Introduction of continuous glucose monitoring (CGM) is a key factor in decreasing HbA1c in war refugee children with type 1 diabetes.

AIMS: Our aim was to describe the changes in therapy and diabetes control in Ukrainian war refugee children with diabetes (CwD) during the first year of their stay in Czechia. METHODS: A total of 124 CwD (62 male, 62 female) were enrolled into this observational study. Anthropometric, laboratory and diabetes management data were acquired at baseline and at 3 months intervals for 12 months. All CwD were offered a CGM device during their first visit. Generalized Estimating Equation models were fitted in order to estimate the dynamics of studied characteristics. RESULTS: Median baseline HbA1c was 58 mmol/mol (IQR [48; 73]mmol/mol) (7.5 %, IQR[6.5;8.8]%). The HbA1c decreased significantly throughout the course of the study at a pace of - 2.2 mmol/mol (-0.2 %pt.) per visit (P = 0.01, CI[-3.2;-1.1]). The pace of the decrease in the average HbA1c was significantly higher in the group of CwD who received CGM in Czechia than in those who already had it from Ukraine by 2.9 mmol/mol (0.27 %pt.) per visit (P < 0.001, CI [-4.4; -1.3]). CONCLUSIONS: The steepest decrease in HbA1c was observed in CwD with newly initiated CGM underlining its vital role in improving the glucose control of CwD regardless of their background.

Substantial proportion of MODY among multiplex families participating in a Type 1 diabetes prediction programme.

AIMS: Patients with maturity-onset diabetes of the young (MODY) might be over-represented in families with histories of Type 1 diabetes. Our aim was to re-evaluate families participating in the Czech T1D Prediction Programme (PREDIA.CZ) with at least two members affected with diabetes to assess the proportion of MODY among these families and determine its most significant clinical predictors. METHODS: Of the 557 families followed up by the PREDIA.CZ, 53 (9.5%) had two or more family members with diabetes. One proband with diabetes from these families was chosen for direct sequencing of the GCK, HNF1A, HNF4A and INS genes. Non-parametric tests and a linear logistic regression model were used to evaluate differences between MODY and non-MODY families. RESULTS: MODY was genetically diagnosed in 24 of the 53 families with multiple occurrences of diabetes (45%). Mutations were detected most frequently in GCK (58%), followed by HNF1A (38%) and INS (4%). MODY families were more likely to have a parent with diabetes and had a higher proportion of females with diabetes than non-MODY families. Higher age (P < 0.001), a lower level of HbA1c (P < 0.001) at clinical onset and at least two generations affected by diabetes were the variables most predictive for probands of MODY families already presenting with diabetes. CONCLUSIONS: A prediction programme for Type 1 diabetes would provide a useful new source of patients with MODY most likely to benefit from an accurate diagnosis. This identification has implications for patient treatment and disease prognosis.

The dynamic changes of zinc transporter 8 autoantibodies in Czech children from the onset of Type 1 diabetes mellitus.

AIMS: The prevalence of autoantibodies to zinc transporter 8 (ZnT8) in Czech children at the onset of Type 1 diabetes mellitus and dynamic changes in ZnT8 autoantibody levels during disease progression were studied. The value of ZnT8 autoantibody measurements in diagnosis of Type 1 diabetes was assessed. METHODS: Serum samples from 227 children with newly diagnosed Type 1 diabetes and from 101 control children without diabetes were analysed in a retrospective cross-sectional study. One hundred and seventy-one samples from 116 of the patients with diabetes were analysed in a follow-up study at (median) intervals of 1, 3, 5 and 10 years after onset of Type 1 diabetes. ZnT8 autoantibodies were measured using a bridging enzyme-linked immunosorbent assay, while antibodies to glutamic acid decarboxylase, insulinoma antigen 2 and insulin were measured by radioimmunoassays. RESULTS: ZnT8 autoantibodies were detected in 163/227 (72%) of children at Type 1 diabetes onset and in 1/101 (1%) of the control subjects. Sixteen out of 227 (7%) patients with Type 1 diabetes were antibody negative based on three antibodies (glutamic acid decarboxylase, insulinoma antigen 2 and insulin). This false-negative rate was reduced to 10/227 (4.4%) (P < 0.05) after inclusion of ZnT8 autoantibody measurements. Of the children, 142/227 (63%) were positive for at least three antibodies and the most common combination was insulinoma antigen 2, glutamic acid decarboxylase and ZnT8. ZnT8 autoantibody levels decreased over time after Type 1 diabetes onset and the presence and level of ZnT8 autoantibodies correlated with IA-2 autoantibodies. CONCLUSIONS: A ZnT8 autoantibody enzyme-linked immunosorbent assay showed 72% disease sensitivity and 99% specificity at Type 1 diabetes onset. Measurements of ZnT8 autoantibodies are important for Type 1 diabetes diagnosis and should be included in the panel of autoantibodies tested at the onset of Type 1 diabetes.

Prepubertal girls with Turner syndrome and children with isolated SHOX deficiency have similar bone geometry at the radius.

CONTEXT: The low bone mineral density (BMD) and alterations in bone geometry observed in patients with Turner syndrome (TS) are likely caused by hypergonadotropic hypogonadism and/or by haploinsufficiency of the SHOX gene. OBJECTIVE: Our objective was to compare BMD, bone geometry, and strength at the radius between prepubertal girls with TS and children with isolated SHOX deficiency (SHOX-D) to test the hypothesis that the TS radial bone phenotype may be caused by SHOX-D. DESIGN AND SETTING: This comparative cross-sectional study was performed between March 2008 and May 2011 in 5 large centers for pediatric endocrinology. PATIENTS: Twenty-two girls with TS (mean age 10.3 years) and 10 children with SHOX-D (mean age 10.3 years) were assessed using peripheral quantitative computed tomography of the forearm. MAIN OUTCOMES: BMD, bone geometry, and strength at 4% and 65% sites of the radius were evaluated. RESULTS: Trabecular BMD was normal in TS (mean Z-score = -0.2 ± 1.1, P = .5) as well as SHOX-D patients (mean Z-score = 0.5 ± 1.5, P = .3). At the proximal radius, we observed increased total bone area (Z-scores = 0.9 ± 1.5, P = .013, and 1.5 ± 1.4, P = .001, for TS and SHOX-D patients, respectively) and thin cortex (Z-scores = -0.7 ± 1.2, P = 0.013, and -2.0 ± 1.2, P < .001, respectively) in both groups. Bone strength index was normal in TS as well as SHOX-D patients (Z-scores = 0.3 ± 1.0, P = .2, and 0.1 ± 1.3, P = .8, respectively). CONCLUSIONS: The similar bone geometry changes of the radius in TS and SHOX-D patients support the hypothesis that loss of 1 copy of SHOX is responsible for the radial bone phenotype associated with TS.

Bone geometry and volumetric bone density at the radius in patients with isolated SHOX deficiency.

UNLABELLED: The short stature homeobox-containing gene (SHOX) plays an important role in bone development and growth. We aimed to assess bone geometry and volumetric bone mineral density at the radius in patients with isolated SHOX deficiency and to relate these bone parameters to the severity of disproportion between the upper and the lower body segment. 17 patients with isolated SHOX deficiency (median age 12.3 yrs, range 6.7-37.2, 12 children and 5 adults) were examined by peripheral quantitative CT (pQCT) at the non-dominant forearm. Results were expressed as Z-scores using published reference data. Linear regression analyses were performed to describe associations between pQCT parameters and the severity of disproportion expressed as sitting height to standing subischial leg height ratio. Trabecular volumetric bone mineral density (vBMD) at the distal radius was normal, whereas cortical vBMD was decreased (mean Z-scores 0.34±1.5, n.s., and -2.2±2.2, p<0.001, respectively). Total bone cross-sectional area was enlarged at the diaphysis (2.1±1.2, p<0.001), while cortical bone cross-sectional area was normal (-0.51±1.4, n.s.). Consequently, cortical thickness was decreased (-1.2±1.3, p<0.01). The polar strength-strain index as a surrogate of long bone strength was normal (0.40±1.4, n.s.). We found no associations between pQCT parameters and the severity of disproportion. CONCLUSIONS: Patients with isolated SHOX deficiency are characterized by decreased cortical vBMD and cortical thickness and enlarged diaphysis. As similar changes have been described in girls with Turner syndrome, these findings suggest that haploinsufficiency of SHOX could cause characteristic skeletal anomalies at the radius.

Healthy first-degree relatives of patients with type 1 diabetes exhibit significant differences in basal gene expression pattern of immunocompetent cells compared to controls: expression pattern as predeterminant of autoimmune diabetes.

Expression features of genetic landscape which predispose an individual to the type 1 diabetes are poorly understood. We addressed this question by comparing gene expression profile of freshly isolated peripheral blood mononuclear cells isolated from either patients with type 1 diabetes (T1D), or their first-degree relatives or healthy controls. Our aim was to establish whether a distinct type of 'prodiabetogenic' gene expression pattern in the group of relatives of patients with T1D could be identified. Whole-genome expression profile of nine patients with T1D, their ten first-degree relatives and ten healthy controls was analysed using the human high-density expression microarray chip. Functional aspects of candidate genes were assessed using the MetaCore software. The highest number of differentially expressed genes (547) was found between the autoantibody-negative healthy relatives and the healthy controls. Some of them represent genes critically involved in the regulation of innate immune responses such as TLR signalling and CCR3 signalling in eosinophiles, humoral immune reactions such as BCR pathway, costimulation and cytokine responses mediated by CD137, CD40 and CD28 signalling and IL-1 proinflammatory pathway. Our data demonstrate that expression profile of healthy relatives of patients with T1D is clearly distinct from the pattern found in the healthy controls. That especially concerns differential activation status of genes and signalling pathways involved in proinflammatory processes and those of innate immunity and humoral reactivity. Thus, we posit that the study of the healthy relative's gene expression pattern is instrumental for the identification of novel markers associated with the development of diabetes.

Immune regulatory T cells in siblings of children suffering from type 1 diabetes mellitus.

Patients with type 1 diabetes are suffering from defects in immune regulatory cells. Their siblings may be at increased risk of type 1 diabetes especially if they are carriers of certain human leucocyte antigen (HLA) alleles. In a prospective non-randomized study, we intended to evaluate 31 healthy siblings of paediatric patients with type 1 diabetes and explore immune regulatory populations of CD4+CD25+ T cells and natural killer (NK) T cells. Tested siblings of type 1 diabetes patients were stratified according to the HLA-associated risk of possible diabetes development. Immune regulatory function of CD4+CD25+ T cells was tested in vitro. Significant differences in CD4+CD25+ but not in NK T cells have been identified. Siblings of type 1 diabetes patients carrying high risk HLA alleles (DQA1*05, DQB1*0201, DQB1*0302) had significantly lower number of immune regulatory CD4+CD25+ T cells than the age-matched healthy controls or siblings carrying low-risk HLA alleles (DQB1*0301, DQB1*0603, DQB1*0602). Regulatory function of CD4+CD25+ T cells demonstrated a dose-escalation effect. In siblings of type 1 diabetes patients, the defect in immune regulatory CD4+CD25+ T cells exists in association with genetic HLA-linked risk for type 1 diabetes.

Glucose evaluation trial for remission (GETREM) in type 1 diabetes: a European multicentre study.

OBJECTIVE: Strict metabolic control during the 1st year of type 1 diabetes is thought to be a key factor for achieving clinical remission. The aims of this study were two-fold: (i) to evaluate the frequency and duration of spontaneous remission (defined according to the parameters issued by the International Diabetic Immunotherapy Group (IDIG)) in a European population of consecutive recent onset type 1 diabetes patients (aged 5-35 years), followed-up for a period of 36 months with a common protocol of intensive insulin therapy and without adjunct immune-intervention; and (ii) to identify the predictive factors for clinical remission. RESEARCH DESIGN AND METHOD: A total of 189 consecutive patients with newly diagnosed type 1 diabetes according to ADA criteria were recruited in participating centres (Belgium, Czech Republic, Estonia, France, Germany, Hungary, Italy, Poland, Romania, Sweden and Turkey) and followed-up for a period of up to 36 months. In all patients, intensive insulin therapy was implemented consisting of three or four injections of regular insulin daily with NPH insulin at bedtime. Adjustment of insulin dose was made according to a common protocol. Various clinical characteristics (age, gender, severity of presentation, etc.), history (presence of diabetic siblings in the family, etc.) and integrated parameters of metabolic control (HbA(1c), blood glucose, the total insulin dose at hospital discharge adjusted for body weight) were collected. RESULTS: Twenty-two patients (11.6%) experienced remission. The median duration of remission was 9.6 months and the range was 31 months. There was a wide variation among centres. Logistic regression analysis focused on the centre as the main variable in achieving remission. CONCLUSION: Remission was shown to be very heterogeneous between centres depending on 'other factors' such as patient care and family awareness of the disease rather than on 'measurable factors' such as sex, age, HbA(1c) and severity of presentation at diagnosis. Using intensive insulin therapy and optimisation of metabolic control, remission occurred in nearly one out of eight patients.

[Prediction of type 1 diabetes in the neonates of diabetic mothers or fathers]. / Predikce diabetu 1. typu u novorozencu diabetických matek nebo otcu.

OBJECTIVE: Verification of the possibility to predict diabetes in the neonates of mothers and fathers with Type 1 diabetes. DESIGN: Prospective clinical study. SETTING: Mother and Child Care Institute, Prague. Paediatric Clinic of the 2nd Faculty of Medicine at the Charles University, Prague. METHODS: In 31 neonates of mothers and fathers with Type 1 diabetes, the long-term and short-term risk of the occurrence of Type 1 diabetes was established. The genotypification of HLA, DQB1, HLA DQA1 and DRB1 *04 was carried out by using the PCR method to establish the long-term risk and according to the result of the examination, the examined child was included into one of the five categories of genetic risk. In all the monitored persons, the levels of antibodies against GAD65, IA-2 and IRA insulin were repeatedly identified by means of the methods, which are the markers of autoimmune insulitis and show the short-term risk of the occurrence of diabetes. The function-related examination of secretion of beta cells was carried out by using the intravenous glucose tolerance test (i.v. GTT) in children with significant titres of one or more antibodies. RESULTS: A very high risk of the occurrence of Type 1 diabetes was identified in 1 child with the genotype DQA1*03-DQB1*0201/DQA1*05-DQB1*0302 (3.23%); an increased risk was identified in 12 children (38.71%); a medium risk was identified in 11 children (35.48%); a relatively low risk was identified in 3 child (9,68%) and a low risk was identified in 4 children (12,90%). In 4 children (12.9%), a strongly protective alelle DQB1*0602 was found. In 4 children, positivity for one of the antibodies was identified. In 1 child of a diabetic father with an increased genetic risk, there was a decrease in the titre of antibodies in the case of repeated check and function-related examination of the insulin secretion (FPIR) will be carried out. In another child, disappearance of antibodies was identified when samples were taken for verification; function-related examination of insulin secretion produced normal results, and the child has remained without clinical manifestation of diabetes. In a third child, the positivity of the antibodies from the umbilical blood was only temporary and was probably caused by a passive transfer from the mother; now, when repeated checks were made, the antibodies have remained negative. In a fourth child, the parents refused further examinations after antibody positivity was observed; the child has been without clinical manifestation of diabetes up until now. CONCLUSION: This scheme for predicting diabetes by means of immunogenetic and immunological examination of risk individuals is a rational measure aimed at timely identification of autoimmune insulitis, which precedes the occurrence of Type 1 diabetes, and it should become a standard part of diabetological care.

HLA-DQ polymorphisms modify the risk of thyroid autoimmunity in children with type 1 diabetes mellitus.

OBJECTIVE: Type 1 diabetes mellitus (DM1) is frequently accompanied by thyroid autoimmunity (TAI). The aims of the present study were to estimate the prevalence of TAI and to determine the contribution of HLA-DQA1 and -DQB1 polymorphisms to TAI susceptibility among children with DM1. PATIENTS AND METLHODS: Screening for TAI was performed in 285 children with DM1 by measuring autoantibodies against thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg). HLA-DQA1 and -DQB1 were genotyped using PCR-SSP. RESULTS: Repeated positivity of anti-TPO and/or anti-Tg was found in 45/285 children with DM1 (15.8%). The prevalence was significantly higher in girls than in boys (26.7% vs 6.7%; p<10(-5)). The HLA-DQB1*0302 allele conferred susceptibility to TAI in children with DM1 (OR 2.7, 95% CI 1.1-6.4), while the DQB1*05 alleles acted protectively (OR 0.2, CI 95% 0.08-0.7). CONCLUSIONS: HLA-DQ polymorphisms significantly modify the risk of TAI in children with DM1.

[Prediction of type 1 diabetes mellitus in first degree Czech relatives of diabetic patients]. / Predikce diabetes mellitus 1. typu u ceských prvostupnových príbuzných diabetických pacientu.

Diagnosis of autoimmune beta cell destruction by genetic risk analysis, autoantibody evaluation and the test of stimulated insulin secretion performance in first-degree relatives of diabetic patients. 208 Czech children and adults (101 boys and 107 girls, 186 siblings, 22 offspring of diabetic parents, aged 1-22 years, mean age 11.5 +/- 5.4 years) were enrolled in the study. Complete DQB1, DQA1 typing and DRB1*04 subtyping were performed by the PCR in 202 subjects. Sera of all children were investigated for anti-GAD65, anti-IA2 and insulin antibodies using RIA methods. The cut-off normal levels were determined as the 99th percentile of 105 non-diabetic children. IVGTT was performed in children with significant titre of one or more autoantibodies. Total level of stimulated insulin secretion < 48 mU/l was assessed as defect of FPIR. Risk genotype DQA1*05-DQB1*0201/DQA1*03-DQB1*0302 (OR = 100, CI 95% 13-730) was found in 24 of 202 first-degree relatives (12%). 22 children (11%) carried strong protective allele DQB1*0602 (OR = 0.03, CI 95% 0.01-0.12). Autoantibody positivity was recognised in 9 of 208 children (2.9%) and IVGTT was performed. Positivity of anti-GAD65, anti-IA2 or IAA was identified in 5 of 24 children with the highest risk genotype (21%) and in 4 children of 113 with lower risk or neutral genotypes (3.5%). Borderline positivity of one autoantibody was found in 1 boy with the highest risk genotype and in 2 children with lower risk genotypes. Only temporary anti-GAD65 positivity was found in girl with protective genotype. Type 1 diabetes mellitus was diagnosed in boy during IVGTT and disease manifested 6 months after IVGTT in girl with defect of FPIR. Standardised methods for prediction of Type 1 diabetes were introduced in first-degree relatives of diabetic patients. These methods are used for Czech registry of diabetic children.

The CTLA4 +49 A/G dimorphism is not associated with type 1 diabetes in Czech children.

We investigated the association of the CTLA4 +49 A/G dimorphism with type 1 diabetes in Czech children. Genotyping of 305 diabetic children and 289 controls by a novel PCR-ARMS assay revealed no significant differences in the genotypic or allelic frequencies. This may be another piece of evidence against the +49 A/G transition as the aetiological polymorphism within the CTLA4 gene.

[Prediction of insulin-dependent diabetes mellitus in children of first-degree relatives of diabetic patients]. / Predikce inzulin dependentního diabetes mellitus u detských prvostupnových príbuzných diabetických pacientu.

BACKGROUND: Individuals at risk for insulin dependent diabetes mellitus (IDDM) can be identified using a combination of genetic, immunological and metabolic markers. Our study was aimed at prediction of IDDM in a cohort of children having a first-degree relative with IDDM. METHODS AND RESULTS: In the period of three years, we investigated 208 non-diabetic children and adolescents, aged 10.0 +/- 5.3 (mean +/- SD), mostly siblings of diabetic children. The genetic risk was determined by the HLA-DQB1, -DQA1 genotyping and subtyping of the DRB1*04 alleles carried on the DQB1*0302 haplotypes. Insulitis was detected using a combination of autoantibody tests against three molecular-defined antigens (insulin, GAD65, IA-2). Prevalence of insulitis (defined as confirmed positivity of at least one autoantibody) was 9/208 (4.3%). In children carrying the IDDM highest-risk genotype (HLA-DQB1*0201-DQA1*05/DQB1*0302-DQA1*03), insulitis was almost 10 times more frequent (5/24, 21%) than in children with other genotypes (4/184, 2.2%, P = 0.003). In all subjects with insulitis, the first phase insulin response (FPIR) was determined by the intravenous glucose tolerance test. Three of the nine children had decreased FPIR, of whom two were later diagnosed with IDDM. None of the remaining children developed IDDM. CONCLUSIONS: We present the first IDDM prediction study in the Czech population, emphasising the utility of genetic risk investigation in the prediction scheme.

HLA class II genetic association of type 1 diabetes mellitus in Czech children.

To examine human leukocyte antigen (HLA) class II association of type 1 diabetes mellitus (DM) in Czech children, we performed a case-control study of 261 patients diagnosed before the age of 15 and 289 non-diabetic control children. Complete HLA-DQA1, DQB1 genotyping and DRB1*04 subtyping were carried out by polymerase chain reactions with sequence-specific primers. The effect of the DRB1*04 subtypes was studied in DRB1*04 alleles carried on DQB1*0302-DQA1*03 haplotypes. The risk was statistically evaluated by testing 2 x 2 tables, considering corrected p-values < 0.05 significant. The DQB1*0302 (odds ratio, OR = 9.0), DQB1*0201 (OR = 3.4) and DQA1*03 (OR = 7.5) alleles were significantly associated with diabetes risk, while the DQB1*0602 (OR = 0.02), DQB1*0301 (OR = 0.08), DQB1*0503 (OR = 0.13), DQB1*0603 (OR = 0.20), DQA1*01 (OR = 0.28) and DQA1*02 (OR = 0.26) alleles were significantly protective. Of the DQA1-DQB1 genotypes, we point out the extremely high risk of OR = 116 conferred by HLA-DQA1*05-DQB1*0201/DQA1*03-DQB1*0302. Among DRB1*04 subtypes, DRB1*0403 was significantly protective (OR = 0.05, CI 95% 0.01-0.45). Since none of the remaining DRB1*04 subtypes was associated with type 1 DM, our study may present another piece of evidence that the DRB1*0401 and DRB1*0404 alleles do not modify type 1 diabetes risk generally in European populations.

Type 1 diabetes mellitus in Czech children diagnosed in 1990-1997: a significant increase in incidence and male predominance in the age group 0-4 years. Collaborators of the Czech Childhood Diabetes Registry.

AIMS: To overview total, age-and sex-specific incidence rates of type 1 diabetes mellitus and their trends in Czech children 0-14 years of age in the period of 1990-1997. METHODS: Type 1 DM cases were ascertained by two independent sources, data of general population were obtained from the annual demographic reports of the State Statistic Bureau. Incidence rates were computed using both ascertainment sources combined. RESULTS: In the study period 1.1.1990-31.12.1997, the total incidence was 10.1 (95% CI 9.6-10.6) per 100,000/year in both sexes, 10.0 (95% CI 9.4-10.7) in boys, and 10.2 (95% CI 9.5-11.0) in girls. The total age-standardized incidence was 9.9 (95% CI 9.4-10.4). The total incidence had a significant increasing trend over the study period (P= 10(-4), annual increment 4.3%). A significant increasing trend was also found in the groups of children 0-4 (P = 0.033, increment 6.9%) and 5-9 years at diagnosis (P = 0.038, increment 4.8%). Statistically significant male predominance was observed in the group diagnosed at age 0-4 years (boys/girls ratio of incidence 1.33, P = 0.035). CONCLUSIONS: We report the first population-based epidemiological data on incidence of childhood Type 1 DM in the Czech Republic. The incidence has increased significantly during the last 8 years. The present incidence is at an intermediate level compared to other European countries.

HLA-DQA1*05-DQB1*0201 positivity predisposes to coeliac disease in Czech diabetic children.

UNLABELLED: The aims of this study were to estimate the prevalence of coeliac disease (CD) in Czech children with insulin dependent diabetes mellitus (IDDM), and to determine the contribution of HLA-DQA1 and DQB1 to CD susceptibility among diabetic children. We screened 345 children with IDDM (186 boys and 159 girls, aged 0 to 18 y) for coeliac disease using the IgA endomysial antibodies (EMA) test. In all EMA-positive children, small bowel biopsy was performed to confirm CD. To determine the role of the HLA-DQA1*05-DQB1*0201 (DQ2) and the DQA1*03-DQB1*0302 (DQ8) molecules in CD susceptibility among diabetic children, the HLA-DQA1-DQB1 was genotyped in all EMA-positive, and in 186 of EMA-negative diabetic patients. EMA positivity was found in 15/345 (4.3%) diabetic children. The diagnosis of CD was established in 14/345 (4.1%) children based on a bioptic finding of villous atrophy, while the remaining EMA-positive patient had a normal bioptic finding, being diagnosed as a potential CD. The HLA DQA1*05-DQB1*0201 (DQ2) molecule conferred a significant risk of CD among diabetic children (odds ratio = 4.1, CI 95% 1.1-15), being found more frequently in diabetic children with CD (80%) than in diabetic children without CD (49%). CONCLUSION: The high prevalence of CD (4.1%) found in Czech children with IDDM emphasizes the need for their regular screening. We suggest that this CD screening protocol may be individualized according to the DQA1*05-DQB1*0201 positivity.

[Autoantibodies to GAD65, IA2 and insulin in Czech children with type 1 diabetes]. / Autoprotilátky proti GAD65, IA2 a inzulinu u ceských detí pri manifestaci diabetu 1. typu.

BACKGROUND: Autoimmune insulitis leading to insulin dependent diabetes mellitus (IDDM, Type 1 Diabetes) is accompanied by autoantibodies as its invaluable markers. The aim of the study was to determine the frequency of autoantibodies against GAD65, IA2 and insulin in Czech diabetic children at the disease onset. METHODS AND RESULTS: Sera of 105 newly diagnosed children with IDDM drawn within 24 hours after the first insulin dose were investigated for anti-GAD65, anti-IA2 and insulin autoantibodies (IAA) using RIA methods. The cut-off normal levels were determined as the 99th percentile of 105 non-diabetic children. At given 99% specificity, the sensitivity was 71% for anti-GAD65, 73% for anti-IA2, and 46% for IAA. 29% diabetic children were positive for all three autoantibodies, 25% had anti-GAD65 and anti-IA2 (IAA negative), 5.7% anti-GAD65 and IAA (anti-IA2 negative), 7.6% anti-IA2 and IAA (anti-GAD65 negative). As the only positive autoantibody, anti-GAD65 was found in 12%, anti-IA2 in 11%, and IAA in 3.8% children. In 5.7% children, none of the investigated autoantibodies was positive. Diabetic children diagnosed before the age of 5 years had significantly higher prevalence of IAA than the older ones. CONCLUSIONS: We have determined normal levels in healthy children, and prevalence at childhood IDDM onset of autoantibodies against three main molecular-defined autoantigens.

Premenarchal and postmenarchal girls with insulin-dependent diabetes mellitus: ovarian and other organ-specific autoantibodies, menstrual cycle.

STUDY OBJECTIVE: To estimate various organ-specific autoantibodies and detect other endocrine autoimmune disorders and menstrual cycle characteristics in girls with Type 1 insulin dependent diabetes mellitus (IDDM). DESIGN: Prospective cohort study from 1993 to 1998, duration 4.5 years. SETTING: Diabetes & Endocrine Clinic of the University Hospital, Motol, Prague. PATIENTS: 53 IDDM girls (group A--43 postmenarchal, group B--10 premenarchal), 15.5 +/- 2.5 (8-19) years old, 6.2 +/- 4.3 years after IDDM onset. MAIN OUTCOME MEASURES: Ovarian autoantibodies directed to ooplasm, zona pellucida, membrana granulosa, theca folliculi interna, and lutein cells, insulin autoantibodies, thyroid peroxidase and thyroglobulin autoantibodies. Menstrual cycle character, endocrine glands disturbance. Diabetes control, body mass index, duration of IDDM. RESULTS: Ovarian autoantibodies in at least one of the followed structures were found in 67.9% of the IDDM girls. In the control group of 21 healthy girls of corresponding age, the positive findings in lutein cells were found in only 4.8% of the girls (P < 0.01 versus IDDM girls). The lutein cells commonly associated with theca folliculi interna cells were the most frequent immunopositive structures in diabetic girls (P < 0.05 versus another positive ovarian autoimmune structure). Autoantibodies directed to ovarian steroid producing cells were frequent in IDDM patients with both irregular and normal menstrual cycles. Irregular menstrual cycles were diagnosed in 27.9% of IDDM girls, polymenorrhea in half of them, and oligomenorrhea in the remainder. Diabetes control in our patients (glycosylated hemoglobin HbA1c in postmenarchal girls 10.1 +/- 2.0%) did not differ between those with regular and those with irregular menstrual cycles. Over a follow-up period one-third of the girls with oligomenorrhea and a long-term noncompliance (HbA1c 13.5%) developed secondary amenorrhea. Insulin autoantibodies were found in 67.8%, thyroid peroxidase autoantibodies in 12.5%, and thyroglobulin autoantibodies in 10.4% of the IDDM girls. Autoimmune thyroiditis was diagnosed in 5 IDDM patients (9.4%); hypothyroidism developed in 3 of them. Menstrual cycle was irregular in 4 of the 5 girls with autoimmune thyroiditis (polymenorrhea in 1, oligomenorrhea in another 3 girls). CONCLUSIONS: An increased incidence of various circulating autoantibodies may be markedly demonstrated in IDDM girls. Their reproductive function might have an important relationship to an evidence of ovarian autoantibodies. Menstrual cycle disturbances could be linked to the poor diabetes control, to the presence of ovarian and other autoantibodies, and also to other autoimmune disease.

Severe hypoglycemia and reduction of insulin requirement in a girl with insulin-dependent diabetes mellitus: first sign of a craniopharyngioma.

A girl with a history of insulin-dependent diabetes mellitus since 5.5 years, and Hashimoto's thyroiditis since 12 years, developed episodes of severe hypoglycemia from the age of 12 years. This was associated with falling insulin requirements, from 0.78 U/kg/day at 11 years to 0.34 U/kg/day at 16 years. At 16 years she was found to have GH, gonadotropin, ACTH, and probably also TSH deficiency with hyperprolactinemia. MRI scan revealed a cystic intrasellar craniopharyngioma with moderate suprasellar extension. In spite of cortisol replacement at 17 years, insulin requirement fell further to 0.25 U/kg/day at 18 years. In this girl, decreasing insulin requirements represented an early manifestation of combined growth hormone and cortisol deficiency.