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Aim: To clarify the prevalence and degree of maternal microchimerism in Japanese children with type 1 diabetes, as well as its effect on phenotypic variation., Methods: We studied 153 Japanese children with type 1 diabetes, including 124 children positive for β-cell autoantibodies, and their 71 unaffected siblings. The number of circulating microchimeric cells per 10 5 host cells was estimated by the use of quantitative-polymerase chain reaction targeting non-transmitted maternal human leukocyte antigen alleles. The results were compared to previous data from white European people. Phenotypic comparison was performed between maternal microchimerism carriers and non-carriers with diabetes., Results: Maternal microchimerism was detected in 15% of children with autoantibody-positive type 1 diabetes, 28% of children with autoantibody-negative type 1 diabetes, and 16% of unaffected siblings. There were no differences in the prevalence or levels of maternal microchimerism among the three groups or between the children with type 1 diabetes and their unaffected siblings. Furthermore, maternal microchimerism carriers and non-carriers exhibited similar phenotypes., Conclusions: Maternal microchimerism appears to be less common in Japanese children with type 1 diabetes than in white European people. Our data indicate that maternal microchimerism is unlikely to be a major trigger or a phenotypic determinant of type 1 diabetes in Japanese children and that the biological significance of maternal microchimerism in type 1 diabetes may differ among ethnic groups., (© 2019 Diabetes UK.)

Aims/introduction: We compared the results of testing for glutamic acid decarboxylase antibodies (GADAb) using a radioimmunoassay (RIA) and an enzyme-linked immunosorbent assay (ELISA) in individuals with childhood-onset type 1 diabetes mellitus., Materials and Methods: Serum specimens were collected from 1,024 Japanese children (426 boys and 598 girls) in 2013. The median age at diagnosis was 7 years (0-18 years). The blood specimens were obtained at a median age of 13 years (2-22 years)., Results: Among the 628 children whose serum specimens were collected within 5 years after diagnosis, the rate of GADAb positivity was 47.9% using RIA and 69.4% using ELISA. The participants were divided into four groups according to their RIA and ELISA results for GADAb as follows: group I (RIA+/ELISA+), group II (RIA+/ELISA-), group III (RIA-/ELISA+) and group IV (RIA-/ELISA-). The clinical and genetic characteristics of group I and group III were quite similar in terms of age at diagnosis, male/female ratio, relatively high positive rates for both autoantibody to protein tyrosine phosphatase IA-2 and autoantibody to the cation efflux transporter zinc transporter 8, and human leukocyte antigen genotype. Group II contained just five patients, and was characterized by a younger age at diagnosis, low positive rates for both autoantibody to protein tyrosine phosphatase IA-2 and autoantibody to the cation efflux transporter zinc transporter 8, and a unique human leukocyte antigen genotype. If the positive rates of either autoantibody to protein tyrosine phosphatase IA-2 or autoantibody to the cation efflux transporter zinc transporter 8 or both were added to the GADAb results using RIA, the percentage of autoimmune type 1 diabetes increased from 47.9% to 78.5%., Conclusions: The diagnosis of autoimmune childhood-onset Japanese type 1 diabetes increased when GADAb results were obtained using a new ELISA method, compared with a previously utilized RIA method., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: To evaluate comprehensively the use of the glycated albumin to HbA 1c ratio for estimation of glycaemic control in the previous month., Methods: A total of 306 children with Type 1 diabetes mellitus underwent ≥10 simultaneous measurements of glycated albumin and HbA 1c . Correlation and concordance rates were examined between HbA 1c measurements taken 1 month apart (ΔHbA 1c ) and glycated albumin/HbA 1c ratio fluctuations were calculated as Z-scores from the cohort value at enrolment of this study cohort (method A) or the percent difference from the individual mean over time (method B)., Results: Fluctuations in glycated albumin/HbA 1c ratio (using both methods) were weakly but significantly correlated with ΔHbA 1c , whereas concordance rates were significant for glycaemic deterioration but not for glycaemic improvement. Concordance rates were higher using method B than method A., Conclusions: The glycated albumin/HbA 1c ratio was able to estimate glycaemic deterioration in the previous month, while estimation of glycaemic improvement in the preceding month was limited. Because method B provided a better estimate of recent glycaemic control than method A, the individual mean of several measurements of the glycated albumin/HbA 1c ratio over time may also identify individuals with high or low haemoglobin glycation phenotypes in a given population, such as Japanese children with Type 1 diabetes, thereby allowing more effective diabetes management., (© 2018 Diabetes UK.)

Background: Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D)., Objectives: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D., Methods: Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers., Results: We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy-number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis., Conclusions: This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin-requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To examine the contribution of PTPN2 coding variants to the risk of childhood-onset Type 1A diabetes., Methods: PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant-positive children., Results: One frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine-protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant-positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles., Conclusions: The results provide the first indication that PTPN2 variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs. PTPN2 coding variants possibly induce non-specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen-mediated disease susceptibility. Our findings warrant further validation., (© 2017 Diabetes UK.)

Aims/introduction: Although genome-wide association studies have identified more than 50 susceptibility genes for type 1 diabetes, low-frequency risk variants could remain unrecognized. The present study aimed to identify novel type 1 diabetes susceptibility genes by newly established methods., Materials and Methods: We carried out whole-exome sequencing and genome-wide copy-number analysis for a Japanese family consisting of two patients with type 1 diabetes and three unaffected relatives. Further mutation screening was carried out for 127 sporadic cases. The functional consequences of identified substitutions were evaluated by in silico analyses and fluorescence-activated cell sorting of blood samples., Results: Whole-exome sequencing and genome-wide copy-number analysis of familial cases showed co-segregation of the p.V863L substitution in CD101, the human homolog of an autoimmune diabetes gene in the non-obese diabetic mouse, with type 1 diabetes. Mutation screening of CD101 in 127 sporadic cases detected the p.V678L and p.T944R substitutions in two patients. The p.V863L, p.V678L and p.T944R substitutions were absent or extremely rare in the general population, and were assessed as 'probably/possibly damaging' by in silico analyses. CD101 expression on monocytes, granulocytes and myeloid dendritic cells of mutation-positive patients was weaker than that of control individuals., Conclusions: These results raise the possibility that CD101 is a susceptibility gene for type 1 diabetes., (© 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aim: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children., Methods: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined., Results: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]., Conclusions: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children., (© 2016 Diabetes UK.)

Aims: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes., Methods: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis., Results: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10 -5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years., Conclusions: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood., (© 2016 Diabetes UK.)

Background: Monogenic mutations, such as those in the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) and insulin (INS) genes, are identified in young patients with type 1B diabetes (non-autoimmune-mediated). We recently reported the results of a test for monogenic forms of diabetes in Japanese children who were diagnosed with type 1B diabetes at <5 years of age. In this study, we tested for monogenic forms of diabetes in Japanese children aged >5 to ≤15.1 years at the diagnosis of type 1B diabetes., Methods: Thirty-two Japanese children (eight males, 24 females) with type 1 diabetes negative for glutamate decarboxylase (GAD) 65 and/or IA-2A autoantibodies and who were aged >5 to 15.1 years at diagnosis were recruited from 16 independent hospitals participating in the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT). We performed mutational analyses of genes with a high frequency of mutation [INS, KCNJ11, hepatocyte nuclear factor 1 alpha (HNF1α) and hepatocyte nuclear factor 4 alpha (HNF4α)]., Results: We identified one missense mutation (G32S) in the INS gene and two mutations (R131Q and R203S) in the HNF1α gene that could be associated with diabetes. No missense change was found in the KCNJ11 gene., Conclusions: Our results suggest that although mutations in the INS gene can be detected in Japanese patients aged >5 years at diagnosis, the frequency of mutations decrease in older age groups. Conversely, the frequency of the mutation in the HNF1α gene increased in patients diagnosed at age 5 or older. Clinicians should consider the possibility of maturity onset diabetes of the young (MODY) in children diagnosed with type 1B diabetes.

Background: The etiology of type 1 diabetes (T1D) is heterogeneous and is according to presence or absence of pancreatic autoantibodies divided into two subtypes: type 1A (autoimmune-mediated) and type 1B (non-autoimmune-mediated). Although several genes have been linked to type 1A diabetes, the genetic cause of type 1B diabetes in Japanese individuals is far from understood., Objective: The aim of this study was to test for monogenic forms of diabetes in auto antibody-negative Japanese children with T1D., Methods: Thirty four (19 males and 15 female) unrelated Japanese children with glutamate decarboxylase (GAD) 65 antibodies and/or IA-2A-negative T1D and diabetes diagnosed at < 5 yr of age were recruited from 17 unrelated hospitals participating in the Japanese Study Group of Insulin Therapy for children and adolescent diabetes (JSGIT). We screened the INS gene and the KCNJ11 gene which encode the ATP-sensitive potassium cannel by direct sequencing in 34 Japanese children with T1D., Results: We identified three novel (C31Y, C96R, and C109F) mutations and one previously reported mutation (R89C) in the INS gene in five children, in addition to one mutation in the KCNJ11 gene (H46R) in one child. These mutations are most likely pathogenic and therefore the cause of diabetes in carriers., Conclusion: Our results suggest that monogenic forms of diabetes, particularly INS gene mutations, can be detected in Japanese patients classified with type 1B. Mutation screening, at least of the INS gene, is recommended for Japanese patients diagnosed as autoantibody negative at <5 yr of age., (© 2012 John Wiley & Sons A/S.)

Objective: To determine the HLA-DRB1, DQB1, DPB1, A, C, and B genotypes among Japanese children with autoimmune type 1 diabetes., Methods: Four hundred and thirty patients who were GADAb and/or IA-2Ab-positive (Type 1A) were recruited from 37 medical centers as part of a nationwide multicenter collaborative study. DNA samples from 83 siblings of the children with Type 1A diabetes and 149 parent-child trios were also analyzed. A case-control study and a transmission disequilibrium test (TDT) were then performed., Results: The susceptible and protective DRB1 and DQB1 alleles and haplotypes were confirmed. DPB1 alleles unique to the Japanese population and those common to multiple ethnic groups were also present. A linkage disequilibrium (LD) analysis showed both susceptible and protective haplotypes. The TDT did not reveal any alleles that were transmitted preferentially from the mother or father to children with Type 1A. Homozygosity for DRB1-09:01-DQB1-03:03 and heterozygosity for DRB1-04:05-DQB1-04:01 and DRB1-08:02-DQB1-03:02 were associated with an extremely high risk of Type 1A. A comparison of children with Type 1A and their parents and siblings suggested a dose effect of susceptible DRB1-DQB1 haplotypes and an effect of protective alleles on immunological pathogenesis. DRB1-09:01 appeared to be strongly associated with an early onset in preschool children with Type 1A diabetes., Conclusions: This study demonstrated the characteristic association of HLA-class II and class I genes with Type 1A diabetes among Japanese children. A TDT did not reveal the genomic imprinting of HLA-class II and class I genes in Type 1A diabetes., (© 2011 John Wiley & Sons A/S.)

The aim of this study was to evaluate the past 10-year status of insulin therapy for preschool-age children with type 1 diabetes in Japan. One-hundred and forty-two patients who had been diagnosed at less than 5 years of age within the past 10 years (1993-2002) at 36 hospitals were registered in this study on April 2003. The methods of daily insulin therapy and episodes of severe hypoglycemia during the preschool period were investigated. Eighty-six (60.6%) children were treated with a pen-type device and 56 (39.4%) were treated with a syringe-type device. The once-a-day insulin regimen was used for 2, a twice-a-day regimen for 104, a three-times-a-day for 28 and a four-times-a-day for 8. Episodes of severe hypoglycemia were recorded in nearly half of the subjects, and one-fourth of the subjects had repeated episodes. One hundred and eleven of their parents were questioned regarding the degree of psychosocial stress experienced during the care of their children. Most parents worried about the glycosylated hemoglobin value at each hospital visit. They were next very afraid of nocturnal severe hypoglycemia, independent of any actual experience. These results suggest that although insulin therapy can involve various methods, the important point is to simultaneously provide good glycemic control and prevent severe hypoglycemia, especially during this age.

Glutamic acid decarboxylase (GAD) catalyzes the formation of gamma-aminobutyric acid (GABA), which is a major transmitter in the central nervous system. Two forms of GAD (GAD65 and GAD67) are known to be expressed in human tissues and GAD65 is predominantly expressed in pancreatic beta-cells. Recent findings revealed that GAD functions as an autoantigen in human autoimmunity, especially in insulin-dependent diabetes mellitus (IDDM). GAD is a key antigen for the development of autoimmunity against beta-cells and the production of GADAb precedes other autoantibodies such as IAA and ICA512/IA-2Ab prior to the clinical onset of IDDM. At onset, GADAb is detected in 50-80% of patients using RIA or RBA method. Factors that influence the positivities and titers of GADAb at onset, such as onset age, sex, presence of autoimmunity against thyroid, HLA type, have been reported. After onset, GADAb titer decreased more slowly than that of ICA512/IA-2Ab. These findings suggest that autoantibodies against beta-cells, such as GADAb, may develop independently. The presence of GADAb in relatives of IDDM patients and NIDDM patients predicts the development of beta-cell destruction in combination with other anti-islet autoantibodies.

Objective: Longitudinal changes in GAD antibody (Ab) and ICA512/IA-2 (ICA512) Ab were examined in relation to age at the onset of diabetes and autoimmunity against the thyroid gland., Research Design and Methods: GADAb, ICA512Ab, and antithyroid autoantibody were examined at onset in 40 juvenile-onset IDDM patients (17 males, 23 females, age at onset 9.4 +/- 4.1 years, range 1.7-20). To assess the changes in antibody levels, 29 patients were followed up with sequential serum samples for up to 5 years., Results: At onset, GADAb, ICA512Ab, and antithyroid autoantibody (thyroglobulinAb or thyroid peroxidaseAb) were found in 70, 58, and 25% of the 40 patients, respectively. Prepubertal patients (n = 21) had a significantly higher prevalence and index of ICA512Ab compared with pubertal patients (n = 19) (76 vs. 37%, P = 0.012, and 2.43 +/- 2.36 vs. 0.66 +/- 1.23, P = 0.011), while GADAb was more prevalent in pubertal patients (57 vs. 84%, P = 0.09). A longitudinal analysis of GADAb and ICA512Ab showed that GADAb levels declined more slowly than those of ICA512Ab (P = 0.008). Patients with continuous extremely high levels of GADAb also had high levels of antithyroid autoantibody., Conclusions: The measurement of ICA512Ab is useful in prepubertal patients, who often show rapid progression of the disease. The presence of autoimmunity against thyroid gland seems to influence the GADAb level but not the ICA512Ab level.

To compare the metabolic consequences of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), glycemic control and energy metabolism were evaluated in 18 children displaying IDDM and 19 NIDDM adult patients. With rising concentrations of fasting blood glucose (FBG), hemoglobin A1C and free fatty acid, the percentage of the ratio of resting energy expenditure (REE) to predicted REE expressed as %REE increased and the respiratory quotient (RQ) decreased. The linear regression between RQ and FBG showed the same gradient in IDDM and NIDDM although the RQ in IDDM was always 0.07 lower than that in NIDDM given various FBG concentrations. Those patients whose RQ values were less than 0.7, indicating ketone body production, included 8 (44%) IDDM and 2 (11%) NIDDM patients. These results may explain the relatively greater manifestation of ketoacidosis in IDDM.