Altered distribution of the debrisoquine oxidative phenotypes in children with type 1 diabetes mellitus.

OBJECTIVE: The recently observed increase in the incidence of type 1 diabetes mellitus (Type 1 DM) suggests a major role of environmental factors in the etiopathogenesis of the disease. The individual variation in cytochrome P(450)IID6 may influence the individual susceptibility to environmentally linked diseases. We aimed to evaluate the prevalence of cytochrome P(450)IID6 phenotypes in Hungarian children with Type 1 DM (n = 69) compared to healthy controls (n = 100). METHODS: Debrisoquine was administered orally and debrisoquine hydroxylation phenotype was determined as a metabolic ratio of urinary recovered debrisoquine and 4-hydroxydebrisoquine. RESULTS: Eight of the 100 healthy subjects (8%) and 15 of the 69 diabetic children (22%) (p < 0.05) had cytochrome P(450)IID6 poor metabolizer phenotype (metabolic ratio > or =12.6). CONCLUSION: Cytochrome P(450)IID6's activity may play a role in the development of Type 1 DM.

HbA1c levels and erythrocyte transport functions in complication-free type 1 diabetic children and adolescents.

Higher erythrocyte sodium-lithium countertransport activity (SLC) is implicated in the development of diabetic nephropathy. Altered glucose homeostasis and genetic susceptibility are claimed to play a role in the elevation of SLC. We aimed to test whether metabolic control or the genetic variants of G protein beta 3 (Gb3) subunits determine SLC and other erythrocyte transport activities in complication-free stage of type 1 diabetes. A total of 96 complication-free type 1 diabetic children and adolescents were enrolled. SLC, Na(+)/K(+)-ATPase (NAK) and Ca(2+)-ATPase (CA) were measured by functional assays in erythrocytes. Gb3-C825T polymorphism was determined by PCR-RFLP. Results were related to HbA(1c) and were compared to those of 97 healthy controls. SLC activity was higher in diabetics (387+/-146 vs. 280+/-65 mmol/RBC. hour) and correlated with HbA(1c) levels (y=0.004x+6.42, r=0.33, n=96, p<0.01). NAK and CA activities were unaltered. The prevalence of (825)T allele was similar in the patient and control groups (0.34 vs 0.37) and no differences in enzyme activities were observed between the (825)T allele-positive and negative subjects. Although metabolic control correlated with SLC, other membrane functions were not affected. Therefore we hypothesize that the relationship between advanced glycation and SLC elevation is not causative. Rather, a genetic susceptibility for the coexistence of poor metabolic control and higher SLC is more likely. However, the presence of Gb3-C825T variant is not likely to be a risk factor for SLC-elevation and altered metabolic control diabetes.

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

Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine, which also influences blood pressure (BP). The G-308A polymorphism of the TNF-alpha gene is associated with altered TNF-alpha production. The prevalence of the TNF-alpha-308A allele is reportedly higher among patients with type 1 diabetes mellitus (T1DM) than in the healthy population. In this study we investigated whether this genetic polymorphism might correlate with BP values in diabetic adolescents. Ambulatory BP monitoring (ABPM) was performed in 126 adolescents with T1DM (mean age: 14 +/- 2.4 years). The TNF-alpha G-308A genotype was determined by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methodologies. ABPM results were related to healthy reference values and are given as standard deviation score (SDS). The prevalence of the -308A allele was higher in diabetic adolescents than the Hungarian reference population (0.26 vs 0.14, p < 0.01). TNF-alpha genotype was associated both with systolic and diastolic BP values (p < 0.01 and p < 0.01, respectively). In patients with TNF-alpha-308GG and -308GA/AA genotypes, the 24-h systolic BP average values were 0.37 +/- 1.33 and -0.38 +/- 1.28 SDS, while 24-h diastolic BP average values were 0.09 +/- 1.30 and -0.67 +/- 1.31 SDS. Hence, the TNF-alpha-308A allele carrier state appears to be associated with lower systolic and diastolic BP values.

No association between asthma or allergy and the CCR5Delta 32 mutation.

AIMS: To investigate whether the presence of the CCR5Delta32 allele was associated with atopy or asthma. METHODS: A total of 118 children with asthma, 145 children with non-asthmatic, but allergic phenotype, and 303 children without allergic or asthmatic disorders were studied. RESULTS: There were no significant differences in the frequency of CCR5Delta32, or in the distributions of genotypes between the groups. The relative eosinophil blood count was slightly lower in patients with heterozygous genotype, than in patients with wild type genotype. CONCLUSION: No association was found between the susceptibility of allergy or asthma and the functional deficient CCR5Delta32 allele.

Lack of association between atopic eczema/dermatitis syndrome and polymorphisms in the promoter region of RANTES and regulatory region of MCP-1.

BACKGROUND: Chemokines play an important role in the pathophysiology of atopic eczema/dermatitis syndrome (AEDS) and allergy. Recently polymorphisms in the promoter region of RANTES (regulated on activation normal T cell expressed and secreted) and in the gene regulatory region of MCP-1 (monocyte chemoattractant protein-1) have been found, which increase the expression of these chemokines. The - 403A allele of the RANTES promoter region was found associated with AEDS in German children. We investigated whether the presence of these polymorphisms was associated with AEDS or allergy in Hungarian children. METHODS: One hundred and twenty-eight children with AEDS, 102 allergic children without AEDS and 303 children of comparable ages without allergic disorders were screened for genotype with a PCR-based assay. RESULTS: There were no significant differences in the frequency of these polymorphisms, or in the distribution of genotypes between the groups. The total IgE concentration, the white blood cell count and the blood eosinophil cell count did not differ between the genotypes. CONCLUSION: In this cohort of Hungarian children there was no association between - 28G, and - 403A alleles in the RANTES promoter, - 2518G polymorphism in the distal regulatory region of the MCP-1 and AEDS, or allergy.

Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity.

BACKGROUND: Chemokines play an important role in the pathophysiology of asthma and allergy. Recently, polymorphisms in the gene regulatory region of monocyte chemoattractant protein 1 (MCP-1) and in the promoter region of RANTES have been found; these polymorphisms increase the expression of the chemokines. OBJECTIVE: We investigated whether the presence of the polymorphisms was associated with atopy or asthma and whether these alleles influenced the severity of asthma in affected individuals. METHODS: Three groups of subjects-160 children with asthma (disease severity being classified according to the Global Initiative for Asthma guidelines, modified for children), 151 children with nonasthmatic but allergic phenotype, and 303 children without allergic or asthmatic disorders-were screened with a PCR-based assay for genotyping. RESULTS: The frequency of the -2518G polymorphism in the gene regulatory region of MCP-1 was significantly higher in asthmatic children than in controls (P <.001; odds ratio [OR] = 2.0 [1.4-2.6]) and nonasthmatic atopic children (P <.001; OR = 2.0 [1.4-2.9]). The MCP-1 G/G genotype correlated with asthma severity. In asthmatic children, the MCP-1 -2518G allele was also associated with an increased blood eosinophil level. The promoter polymorphisms in the RANTES gene did not have a detectable effect on the susceptibility to asthma or allergy or on the blood eosinophil count. CONCLUSION: In this cohort of children, there are associations between carrying G at -2518 of the MCP-1 gene regulatory region and the presence of asthma as well as between asthma severity and homozygosity for the G allele. In asthmatic children, the MCP-1 -2518G polymorphism correlated with increased eosinophil levels. This variant of MCP-1 might belong to the predictor gene set for asthma.

[Diabetic ketoacidosis in childhood]. / Gyermekkori diabeteses ketoacidosis.

Diabetic ketoacidosis is the most serious acute complication of insulin-dependent diabetes mellitus and the most frequent reason for hospital admission of diabetic children. The most frequent cause of death of these patients is also the diabetic ketoacidosis. The mortality rate of the disease has not changed since the seventies (1-2%). In this work, the data of 89 patients with diabetic ketoacidosis were analyzed. These patients were admitted to the 1. Department of Pediatrics of the Semmelweis University of Medicine between 1992-1997. The data (metabolic parameters, the causes of ketoacidosis and the length of hospital stay) of previously known diabetic children was compared with the data of previously unknown diabetic children. Our patients were divided in 2 groups: serious (n = 11), and mild-to-moderate (n = 48) acidosis. Their laboratory findings, their intravenous infusion-, and insulin demand and the length of their hospital stay were compared. The state of consciousness at their hospitalisation and the concomitant complications were also examined. Significant difference was found only in the duration of intravenous insulin administration (with the exception of pH and BE, of course). There was no relationship between the seriousness of the disease and the duration of hospital treatment. It is noteworthy that even the previously known diabetic children with the shortest hospitalization spent more than 7 days at the department.