Shigeki Miyamoto

Association of HLA-DR, DQ genotype with different beta-cell functions at IDDM diagnosis in Japanese children.

Japanese IDDM patients have been demonstrated to have unique and different HLA associations from white patients. To elucidate the effect of HLA-associated genetic factors on the clinical heterogeneity of IDDM in Japanese people, HLA-DRB1, DQA1, and DQB1 genotypes in 88 childhood-onset Japanese IDDM patients were examined by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) or sequence-specific primers (SSP). Of the 88 IDDM patients, 26 (29.5%) had DRB1*0405-DQA1*0302-DQB1*0401/X (DR4-DQ4/X), 38 (43.2%) had DRB1*0901-DQA1*0302-DQB1*0303/X (DR9-DQ9/X), and 9 (10.2%) were DR4/9-DQ4/9 heterozygous in the present study (X does not contain protective alleles). Clinical heterogeneity such as age distribution at onset, prevalence and serum level of anti-GAD antibodies (GADAb), and residual pancreatic β-cell function after diagnosis were compared between patients with HLA-DR4-DQ4 and DR9-DQ9. The frequency of DR9-DQ9 genotype was significantly higher in the younger (0–10 years) than in the older (11–16 years) age-group of onset, but the frequency of DR4-DQ4 was higher in the older (11–16 years) age-group. Although no association of DR-DQ genotypes with the prevalence and serum level of GADAb was found among newly diagnosed patients, long-standing DR9-DQ9 patients had significantly higher levels of GADAb than those with DR4-DQ4. While no difference in time course of serum C-peptide (CPR) levels was detected between GADAb+ and GADAb− patients, a remarkable difference was demonstrated between DR9-DQ9 and DR4-DQ4 patients. The residual pancreatic β-cell function was retained more in patients with DR4-DQ4 than in those with DR9-DQ9 at diagnosis through 12–18 months after diagnosis. These results suggest that the DR9-DQ9 genotype may induce stronger autoimmune destructive response (T-helper 1 function) against target β-cells than the DR4-DQ4 genotype does. Our findings may warrant further studies on the association of diabetogenic autoimmune response with HLA class II molecules and contribute to a clarification of interracial differences in HLA-encoded susceptibility to IDDM.

Cytotoxic T lymphocyte antigen 4 gene polymorphism confers susceptibility to Type 1 diabetes in Japanese children: analysis of association with HLA genotypes and autoantibodies

OBJECTIVE Although the polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA4) gene have been shown to be associated with Type 1 diabetes in Caucasians, some conflicting results have been reported among subjects of different ethnic backgrounds. We examined a CTLA4 polymorphism and its relationship to human leucocyte antigen (HLA) genotypes and autoantibodies for glutamic acid decarboxylase 65 (GAD65) and IA‐2 in Japanese children with Type 1 diabetes.

Psychiatric disorders in juvenile patients with insulin-dependent diabetes mellitus

The relationships of psychiatric characteristics to metabolic control and psychosocial functioning were examined in a group of 16 patients with insulin-dependent diabetes mellitus (IDDM) (mean age: 14.3+/-5.1 years, mean duration of follow-up: 5.0+/-2.3 years) and psychiatric disorders. The comparison is also made to 69 IDDM controls (mean age: 17.0+/-6.7 years) without psychiatric disorders. Metabolic control was evaluated in terms of glycosylated hemoglobin (HbA1c). Psychosocial functioning at both psychiatric treatment entry and discharge was assessed using the global assessment of functioning (GAF) scale. Subjects were divided into three subgroups - Somatoform Type (25%), Behavioral Type (50%) or Psychotic Type (25%) - according to the Diagnostic and Statistical Manual of Mental Disorders, third edition revised (DSM-III-R), based on semi-structured interviews. Four patients (25%) were diagnosed as having schizophrenia or schizoaffective disorder (Psychotic Type), which is rather rare. The mean HbA1c level in the Behavioral Type patients was significantly higher than in the other subgroups (P<0. 01). After psychiatric treatment a significant difference (P<0.0001) in the GAF Scale was observed in the Psychotic Type compared with the other subgroups. We conclude that the Behavioral Type is associated with poor metabolic control and that for the Psychotic Type, improved psychosocial functioning can be achieved through psychiatric treatment.

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT): initial aims and impact of the family history of type 1 diabetes mellitus in Japanese children

Abstract: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT) was established in July 1994 with the chief aim to improve the quality of therapy for type 1 diabetes in children, an entity far less common in Japan than in Europe. We proposed four initial research topics: (i) to determine the current status of medical care and glycemic control in Japanese children with type 1 diabetes mellitus; (ii) to standardize the measurement of hemoglobin A1c; (iii) to establish a registry of a large cohort of patients in order to enable prospective studies to improve the quality of therapy for children with type 1 diabetes in Japan; and (iv) to enable participants of the JSGIT to hold a workshop twice annually.

Treatment for B‐cell‐type lymphoma in a girl associated with Bloom's syndrome

Ota S, Miyamoto S, Kudoh F, Horie H, Kinugawa N, Okimoto Y. Treatment for B‐cell‐type lymphoma in a girl associated with Blooms syndrome. Clin Genet 1992:41:46–50.

Marriage rate and number of children among young adults with insulin-dependent diabetes mellitus in Japan

The main purpose of our study was to identify the social circumstances and lifestyle of IDDM patients in Japan. The present study focused on the marriage status of both men and women with IDDM as well as the number of children of women with IDDM. A questionnaire was sent to hospitals across the country. Doctors handed it or mailed it to IDDM patients aged 18 years or older. Unsigned answer sheets were returned directly by the patients. Data on the marriage rate and number of children were obtained, and possible factors affecting these indices were assessed. One thousand and thirteen patients (354 men and 659 women) answered the questionnaire. Both men and women with IDDM were less likely to be married in comparison with age-matched Japanese. The number of children of married IDDM women in various age groups was also lower in comparison with the general Japanese female population. Several factors other than diabetes complications including job discrimination, high medical costs, and psychological pressures, were thought to be responsible for these results.

A questionnaire survey on the use of quick-acting insulin analog in Japanese children and adolescents with type 1 diabetes.

Abstract Background : The aim of this study was to investigate the actual condition of quick‐acting insulin analog (Q) in Japanese children and adolescents with type 1 diabetes.

Comparison of Final Height in Monozygotic Twins, One with Idiopathic and Isolated Growth Hormone Deficiency Treated with Low Dose of Growth Hormone

Objective: We report final heights in a pair of monozygotic twins, one unaffected and the other affected with idiopathic and isolated growth hormone (GH) deficiency treated with human GH, and discuss the effect of GH dosage on the attainment of the genetic height potential in GH deficiency. Patients: Male monozygotic twins were born at 35 weeks of gestation; birth weights were 1,876 g in the unaffected and 1,510 g in the affected twin. At 4.9 years of age, the affected twin was studied for short stature (–3.38 SD) and was diagnosed as having idiopathic and isolated GH deficiency, whereas the unaffected twin was normal in height (± 0 SD). GH treatment was started at the age of 5.7 years and continued throughout childhood and adolescence. The average dose of GH administered during the treatment period was 0.35 IU (0.12 mg)/kg/week. The affected twin appeared to grow normally without other hormone replacement and achieved a final height of 165.6 cm (–0.86 SD) compared with that of 166.4 cm (–0.71 SD) in the unaffected twin at 17.5 years of age. Conclusion: Our results indicate that a relatively low dose of GH treatment started at an early age may preserve genetic height potential in patients with isolated GH deficiency.

C-Peptide/Creatinine Ratio in Early Morning Urine as an Indicator of Residual B-Cell Function in Insulin-Dependent Diabetes

The C‐peptide/creatinine (Cr) ratio in early morning urine was evaluated to assess B‐cell function. The subjects were 12 boys and 36 girls with insulin‐dependent diabetes mellitus (IDDM). The controls were 130 boys and 137 girls aged 4–15 years. There was a significant inverse correlation of this ratio with the duration of insulin therapy (r = ‐0.5807, P<0.01). The daily insulin dose in U/kg was significantly different among the following groups: 1.22 ± 0.31 U/kg in group 1 with undetectable C‐peptide, 0.94 ± 0.37 in group 2 with a decreased ratio and 0.45 ± 0.28 in group 3 with a normal ratio. HbAl levels were 11.3 ±1.6% in group 1 and 9.2 ± 1.1% in group 3. The difference was significant. The result shows that the C‐peptide/ Cr ratio in early morning urine is useful for assessing B‐cell function in diabetic children.

Absence of Heterozygous K83E and R257X Mutations of the AIRE-1 Gene in 46 Children with Type 1 Diabetes and 44 Children with Graves' Disease

Type 1 diabetes mellitus (DM) and Graves’ disease are autoimmune diseases, and a number of genetic factors, including HLA and CTLA-4 genes, have been reported to contribute to their etiology. The gene responsible for autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED) has been cloned and named the autoimmune regulator-1 (AIRE-1) gene. AIRE-1 protein is thought to be a transcription regulatory protein and to have a role in the maintenance of immunological tolerance. The aim of this study was to determine whether heterozygous AIRE-1 gene mutations are associated with childhood-onset type 1 diabetes and Graves’ disease in the Japanese population. We investigated 46 children with type 1 DM (29 females and 17 males; age at the time of diagnosis, 0.5–16 yr) and 44 children with Graves’ disease (34 females and 10 males; age at the time of diagnosis, 3–16 yr) for the presence of the K83E mutation in exon 2 and the R257X mutation in exon 6 of the AIRE-1 gene. The alleles were identified by polymerase chain reaction of genomic DNA and restriction fragment-length polymorphism analysis (PCR-RFLP) with endonuclease TaqI. Since no patients with type 1 DM or Graves’ disease were found to carry the K83E or the R257X heterozygous mutation, we concluded that neither the K83E nor the R257X heterozygous mutation in the AIRE-1 gene seem to be the cause of the more common isolated endocrinopathies, i.e., type 1 diabetes mellitus and Graves’ disease, in Japanese children.