Study). Diabetes Care 25:995–1001
Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles WJ, Mackay IR (1993) Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes in adults with a non-insulin-dependent onset of diabetes. Diabetes 42:359–362
Park Y, Lee H, Koh CS et al (1996) Low prevalence of immunogenetic markers of IDDM in adult Koreans with diabetes detected on OGTT. Diabetes Res Clin Pract 34(Suppl):S37–S43
Data from the Annual Japanese Health and Welfare Statistics (monograph) (2002) Health and statistics association, ministry of health, Tokyo, Japan
Imagawa A, Hanafusa T, Uchigata Y et al (2003) Fulminant type 1 diabetes: a nationwide survey in Japan. Diabetes Care 26:2345–2352
Awata T, Kanazawa Y (1994) Genetic markers for insulin-dependent diabetes mellitus in Japanese. Diabetes Res Clin Pract 24(Suppl):S83–S87
Kawasaki E, Noble J, Erlich H, Mulgrew CL, Fain PR, Eisenbarth GS (1998) Transmission of DQ haplotypes to patients with type 1 diabetes. Diabetes 47:1971–1973
Heward JM, Mijovic CH, Kelly MA, Morrison E, Barnett AH (2002) HLA-DQ and DRB1 polymorphism and susceptibility to type 1 diabetes in Jamaica. Eur J Immunogenet 29:47–52
Slattery RM, Miller JF (1996) Influence of T lymphocytes and major histocompatibility complex class II genes on diabetes susceptibility in the NOD mouse. Curr Top Microbiol Immunol 206:51–66
Kawasaki E, Eguchi K (2004) Is type 1 diabetes in the Japanese population the same as among Caucasians? Ann NY Acad Sci 1037:96–103
Nepom BS, Schwartz D, Palmer JP, Nepom GT (1987) Transcomplementation of HLA genes in IDDM. Diabetes 36:114–117
Ronningen KS, Gjertsen HA, Iwe T, Spurkland A, Hansen T, Thorsby E (1991) Particular HLA–DQab heteodimer associated with IDDM susceptibility in both DR4–DQw4 Japanese and DR4–DQw8–DQw4 Whites. Diabetes 40:759–763
Kawabata Y, Ikegami H, Kawaguchi Y et al (2002) Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes. Diabetes 51:545–551
Kennedy GC, German MS, Rutter WJ (1995) The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat Genet 9:293–298
Guo D, Li M, Zhang Y et al (2004) A functional variant of SUMO4, a new IkBa modifier, is associated with type 1 diabetes. Nat Genet 36:837–841
Nistico L, Buzzetti R, Pritchard LE et al (1996) The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type I diabetes. Hum Mol Genet 5:1075–1080
Morahan G, Huang D, Ymer SI et al (2001) Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nat Genet 27:218–221
Awata T, Kurihara S, Kikuchi C et al (1997) Evidence for association between the class I subset of the insulin gene minisatellite (IDDM2 locus) and IDDM in the Japanese population. Diabetes 46:1637–1642
Abe T, Yamaguchi Y, Takino H et al (2001) CTLA4 gene polymorphism contributes to the mode of onset of diabetes with antiglutamic acid decarboxylase antibody in Japanese patients: genetic analysis of diabetic patients with antiglutamic acid decarboxylase antibody. Diabet Med 18:726–731
Ide A, Kawasaki E, Abiru N et al (2004) Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes. J Autoimmun 22:73–78
Kawabata Y, Ikegami H, Kawaguchi Y et al (2000) Age-related association of MHC class I chain-related gene A (MICA) with type 1 (insulin-dependent) diabetes mellitus. Hum Immunol 61:624–629
Bennett ST, Lucassen AM, Gough SC et al (1995) Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9:284–292
Marron MP, Raffel LJ, Garchon HJ et al (1997) Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. Hum Mol Genet 6:1275–1282
Kretowski A, Mironczuk K, Karpinska A et al (2002) Interleukin-18 promoter polymorphisms in type 1 diabetes. Diabetes 51:3347–3349
Gambelunghe G, Ghaderi M, Tortoioli C et al (2001) Two distinct MICA gene markers discriminate major autoimmune diabetes types. J Clin Endocrinol Metab 86:3754–3760
Pociot F, Veijola R, Johannesen J et al (1997) Analysis of an interferon-g gene (IFNG) polymorphism in Danish and Finnish insulin-dependent diabetes mellitus (IDDM) patients and control subjects. Danish study group of diabetes in childhood. J Interferon Cytokine Res 17:87–93
Vella A, Howson JM, Barratt BJ et al (2004) Lack of association of the Ala(45)Thr polymorphism and other common variants of the NeuroD gene with type 1 diabetes. Diabetes 53:1158–1161
Nejentsev S, Cooper JD, Godfrey L et al (2004) Analysis of the vitamin D receptor gene sequence variants in type 1 diabetes. Diabetes 53:2709–2712
Zavattari P, Deidda E, Pitzalis M et al (2004) No association between variation of the FOXP3 gene and common type 1 diabetes in the Sardinian population. Diabetes 53:1911–1914
Bottini N, Musumeci L, Alonso A et al (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36:337–338
Begovich AB, Carlton VE, Honigberg LA et al (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75:330–337
Kyogoku C, Langefeld CD, Ortmann WA et al (2004) Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 75:504–507
Velaga MR, Wilson V, Jennings CE et al (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab 89:5862–5865
Smyth D, Cooper JD, Collins JE et al (2004) Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53:3020–3023
Kawasaki E, Awata T, Ikegami H et al (2006) Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations. Am J Med Genet 140A:586–593
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1997) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183–1197
Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553
Sera Y, Kawasaki E, Abiru N et al (1999) Autoantibodies to multiple islet autoantigens in patients with abrupt onset type 1 diabetes and diabetes diagnosed with urinary glucose screening. J Autoimmun 13:257–265
Banerji MA, Chaiken RL, Huey H et al (1994) GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of human leukocyte antigen DR3 and DR4. Flatbush diabetes. Diabetes 43:741–745
Pinero-Pilona A, Litonjua P, Aviles-Santa L, Raskin P (2001) Idiopathic type 1 diabetes in Dallas, Texas: a 5-year experience. Diabetes Care 24:1014–1018
Kawasaki E, Sera Y, Yamakawa K et al (2000) Identification and functional analysis of mutations in the hepatocyte nuclear factor-1a gene in anti-islet autoantibody-negative Japanese patients with type 1 diabetes. J Clin Endocrinol Metab 85:331–335
Wakisaka M, Nunoi K, Wada M et al (1987) Two cases of abrupt onset type 1 diabetes associated with elevation of elastase 1 and diabetic ketoacidosis. J Jpn Diab Soc 30:619–624
Imagawa A, Hanafusa T, Uchigata Y et al (2005) Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus. Diabetologia 48:294–300
Kotani R, Nagata M, Imagawa A et al (2004) T lymphocyte response against pancreatic beta cell antigens in fulminant type 1 diabetes. Diabetologia 47:1285–1291
Tanaka S, Kobayashi T, Momotsu T (2000) A novel subtype of type 1 diabetes mellitus. N Engl J Med 342:1835–1837
Park YS, She JX, Noble JA, Erlich HA, Eisenbarth GS (2001) Transracial evidence for the influence of the homologous HLA DR–DQ haplotype on transmission of HLA DR4 haplotypes to diabetic children. Tissue Antigens 57:185–191
Urakami T, Miyamoto Y, Fujita H, Kitagawa T (1989) Type I (insulin-dependent) diabetes in Japanese children is not a uniform disease. Diabetologia 32:312–315
Kawasaki E, Eguch K (2005) Molecular genetics and epidemiology of Japanese type 1 diabetes. Curr Pharmacogenomics 3:191–199
Pozzilli P, Visalli N, Leslie D (2000) No evidence of rapid onset (Japanese) type I diabetes in Caucasian patients. IMDIAB Group. Diabetologia 43:1332
Sekine N, Motokura T, Oki T et al (2001) Rapid loss of insulin secretion in a patient with fulminant type 1 diabetes mellitus and carbamazepine hypersensitivity syndrome. JAMA 285:1153–1154
Nagaoka T, Terada M, Miyakoshi H (2001) Insulin-dependent diabetes mellitus following acute pancreatitis caused by herpes simplex virus: a case report. J Jpn Diab Soc 44:335–340
Imagawa A, Hanafusa T, Makino H, Miyagawa JI, Juto P (2005) High titres of IgA antibodies to enterovirus in fulminant type-1 diabetes. Diabetologia 48:290–293
Kawasaki E, Eguchi K (2004) Is type 1 diabetes in the Japanese population the same as among Caucasians? Ann NY Acad Sci 1037:96–103
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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Kawasaki, E., Matsuura, N. & Eguchi, K. Type 1 diabetes in Japan. Diabetologia 49, 828 (2006). https://doi.org/10.1007/s00125-006-0213-8
- Type 1 diabetes