Absence of shared HLA class II (DR, DQ)-linked genetic basis between IDDM and autoimmune thyroid disease in Japanese.
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Diabetes Mellitus, Type 1↗
Biomedical subjects
Y Uchigata
Publications and source records attributed to Y Uchigata.
A novel concept of type VII hypersensitivity introduced by insulin autoimmune syndrome (Hirata's disease)
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Autoimmune Diseases↗
Development of proliferative retinopathy in Japanese patients with IDDM: Tokyo Women's Medical College Epidemiologic Study.
We studied the development of proliferative diabetic retinopathy (PDR) in Japanese insulin-dependent diabetes mellitus (IDDM). Subjects were 373 patients who were diagnosed as IDDM between 1951 and 1984, before the age of 30 years, and had no PDR at the first visit to the Diabetes Center. Development of PDR was analyzed by Kaplan-Meier's life-table method in relation to the duration of IDDM. The cumulative incidence of PDR was 20% at 15 years of duration of IDDM, 40% at 19 years, and 70% at 29 years. Female patients (n = 233) developed PDR significantly faster than males (n = 140) (P < 0.002). In both sexes, patients with onset of IDDM at 0-8 years showed significantly slower development than patients with the onset at 9-17 (P < 0.0001) and 18-29 years (P < 0.001). Impact of femaleness on the development was the greatest in patients with age at onset of IDDM at 9-17 years (P < 0.005). Analysis according to the calendar year at onset of IDDM and diabetes duration at the first visit to the Diabetes Center did not show any significant influence on the development of PDR. In conclusion, sex and age at onset of IDDM may be associated with increased risk for the development of PDR in relation to the duration of diabetes in Japanese IDDM.
Adolescent↗
Insulin autoimmune syndrome (Hirata disease): clinical features and epidemiology in Japan.
Since Hirata et al. first reported a patient with insulin autoimmune syndrome in 1970, 197 cases have been reported in Japan as of December, 1992. The clinical profiles of these 197 cases were as follows; the peak age at onset was 60-69 years and peak duration of hypoglycemic attacks was more than 1 and less than 3 months. There was no gender difference in the peak age of onset or duration of hypoglycemic attacks. Approximately 82% of the IAS patients had spontaneous remission without any positive treatment. Before diagnosis of IAS, 43% of the patients with IAS had been taking medication; methimazole (MTZ) for Graves' disease, alpha-mercaptopropionyl glycine (MPG) for cataracts, liver disease or rheumatoid arthritis, or glutathione for liver disease, all of which are sulfhydryl compounds. After such sulfhydryl compounds were discontinued, the hypoglycemic attacks subsided. Three patients with IAS experienced recurrence of the hypoglycemic attacks after re-administration of MTZ and MPG, although 6 patients who developed IAS without exposure to any drug had recurrent attacks without exposure to any drug around 1 year after the first hypoglycemic attacks had stopped. Thus, hypoglycemia in IAS is mainly transient and the development of IAS may be related to sulfhydryl compounds.
Age Factors↗
Insulin autoimmune syndrome in Japan.
Since 1970, 197 patients with insulin autoimmune syndrome (IAS) showing severe spontaneous hypoglycemia have been reported in Japan. This is characterized by a high titer of anti-insulin autoantibodies without evidence of exogenous insulin administration. IAS is the third leading cause of spontaneous hypoglycemia in Japan, while only 21 cases have been reported in Europe and the United States. High levels of the extractable native human insulin and of the characteristic insulin autoantibodies in the sera of the IAS patients have been proved. Recently a significant association of HLA-DRB1*0406/DQA1*0301/DQB1*0302 with this syndrome has been found in the IAS patients in Japan.
Adolescent↗
Longitudinal changes of serum insulin concentration and insulin antibody features in persistent insulin autoimmune syndrome (Hirata's disease).
In a 56-year-old woman with granulomas of gold thioglucose in her hips, who developed insulin autoimmune syndrome, the relationships among the frequency or severity of hypoglycemic attacks, serum insulin (IRI) concentration, and characteristics of insulin antibodies were investigated during the clinical course with steroid treatment and two resection operations for the gold-thioglucose granulomas. When hypoglycemia was severe, the total IRI level was elevated, and Scatchard analysis showed that a high-affinity (k1), low-capacity (b1) population of antibodies had a relatively low affinity constant and very high binding capacity compared with the same population of antibodies in insulin-treated diabetic patients. When the attacks were relieved by steroid treatment and/or granuloma resection operation, the total IRI level was decreased and the high-affinity (k1), low-capacity (b1) population of antibodies showed a higher affinity constant and a lower binding capacity than those during the attacks. This indicated that the antibodies changed their characteristics to release insulin into the serum. The k1/b1 population of insulin antibodies with the lower affinity constant and higher binding capacity may easily release human insulin into the serum, leading to hypoglycemia. The longitudinal change of the k1/b1 population suggests a clonal change of the B cells producing the insulin antibody in insulin autoimmune syndrome.
Aurothioglucose↗
Recognition of human insulin in the context of HLA-DRB1*0406 products by T cells of insulin autoimmune syndrome patients and healthy donors.
Our recent study indicated that all the insulin autoimmune syndrome (IAS) patients had specific HLA class II alleles, the DRB1*0406, DQA1*0301, and DQB1*0302, which allowed T cells to proliferate when autologous APC were exposed to human insulin. The study implied that gene products of DRB1*0406, DQA1*0301, and/or DQB1*0302 may be involved in the presentation of human insulin to T cells. We therefore examined T cell response of healthy donors with different HLA phenotypes to human insulin using an autologous MLR system. The T cells from not only IAS patients but also healthy donors were able to proliferate after exposure of human insulin to autologous APC with DRB1*0406, DQA1*0301, and DQB1*0302 products. The class II molecules are considered to be involved in the recognition of human insulin by T cells. The proliferative response of T cells was completely blocked by anti-HLA-DR mAb and not by anti-HLA-DQ mAb or other mAb. Furthermore, human insulin-specific CD4-positive T cell clones were established from blast cells in autologous MLR of PBMC from two healthy donors with DRB1*0406 in the presence of human insulin. Using DRB1*0406-transfected L cells as APC, we confirmed that these T cells clones recognize human insulin in the context of gene products of DRB1*0406. These results provide the first evidence that HLA-DRB1*0406 products act as the dominant restriction element for the presentation of human insulin to T cells, and suggest that this particular class II gene, HLA-DRB1*0406, contributes to the development of IAS.
Antibodies, Monoclonal↗
Patients with Graves' disease who developed insulin autoimmune syndrome (Hirata disease) possess HLA-Bw62/Cw4/DR4 carrying DRB1*0406.
The insulin autoimmune syndrome (IAS) is characterized by the following diagnostic criteria: severe spontaneous hypoglycemia without evidence of exogenous insulin administration, high levels of total serum immunoreactive insulin, and the presence of a high titer of antiinsulin antibody. Just before the onset of IAS, 13 of the 35 (37%) patients with IAS examined in this study had taken methimazole for the treatment of Graves' disease. To investigate the difference between the Graves' disease patients treated with methimazole who developed IAS and other IAS patients, HLA class II genes in both groups were analyzed by serological and DNA typing methods. All 13 patients with Graves' disease who developed IAS possessed a specific allelic combination, Bw62/Cw4/DR4 carrying DRB1*0406, whereas only 1 of 50 Graves' disease patients without IAS had Bw62/Cw4/DR4 (odds ratio, 891; P < 1 x 10(-10)) and carried not DRB1*0406 (odds ratio, 2727; P < 1 x 10(-10)), but DRB1*0405. Of the 22 IAS patients without Graves' disease, 13 had the combination Bw62/Cw4/DR4 carrying DRB1*0406 (odds ratio, 19.0; P < 0.07). Thus, it is highly likely that patients with Graves' disease develop IAS via treatment with methimazole when their Bw62/Cw4/DR4 carry DRB1*0406.
Adolescent↗
HLA-DR4 genotype and insulin-processing in insulin autoimmune syndrome.
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Antigen-Presenting Cells↗
Strong association of insulin autoimmune syndrome with HLA-DR4.
Insulin autoimmune syndrome is characterised by spontaneous hypoglycaemia without evidence of exogenous insulin administration, a high serum concentration of total immunoreactive insulin, and the presence of insulin autoantibodies in high titre. HLA typing of 27 patients with insulin autoimmune syndrome showed that all had DR4, which was present in only 43% of 51 healthy controls (odds ratio 72.1, p less than 2 x 10(-6), and 19 (70%) of the patients were positive for the allelic combination, Cw4, Bw62, and DR4. Analysis of the nucleotide sequences of the DRB1, DQA1, and DQB1 genes showed that all the patients had DRB1*0406, DQA1*0301, and DQB1*0302, compared with only 14% of the controls (odds ratio 281, p less than 1 x 10(-10). We conclude that the development of insulin autoimmune syndrome is associated with a strong genetic predisposition.
Adult↗
Human insulin-specific immunoglobulin G antibody and hypoglycemic attacks after the injection of gold thioglucose.
A 56-year-old woman with granulomas of gold thioglucose in her hips exhibited recurrent bouts of hypoglycemic attacks. The first attack occurred 2 years after the last injection of gold thioglucose, when large amounts of extractable insulin and human insulin-specific antibody were noted in her serum. Histological examination of the resected granulomas showed marked infiltration of lymphocytes, plasma cells, and macrophages containing yellowish-brown granules, which proved to be gold by electron microscopy using X-ray microanalysis. After resection of the granuloma, however, the frequency of the hypoglycemic attacks decreased remarkably as well as the levels of both extractable insulin and human insulin-specific antibody.
Antibody Specificity↗
An investigation of Japanese subjects maps susceptibility to type 1 (insulin-dependent) diabetes mellitus close to the DQA1 gene.
Insulin-dependent diabetic and control subjects of Japanese origin were HLA-DRB1, -DQB1, and -DQA1 typed using restriction fragment length polymorphism analysis and sequence-specific oligonucleotide gene probing. The DQA1 allele DQA1*0301 was positively associated with the disease [48/52 (92%) diabetic patients versus 44/64 (69%) control subjects, Pc less than 0.03, RR = 4.97]. Alleles of the DRB1 and DQB1 genes showed no significant association with the disease. The frequency of DQB1 genotypes encoding the amino acid aspartic acid at position 57 of the DQ beta chain did not differ significantly between subjects with insulin-dependent diabetes mellitus (IDDM) and controls. These findings suggest that a susceptibility allele for IDDM in the Japanese is more closely associated with the DQA1 gene than the DQB1 gene.
Alleles↗
Investigation of the mode of inheritance of insulin-dependent diabetes mellitus in Japanese subjects.
Previous studies have shown that insulin-dependent diabetes mellitus is positively associated with HLA-DR4 and HLA-DR9 in Japanese populations. It was proposed that susceptibility to the disease is determined by a single HLA allele associated with both DR4 and DR9. DR genotypes in a Japanese population with insulin-dependent diabetes mellitus were determined by DRB/DQB RFLP analysis. A single disease-susceptibility-allele model was tested by the antigen-genotype-frequency-among-patients method. Recessive and additive inheritance of a single susceptibility allele were rejected. The DR9-associated disease-susceptibility allele in Japanese subjects is distinct from both the DR3- and DR4-associated susceptibility alleles in white Caucasians. The data suggest further complexity in the inheritance of HLA-associated susceptibility to insulin-dependent diabetes mellitus.
Adult↗
Comparison of diagnostic criteria of IGT, borderline, and GDM. Blood glucose curve and IRI response.
A 75-g oral glucose tolerance test (OGTT) was performed in 615 nonobese pregnant women (mean +/- SD age 29.7 +/- 4.3 yr) who were referred to the Division of Internal Medicine at our diabetes center because of glycosuria. Seventy-seven cases were found to have urinary glucose at the first trimester, 185 at the second trimester, and 353 at the third trimester. With their 75-g OGTT results, the diagnostic criteria of borderline (formulated by the Japan Diabetes Society), impaired glucose tolerance (IGT; defined by the World Health Organization [WHO]), and gestational diabetes mellitus (GDM; determined by the Japan Society of Obstetrics & Gynecology standards) were compared through blood glucose (BG) curves and immunoreactive insulin (IRI) responses. Borderline (fasting BG greater than or equal to 6.1 and less than 7.8 mM and 2-h BG greater than or equal to 6.7 and less than 11.1 mM) is neither diabetes nor normal. IGT is as referred to by the WHO. GDM exceeds two points of fasting BG greater than or equal to 5.6 mM, 1-h BG greater than or equal to 10.0 mM, or 2-h BG greater than or equal to 8.3 mM. Diabetes mellitus (DM) is as referred to by the Japan Diabetes Society (same as the WHO). The prevalence of abnormal glucose tolerance among all 615 pregnant women was 54.6% in borderline, 24.5% in IGT, 7.3% in GDM, and 3.4% in DM. The 2-h BG levels in IGT during the first trimester were higher than in borderline (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Inducement of antibody that mimics insulin action on insulin receptor by insulin autoantibody directed at determinant at asparagine site on human insulin B chain.
We previously showed that purified human IgG1 insulin autoantibody (IAA) from the serum of male patient T.H. with insulin autoimmune syndrome is directed at a determinant at the asparagine site on the human insulin B chain. An anti-idiotypic antibody (anti-TH) that inhibited TH-IAA binding to human insulin was obtained by immunizing BALB/c mice with TH-IAA. Anti-TH bound to viable IM-9 cells and the purified insulin receptor from IM-9 cells. Anti-TH binding to IM-9 cells and the insulin receptor was inhibited by TH-IAA but not by human IgG. Moreover, incubation of HepG2 cells with anti-TH had an inhibitory effect on insulin binding to HepG2 cells. Anti-TH, like insulin, stimulated amino acid uptake in HepG2 cells. These findings indicate that the conformation of TH-IAA idiotope is a mirror image of the determinant on the insulin B chain, the binding site for TH-IAA on anti-TH is also related to the insulin binding site on the insulin receptor, and anti-TH mimics insulin action on the insulin receptor.
Aminoisobutyric Acids↗
The range of albumin concentrations in the single-void first morning urine of 1090 healthy young children.
To predict microalbuminuria easily in the diabetic outpatient clinic, we determined the range of albumin concentrations in the single-void first morning urine in 1090 healthy subjects of age 6-11 by the modified turbidimetry immunoassay (TIA) method, which uses 96-well microplates and a microplate reader to perform the assay quickly and conveniently. As the correlation coefficient of albumin concentration by the TIA uncorrected for creatinine versus corrected for creatinine was r = 0.79 (P less than 0.005), the values uncorrected for creatinine were used. When the distribution of values from 1090 healthy young children was simulated by using the chi-square test (k = 1), the 95% confidence interval was 0-18 micrograms/ml.
Albuminuria↗
[Clinical significance of insulin antibody assay].
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Binding, Competitive↗
Human monoclonal IgG1 insulin autoantibody from insulin autoimmune syndrome directed at determinant at asparagine site on insulin B-chain.
Purified human insulin autoantibody (IAA) collected from the serum of a man (T.H.) with insulin autoimmune syndrome was characterized. The TH-IAA was found to be of IgG1 (lambda-light-chain) subclass. In addition to the single-binding affinity of TH-IAA to human insulin that we have shown in previous studies, the TH-IAA binding to human insulin was completely inhibited by a mouse monoclonal anti-idiotypic antibody against TH-IAA. A competitive inhibition study with various insulins revealed an epitope of human insulin against TH-IAA. These findings suggest that TH-IAA is monoclonal and is directed at a determinant at B-3 (asparagine) on the human insulin B-chain.
Animals↗