Evaluation of glucose metabolism in children with growth hormone deficiency during long-term growth hormone treatment.

Growth hormone (GH) affects carbohydrate metabolism through direct negative effect on insulin sensitivity and indirectly, via insulin-like growth factor-1 (IGF-1), which exerts positive insulin-mimetic action. The aim of this retrospective study was to evaluate the influence of long-term GH treatment on glucose homeostasis in 118 children with isolated idiopathic GH deficiency (GHD). Based on this analysis we wanted to determine the usefulness of glycated haemoglobin (HbA1c) and parameters derived from the oral glucose tolerance test (OGTT) in the monitoring of disturbed glucose metabolism during GH treatment and to assess the value of IGF-1 in prediction of those changes. Mean duration of GH treatment was 2.5 ± 1.2 years. Data were analysed in the whole group and according to baseline pubertal status. Significant increases in insulin concentrations, both fasting and during the OGTT, accompanied by a significant increase in fasting glucose and unchanged glucose concentrations during the OGTT, were found after the initiation of GH treatment. HbA1c did not change significantly during GH treatment in comparison to baseline values and remained normal, even in patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) found during GH treatment. Changes in glucose metabolism observed after the onset of GH treatment were related to increment in IGF-1 SDS and to GH doses. Significant associations between changes in IGF-1 SDS in the first year of GH treatment and some of the glucose metabolism parameters evaluated after the first, the second and the third year of GH treatment were also confirmed in multiple regression analysis after taking the GH dose into consideration. All cases of IFG and/or IGT detected during GH treatment are reversible after dietary intervention, independently of pubertal status, and do not lead to diabetes mellitus.

Relationship Between 25(OH)D and IGF-I in Children and Adolescents with Growth Hormone Deficiency.

Recent studies have shown that vitamin D has an impact on the production and secretion of IGF-I in the liver. The aim of our study was to investigate the relationship between the concentrations of 25-hydroxy vitamin D [25(OH)D] and insulin-like growth factor I (IGF-I) in growth hormone deficient children and adolescents before recombinant human growth hormone (rhGH) treatment. The study was retrospective and included 84 children and adolescents aged 4-17. Prior to initiating rhGH therapy, concentrations of 25(OH)D and IGF-I were measured in all patients. IGF-I concentrations were normalized for bone age. The studied group was divided into two subgroups according to serum 25(OH)D levels. Significant positive correlations between 25(OH)D concentration and IGF-I SDS-normalized for bone age were observed in both studied subgroups. The results of our study suggest that vitamin D deficiency could influence IGF-I concentrations in children and adolescents with growth hormone deficiency, and vitamin D deficiency should be normalized before the measurement of IGF-I concentrations to obtain the reliable and unbiased IGF-I values.

Brown Adipose Tissue and Browning Agents: Irisin and FGF21 in the Development of Obesity in Children and Adolescents.

In the pediatric population, especially in early infancy, the activity of brown adipose tissue (BAT) is the highest. Further in life BAT is more active in individuals with a lower body mass index and one can expect that BAT is protective against childhood obesity. The development of BAT throughout the whole life can be regulated by genetic, endocrine, and environmental factors. Three distinct adipose depots have been identified: white, brown, and beige adipocytes. The process by which BAT can become beige is still unclear and is an area of intensive research. The "browning agents" increase energy expenditure through the production of heat. Numerous factors known as "browning agents" have currently been described. In humans, recent studies justify a notion of a role of novel myokines: irisin and fibroblast growth factor 21 (FGF21) in the metabolism and development of obesity. This review describes a possible role of irisin and FGF21 in the pathogenesis of obesity in children.

Metabolic and immunological consequences of vitamin D deficiency in obese children.

Numerous studies highlighted the link between vitamin D deficiency and cardiovascular, autoimmune, metabolic diseases, and obesity. However, a clear role of vitamin D in these disorders is still unknown. Vitamin D deficiency in children can be a potential risk factor for developing diseases at a later age. Early prevention and vitamin D supplementation should become a public health priority. This review highlights the clinical implications of vitamin D deficiency in adults and children with obesity.

Immunological Characteristics of Children with Hashimoto's Autoimmune Thyroiditis.

The main cause of autoimmune thyroiditis of Hashimoto's type (HT) is a pathological immune response to thyroid antigens. The aim of the study was to present clinical characteristics and immune profile of children with HT. Ninety five children were examined: 45 with HT (age: 8-18 years) and 50 healthy age-matched controls. The peripheral blood mononuclear cells' (PBMC) phenotype was evaluated using a Beckman Coulter flow cytometer with the following monoclonal antibodies: CD4-FITC, CD28-PC5, CD152-PE and CD8-FITC, CD28-PC5, CD152-PE. The thyroid stimulating hormone, thyroid hormones, and antibodies against thyroid peroxidase (TPO) and thyroglobulin (TG) were evaluated by a microparticle enzyme immunoassay. We found that goiter was present in 53% of children, the thyroid had an increased density in palpation in 98%, and hypothyroidism was diagnosed in 11% of HT patients. The number of CD152+ was lower in HT than in healthy children (p<0.05). CD4+ and CD8+ PBMC subsets did not differ between the groups at baseline. After stimulation with phytohemagglutinine (PHA), CD4+ cells decreased in healthy controls and remained constant in HT children. Anti-TPO and anti-TG antibodies were higher in children with a lower percentage of CD152+. No other markers correlated with the immunological profile of PBMC. The percentages of CD4+ and CD152+ negatively correlated with the anti-TG concentration. We conclude that children with HT have a different PBMC profile than healthy children and show a different pattern of response to stimulation.

Decreased CD4+CD152+ T cell subset and its correlation with the level of antithyroid antibodies in children with chronic autoimmune thyroiditis.

OBJECTIVE: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is one of the basic antigens involved in immune responses regulation associated with autoimmune thyroid diseases. The aim of the study was to evaluate whether the surface expression of CTLA-4(CD152) on T cells is correlated with laboratory autoimmune markers in children with Hashimoto's disease. MATERIAL AND METHODS: Blood samples were obtained from 45 children with Hashimoto's thyroiditis of the mean age 14.8 ±2.35 years, and from 55 healthy age-matched children, free of allergic, immune and hematological disorders, and with a normal thyroid function. The anti-thyroid antibodies were measured with Microparticle Enzyme Immunoassay (AxSYM Anti-Tg, AxSYM Anti-TPO). The T cell phenotype was evaluated flow cytometery, with the use of monoclonal antibodies combination: CD4- FITC/ CD28 -PC5/ CD152 -PE and CD8 -FITC/ CD28 -PC5/ CD152 -PE. - RESULTS: The percentage of T cells with CD152 expression was significantly decreased in children with Hashimoto's thyroiditis compared with healthy controls (P<0.001). A significant negative correlation was found between the level of anti-thyroglobulin antibodies and the percentage of CD4+CD152+ T cells (r = -0.34; P<0.05). Anti-thyroperoxidase antibodies did not correlate with CD152 expression. CONCLUSIONS: In children with Hashimoto's thyroiditis, the number of CD4+CD152+ T cells is decreased and negatively correlates with the level of anti-thyroglobulin antibodies.

Proinflammatory cytokines Il-6 and TNF-α and the development of inflammation in obese subjects.

BACKGROUND: The development of obesity and related disorders, e.g., type II diabetes (T2D), hypertension, and metabolic disturbances is strongly related to increased levels in proinflammatory cytokines (IL-1, IL-6, and TNF-α). Both IL-6 and TNF-α are secreted by adipocytes and their concentration correlates with the percentage and distribution of fat tissue in the body. Both cytokines are the main factors responsible for the induction of acute phase proteins production (e.g., CRP) and to inflammatory state. OBJECTIVE: To compare of TNF-α and IL-6 concentrations in serum from obese subjects with those in subjects with normal BMI and to analyze the relation between TNF-α, IL-6, BMI and the inflammatory state as measured by the level of CRP. MATERIAL AND METHODS: The study included 80 obese subject (54 males and 26 females) BMI >25 kg/m⊃2. A control group consisted of 53 healthy subjects (24 males and 29 females) with BMI <25 kg/m⊃2. To determine the blood plasma concentration of IL-6 and TNF, commercial ELISA assay kits were used. RESULTS: The concentration of IL-6 was lower in the control compared with the obese patients, but a significance difference concerned only female subjects (P = 0.001). TNF-α concentration was significantly higher in all obese subjects (P<0.001). A higher level of this cytokine was also found in patients with obesity suffering from T2DM. A positive correlation was present between IL-6 and TNF-α concentrations. Only did the IL-6 level correlate with the concentration of CRP in serum. CONCLUSIONS: The study confirmed that increased inflammatory cytokines lead to the persistence of inflammation in obese subjects. However, some other factors, such as gender, may contribute to the development of obesity-related inflammatory states.

Influence of proinflammatory cytokine gene polymorphism on childhood obesity.

BACKGROUND: Obesity development is a complex process which can be influenced by genetic predisposition modified by environmental factors. Nowadays, the problem of overweight and obesity, including related complications, occurs in increasingly younger children. Thus, there is a need for new genetic markers of increased risk of excessive body mass. OBJECTIVE: The aim of the present study was to examine the relation between polymorphisms located in promoter regions of IL-1beta, IL-6, and TNF-alpha genes and obesity development in children. Fifty obese and 55 normal weighing children were enrolled into the study. Genetic examination was performed using PCR-RFLP technique. RESULTS: We found a relation between G174C polymorphism in IL-6 gene and G308A in TNF-alpha gene with the occurrence of obesity. Allele A in G308A was more frequent in the obese group than in the control one (P=0.04). The presence of allele C in promoter region of IL-6 gene was more frequent in obese children and connected with a statistically significant increase in the sum of 10 skin fold thickness measurements (P=0.03). CONCLUSIONS: The polymorphism C3954T in IL-1beta gene showed no such relation. The examined polymorphisms of proinflammatory cytokines play a role in the regulation of body mass through their influence on metabolism and energetic homeostasis.

Expression of CD152 (CTLA-4) in children with autoimmune thyroiditis and +49 A/G polymorphism of exon 1 of the CTLA-4 gene.

CTLA-4 gene is one of the strongest locus of genetic susceptibility to autoimmune thyroid diseases. The aim of the present study was to investigate surface expression of CTLA-4 on peripheral T cells in homozygotes AA and GG at position +49 of CTLA-4 gene in children with Hashimoto's thyroiditis and in healthy controls. Blood samples were obtained from 100 children: 45 with Hashimoto's thyroiditis and 55 controls. CTLA-4 exon 1 polymorphism was defined by SSCP and RFLP with BbvI enzyme. T cells were analyzed with three color flow cytometry by Coulter EPICS XL. We found that CTLA-4 expression was significantly lower in the thyroiditis patients than in controls, but CTLA-4 expression in homozygotes GG and AA was comparable. We therefore conclude that decreased expression of CTLA-4 on T cells in children with Hashimoto's thyroiditis is not dependent on polymorphic changes at position +49 of CTLA-4 gene.

Association between metabolic disturbances and G-174C polymorphism of interleukin-6 gene in obese children.

OBJECTIVE: The aim of the study was to investigate whether the G-174C polymorphism of the IL-6 gene is related to obesity and the incidence of the metabolic syndrome (MetS) according to IDF definition in children. MATERIALS AND METHODS: The examined group included 124 obese children with BMI > or = 2 SDS, and the control group consisted of 56 non-obese children with BMI <1.0 SDS. Polymorphism identification was performed in total genomic DNA using PCR-RFLP method. RESULTS: In the obese children, carriers of C allele in homozygotic and heterozygotic genotypes were more frequent than in the control group. The carriers of C alleles presented with lower thickness of subcutaneous tissue and higher concentrations of HDL-C than the wild type. The incidence of MetS was 33% of the group of obese children. Analysis of the presence of MetS factors showed that there is more frequent MetS in the group with the wild homozygous genotype type. CONCLUSION: Polymorphism 174G>C in the IL-6 gene does not seem to be associated with obesity and with the incidence of MetS in children.

No association of LEPR Gln223Arg polymorphism with leptin, obesity or metabolic disturbances in children.

OBJECTIVE: The aim of the study was to investigate whether the Gln223Arg in the leptin receptor may influence body weight, leptin concentration, and metabolic parameters in children. MATERIALS AND METHODS: The examined group included 101 obese children (58 girls and 43 boys) with BMI 31.41 +/-5.03 kg/m(2) (BMI > or = 2 SDS) and the control group consisted of 41 children with BMI 20.0 +/-0.80 kg/m2 (BMI <1.0 SDS). Polymorphism identification was performed in total genomic DNA using PCR-RFLP method. RESULTS: The distribution of genotypes LEPR was the following: in the obese group: AA - 20.8%, AG- 55.4%, GG-23.8 %; in the control group AA-31.7%, AG- 53.65%, GG-14.65%. Comparative analyses between AA homozygous children and carriers of G alleles did not confirm any relation between the analyzed polymorphism and BMI, leptin concentrations, and metabolic disturbances in children with obesity. CONCLUSION: In children with obesity we did not observe association of the LEPR Gln223Arg gene polymorphism with obesity, leptin, insulin resistance, and metabolic abnormalities.

Type 1 diabetes and prediabetic state in a monozygotic triplet.

Type 1 diabetes mellitus (IDDM) results from a chronic process of autoimmune destruction of beta cells of the Langerhans islets. The presence of autoantibodies (ICA, GADA, anti-IA2, IAA) in serum precedes the clinical onset of the disease. Genetic predisposition for IDDM is connected with HLA, CTLA-4 and insulin gene region. The aim of the study was the genetic and immunological analysis of a triplet. One of them developed Type 1 diabetes mellitus. We analysed HLA class II, CTLA-4 and insulin gene polymorphisms in the whole family. Besides, we investigated immunological status of three brothers. All patients present identical genotype for VNTR loci: D1S80, D17S5 and Apo B, as well as for HLA-DRB1, -DQA1, -DQB1, CTLA-4 gene and all studied insulin gene polymorphisms. That proves their monozigosity. The triplet presents strong genetic predisposition for IDDM. The two patients without overt diabetes have increased levels of ICA, GADA, IA2 and IAA.