László Madácsy

Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: experience of the PedPump Study in 17 countries

Aims/hypothesisTo assess the use of paediatric continuous subcutaneous infusion (CSII) under real-life conditions by analysing data recorded for up to 90xa0days and relating them to outcome.MethodsPump programming data from patients aged 0–18xa0years treated with CSII in 30 centres from 16 European countries and Israel were recorded during routine clinical visits. HbA1c was measured centrally.ResultsA total of 1,041 patients (age: 11.8u2009±u20094.2xa0years; diabetes duration: 6.0u2009±u20093.6xa0years; average CSII duration: 2.0u2009±u20091.3xa0years; HbA1c: 8.0u2009±u20091.3% [meansu2009±u2009SD]) participated. Glycaemic control was better in preschool (nu2009=u2009142; 7.5u2009±u20090.9%) and pre-adolescent (6–11xa0years, nu2009=u2009321; 7.7u2009±u20091.0%) children than in adolescent patients (12–18xa0years, nu2009=u2009578; 8.3u2009±u20091.4%). There was a significant negative correlation between HbA1c and daily bolus number, but not between HbA1c and total daily insulin dose. The use of <6.7 daily boluses was a significant predictor of an HbA1c level >7.5%. The incidence of severe hypoglycaemia and ketoacidosis was 6.63 and 6.26 events per 100 patient-years, respectively.Conclusions/interpretationThis large paediatric survey of CSII shows that glycaemic targets can be frequently achieved, particularly in young children, and the incidence of acute complications is low. Adequate substitution of basal and prandial insulin is associated with a better HbA1c.

Chemokine receptor CCR2 and CCR5 polymorphisms in children with insulin- dependent diabetes mellitus

Studies have shown the important roles of several regulatory and proinflammatory cytokines in insulin-dependent diabetes mellitus (IDDM). CC-chemokine receptors CCR2 and CCR5 bind chemokines that are involved in the trafficking of leukocytes in both basal and inflammatory states. A common 32-bp deletion mutation in the CCR5 gene (CCR5Δ32) and a G-to-A nucleotide substitution in the CCR2 at position 190 (CCR2-64I) have recently been described. In the present study, we have determined the frequency of the CCR5Δ32 and CCR2-64I alleles in children with IDDM [n = 115; age 1-14 (9.3 ± 4.3) y] and in nondiabetic subjects [n = 280; age 1-14 (8.5 ± 4.5) y]. The CCR5Δ32 allele frequencies were 0.117 in children with IDDM and 0.111 in nondiabetic subjects, indicating that the deletion allele has no association with IDDM. The CCR2-64I allele frequency in children with IDDM was 0.226, which differed significantly from the allele frequency in controls (0.114, p = 0.001). The role of this mutation in IDDM cannot be explained yet, but, because CCR2 mediates the chemotaxis of CD4+ and CD8+ T cells to areas of inflammation and because these cells play important roles in insulitis, a mutation in the CCR2 gene may contribute to the susceptibility to the disease. Alternatively, the 64I allele could be a marker of a linked mutation through linkage disequilibrium. According to these results, the CCR2 gene may be a new candidate for the susceptibility locus of IDDM. However, because no IDDM locus has been identified near 3p21 until now, further investigations are needed to confirm this statement.

Screening detected celiac disease in children with type 1 diabetes mellitus : Effect on the clinical course - (A case control study)

Objective: To investigate clinical and metabolic characteristics of diabetic children with screening detected celiac disease in a multicenter case-control study. Methods: Cases: 98 diabetic patients were diagnosed as having silent celiac disease by screening with endomysial antibodies and subsequent biopsy. Controls: two controls in the same center were chosen, (stratified by age and age-at-diabetes onset) who were negative for endomysial antibodies (n = 195). Height, weight, HbA1c, insulin dosage and acute complications were documented for at least 1 year of follow up. Results: Mean age of diabetes manifestation was 6.5 ± 4.1 years and diagnosis of celiac disease was made at 10.0 ± 5.4 years. Biopsy showed total or subtotal mucosal atrophy in 74 patients. The mean observation period after the diagnosis of celiac disease was 3.3 ± 1.9 years. Mean HbA1c levels were similar between cases and controls (8.63% ± 1.45% versus 8.50% ± 1.39%; P = 0.35). There was also no difference in the frequency of severe hypoglycemia, ketoacidosis and the applied insulin dosage (P = 0.45). Body mass index-standard deviation score at celiac disease diagnosis (0.57 ± 1.24 versus 0.52 ± 1.07) and height-standard deviation score (0.14 ± 1.13 versus 0.30 ± 0.95) did not differ between cases and controls. After diagnosis of celiac disease, weight gain was diminished in boys with celiac disease compared with their controls (P < 0.05). Female cases also had a lower body mass index than female controls (P = 0.067). Conclusion: In a cohort of diabetic children, silent celiac disease had no obvious effect on metabolic control but negatively influenced weight gain.

The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study

Aims/hypothesisThe variants of transcription factor 7-like 2 (TCF7L2) gene have been proposed to be associated with latent autoimmune diabetes in adults (LADA). We sought to confirm the possible association in Europeans and to examine the interaction between one gene variant and clinical data.MethodsThe TCF7L2 rs7903146 C-to-T polymorphism was genotyped in 211 LADA, 1,297 type 2 diabetic, 545 type 1 diabetic and 1,497 control individuals from Hungary. A meta-analysis of our and previously published studies was performed to evaluate the size and the heterogeneity of the gene effect.ResultsThe meta-analysis yielded a significant effect of TCF7L2 T allele (OR 1.28; pu2009<u20090.0001) on LADA risk without heterogeneity among Europeans. The T allele conferred equally strong susceptibility to LADA and type 2 diabetes. In the Hungarian dataset, the T allele was associated with LADA and type 2 diabetes, but not with type 1 diabetes. T allele carriers had significantly lower BMI than patients with the CC genotype in the LADA and type 2 diabetes groups (pu2009=u20090.0021 and pu2009=u20090.0013, respectively). In both diseases, the diabetes risk was significantly higher in the non-overweight than in the overweight BMI category (pu2009=u20090.0013 and pu2009<u20090.0001, respectively); susceptibility to LADA was increased by 2.84-fold in non-overweight individuals compared with overweight ones.Conclusions/interpretationThe meta-analysis demonstrates that TCF7L2 rs7903146 polymorphism is a population-independent susceptibility locus for LADA in Europeans. The effect size is similar for LADA and type 2 diabetes. The gene effect on diabetes risk may be modulated by BMI, such that the lower the BMI, the higher the gene effect.

Cardiovascular autonomic dysfunction in diabetes mellitus.

The aim was to assess cardiovascular autonomic dysfunction in children and adolescents with diabetes mellitus. A total of 110 children and adolescents with type 1 (insulin dependent) diabetes (aged 6 to 18 years) and 130 non-diabetic controls were studied. Resting heart rate, heart rate variation to deep breathing, heart rate response to standing from a lying position, fall in systolic blood pressure on standing, and rise in diastolic blood pressure during sustained handgrip were measured. A reference range of results was obtained in the controls. Diabetic children had significantly increased resting heart rate [92.4 (SEM 2.5) v 84.2 (2.2) beats/min], decreased deep breathing heart rate variation [25.3 (0.9) v 32.8 (0.6) beats/min], and lower standing/lying heart rate ratio [1.23 (0.04) v 1.31 (0.03)] compared with controls. 46 diabetic children (42%) had at least one abnormal autonomic test result. Of these, 20 (15%) had only one abnormal test and 26 (24%) had two or more abnormal tests. Using multiple logistic regression analysis, longer diabetes duration and worse long term metabolic control were independently predictive of cardiovascular autonomic dysfunction as the dependent variable [adjusted OR (95% CI): 2.9 (1.1-5.9) and 3.3 (1.2-6.4), respectively]. Cardiovascular autonomic dysfunction is not rare in children with diabetes. Efforts should be made to maintain the best metabolic control to prevent or delay these complications.

Frequency of coeliac disease in Hungarian children with type 1 diabetes mellitus.

Abstract. Coeliac disease and type 1 diabetes mellitus can frequently coexist, presumably due to a common genetic predisposition. The present study was designed to evaluate the frequency of coeliac disease among Hungarian diabetic children and to study the effect of gluten-free diet on glycaemic control. A total of 205 diabetic children (age range 2.0–17.0 years, median 11.6 years) were screened for coeliac disease by determination of IgA-endomysium (EMA) antibodies. In the positive cases, a jejunal biopsy was performed and, in addition to routine histology, the number of intraepithelial γ/δ T-cells was also determined. Insulin requirement, glycosylated haemoglobin level and body mass index of diabetic children with coeliac disease were determined before and 3 months after the introduction of gluten-free diet. IgA-EMA was positive in 24 cases, 17 of them (8.3% of all diabetic children) had a subtotal villous atrophy and thus coeliac disease was diagnosed. In all but two of these children, the mean number of γ/δ T-cells was elevated (above 7 cells/mm). Of the remaining seven patients with positive EMA but normal villous structure, five (2.4%) had elevated number of epithelial γ/δ T-cells, indicating probable latent coeliac disease. The insulin requirement of the children had significantly increased 3 months after the introduction of gluten-free diet (median values 0.64 versus 0.48xa0U/kg per day, P<0.05). Median body mass indices also showed significant elevation after this period (16.8 versus 14.2xa0kg/m2, P<0.05) Conclusion: the frequency of coeliac disease was high in the studied group. Introduction of a gluten-free diet improved the somatic development of these children. A latent form of coeliac disease is also frequent in children with type 1 diabetes mellitus.

Frequencies of genetic polymorphisms of TLR4 and CD14 and of HLA-DQ genotypes in children with celiac disease, type 1 diabetes mellitus, or both

Objectives: Besides the central role of the adaptive immune system, a disturbance of innate immunity is also involved in the pathogenesis of celiac disease (CD). Inasmuch as CD and type 1 diabetes mellitus (T1DM) frequently coexist because of a common genetic predisposition, our aim was to study the frequency of CD14 C-260T and TLR4 A+896G single nucleotide polymorphisms (SNPs) and the distribution of HLA-DQ genotypes in children affected by CD, T1DM, or both. Patients and Methods: TLR4 and CD14 SNPs were tested by polymerase chain reaction, followed by restriction fragment length polymorphism analysis in 80 children with T1DM, 100 children with CD, and 47 children with both CD and T1DM. Determination of HLA-DQ alleles was done by sequence-specific polymerase chain reaction. Frequencies were compared with those of healthy control children. Results: The prevalence of the homozygous CD14 C-260TT genotype was significantly (P = 0.0081) lower in children with T1DM but not in those with CD and T1DM, compared with control children. No difference was found in the genotype and allele frequencies of TLR4 between the studied groups. In patients with T1DM, the frequency of the homozygous HLA-DQ8 genotype was significantly higher than in CD, whereas the frequency of homozygous or heterozygous HLA-DQ2 genotypes did not differ from that in control children. In patients with CD, both homozygous and heterozygous HLA-DQ2 genotypes were significantly more frequent than in the control and T1DM groups, and no elevation in the frequency of the HLA-DQ8 genotypes was observed. In patients with T1DM and those with CD and T1DM, the occurrence of HLA-DQ2/8 heterozygosity was significantly higher than in children with CD only and in control children. Conclusions: Our results suggest that in patients with T1DM, the CD14 C-260TT homozygous genotype increases the risk for the development of CD. The distribution of HLA-DQ genotype is different in children with CD and T1DM than in children with CD or T1DM only. Determination of the HLA-DQ genotype in children with T1DM may help in estimating the risk for the development of CD.

Insulin pump therapy in children with type 1 diabetes: analysis of data from the SWEET registry

Intensified insulin delivery using multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) is recommended in children with type 1 diabetes (T1D) to achieve good metabolic control.

Type 1 diabetes associated with Hashimoto's thyroiditis and juvenile rheumatoid arthritis: a case report with clinical and genetic investigations

Nagy KH, Lukacs K, Sipos P, Hermann R, Madacsy L, Soltesz G. Type 1 diabetes associated with Hashimotos thyroiditis and juvenile rheumatoid arthritis: a case report with clinical and genetic investigations.

Association between G−308A polymorphism of the tumor necrosis factor‐α gene and 24‐hour ambulatory blood pressure values in type 1 diabetic adolescents

Krikovszky D, V´s´rhelyi B, Tóth‐Heyn P, Körner A, Tulassay T, Madácsy L. Association between G−308A polymorphism of the tumor necrosis factor‐α gene and 24‐hour ambulatory blood pressure values in type 1 diabetic adolescents. u2028Clin Genet 2002: 62: 474–477.