Growth disorders in children with type 1 diabetes mellitus

The aim of the research was to analyze anthropometric variables in children with type 1 diabetes mellitus (DM) in relation with the stage of pubertal development at onset of disease and quality of metabolic control over five-year long observation. Diagnosed children were taller than their peers. This especially referred to age group between 4 and 9.5 years. On the whole, weight of the patients and healthy controls did not differ. However, the diagnosed children had substantially lower weight in puberty than healthy controls. Body mass index was significantly lower in the group of diagnosed children on the whole and in puberty. During a five-year long observation patients have had a significant retardation of growth. However, that retardation referred primarily to patients in prepuberty. Growth retardation was more pronounced with bad metabolic control. Growth was satisfactory if onset of disease had been in puberty. A significant weight gain was observed in patients in puberty whereas in those in prepuberty there was no significant change of body weight at the end of five-year long observation. Metabolic control did not affect observed changes. There were significant differences of anthropometric variables between those suffering from type 1 DM and their peers. The differences depended on the age at onset. The disease had a negative effect on growth with onset in prepuberty, whereas in puberty growth was satisfactory. However, puberty was a period in which patients increased their weight excessively. Prepuberty was a period in which growth had been significantly affected by metabolic control.     

Actual treatment with insulin in children and adolescents with diabetes type 1

A significant progress in the therapy of type 1 diabetes has been achieved. This was mainly because glucometers are now introduced in the majority of patients, better pens for insulin injections are now available. A progress was done in the methods of education and insulin analogues like Humalog were introduced. Therefore it is now possible to achieve a better metabolic compensation because of a more physiologic insulin action. A further progress is the introduction of long acting analogues and personal insulin pumps for the therapy. There are a lot of examinations about the epidemiology and prophylaxis of diabetes.     

Early markers of glycaemic control in children with type 1 diabetes mellitus

Background

Type 1 diabetes mellitus (T1DM) may lead to severe long-term health consequences. In a longitudinal study, we aimed to identify factors present at diagnosis and 6 months later that were associated with glycosylated haemoglobin (HbA_1c) levels at 24 months after T1DM diagnosis, so that diabetic children at risk of poor glycaemic control may be identified.

Methods

229 children <15 years of age diagnosed with T1DM in the Auckland region were studied. Data collected at diagnosis were: age, sex, weight, height, ethnicity, family living arrangement, socio-economic status (SES), T1DM antibody titre, venous pH and bicarbonate. At 6 and 24 months after diagnosis we collected data on weight, height, HbA_1c level, and insulin dose.

Results

Factors at diagnosis that were associated with higher HbA_1c levels at 6 months: female sex (p<0.05), lower SES (p<0.01), non-European ethnicity (p<0.01) and younger age (p<0.05). At 24 months, higher HbA_1c was associated with lower SES (p<0.001), Pacific Island ethnicity (p<0.001), not living with both biological parents (p<0.05), and greater BMI SDS (p<0.05). A regression equation to predict HbA_1c at 24 months was consequently developed.

Conclusions

Deterioration in glycaemic control shortly after diagnosis in diabetic children is particularly marked in Pacific Island children and in those not living with both biological parents. Clinicians need to be aware of factors associated with poor glycaemic control beyond the remission phase, so that more effective measures can be implemented shortly after diagnosis to prevent deterioration in diabetes control.     

Humoral reaction to Bordetella pertussis antigens: pertussis toxin, filamentous hemagglutinin and lipopolysaccharide in children with clinical symptoms of whooping cough. II. Occurence and level of B. pertussis antigens in children with suspected whooping cough

The aim of this study was to determine and evaluate IgG, IgM and IgA levels to pertussis toxin (PT), filamentous hemagglutinin (FHA) and endotoxin (LPS) of B. pertussis in children with clinical symptoms of whooping cough. The serum samples obtained from 265 children (age range: 2 months-16 years) suspected of pertussis were examined by indirect haemagglutination (IH) and ELISA tests. Higher antibody level was most frequently observed in IgA class to PT, FHA and LPS in 45.3%, 35.1% and 66% of pertussis patients sera respectively. The least positive results were obtained in IgM class to PT and FHA (in 9.8% and 2.6% of children sera respectively) but in the case of LPS applied as the antigen in ELISA, higher IgM level was determined in 46.8% of pertussis patients sera. The four times increase of antibody level to LPS determined by IH was observed in 86.7% of children suspected of pertussis. Humoral response to B. pertussis infection is mainly connected with higher IgA level to PT, FHA, LPS and IgM to LPS in children with clinical symptoms of whooping cough.     

Effect of prior hyperglycemia on IL-6 responses to exercise in children with type 1 diabetes

The proinflammatory cytokine interleukin-6 (IL-6) may modulate the onset and progression of complications of diabetes. As this cytokine increases after exercise, and many other exercise responses are altered by prior glycemic fluctuations, we hypothesized that prior hyperglycemia might exacerbate the IL-6 response to exercise. Twenty children with type 1 diabetes (12 boys/8 girls, age 12-15 yr) performed 29 exercise studies (30-min intermittent cycling at approximately 80% peak O2 uptake). Children were divided into four groups based on highest morning glycemic reading [blood glucose (BG) < 150, BG 151-200, BG 201-300, or BG > 300 mg/dl]. All exercise studies were performed in the late morning, after hyperglycemia had been corrected and steady-state conditions (plasma glucose < 120 mg/dl, basal insulin infusion) had been maintained for > or = 90 min. Blood samples for IL-6, growth factors, and counterregulatory hormones were drawn at pre-, end-, and 30 min postexercise time points. At all time points, circulating IL-6 was lowest in BG < 150 and progressively higher in the other three groups. The exercise-induced increment also followed a similar dose-response pattern (BG < 150, 0.6 +/- 0.2 ng/ml; BG 151-200, 1.2 +/- 0.8 ng/ml; BG 201-300, 2.1 +/- 1.1 ng/ml; BG > 300, 3.2 +/- 1.4 ng/ml). Other measured variables (growth hormone, IGF-I, glucagon, epinephrine, cortisol) were not influenced by prior hyperglycemia. Recent prior hyperglycemia markedly influenced baseline and exercise-induced levels of IL-6 in a group of peripubertal children with type 1 diabetes. While exercise is widely encouraged and indeed often considered part of diabetic management, our data underscore the necessity to completely understand all adaptive mechanisms associated with physical activity, particularly in the context of the developing diabetic child.     

Humoral reaction to Bordetella pertussis antigens: pertussis toxin, filamentous hemagglutinin and lipopolysaccharide in children with clinical symptoms of whooping cough. I. Antibody level for B pertussis antigens in children without respiratory tract infection symptoms

The aim of the first part of this study was to determine antibody level to pertussis toxin, filamentous hemagglutinin and endotoxin of B. pertussis in children without symptoms of respiratory tract infection. The serum samples obtained from 276 children (age range: 6 weeks-16 years) were examined using indirect hemagglutination and ELISA tests. Normal antibody levels to 3 B. pertussis antigens were determined for 95% of the serum samples as the upper cut-off levels depending on children age. Very high level of IgG antibodies to B.perussis antigens was observed in the control population. The lowest antibody level was found in IgA class to pertussis toxin and lipopolysaccharide. It was also established that the IgM level to 3 B. pertussis antigens was rising together with children age.     

Effect of vaccination against pneumococcal infection in children with type 1 diabetes mellitus

Vaccination with polysaccharide pneumococcal vaccine "Pneumo 23" (Sanofi Pasteur, France) was performed in 31 children with type 1 diabetes mellitus (DM1) as well as in 19 children with respiratory tract diseases (asthma, chronic pneumonia), which formed comparison group. Fourty-three unvaccinated children with DM1 were included in the control group. Dynamics of IgG levels to mixture of pneumococcal polysaccharides (PS) included in the vaccine as well as to PS of serotypes 3, 6B, 9N, 23F, and to cell wall polysaccharides of Streptococcus pneumoniae were assessed. Using ELISA method, significant increase of IgG levels to mixture of PS and to PS of pneumococcal serotype 3 was detected. Although intensity of immune response to vaccination in children with respiratory diseases was significantly higher compared to children with DM1 (mean geometric titer of antibodies, proportion of patients with high antibody titers, and with 4-fold seroconversion). Development of methods to strengthen immune response in children with DM1 vaccinated against pneumococcal infection is required.     

Screening for vascular complications in children and adolescents with type 1 diabetes mellitus

Type 1 diabetes mellitus poses a significant health burden, particularly as a result of its microvascular complications. Clinically evident diabetes-related microvascular complications are extremely rare in childhood and adolescence. However, early functional and structural abnormalities may be present a few years after the onset of the disease. Therefore, regular screening for diabetic microvascular disease, particularly retinopathy and nephropathy, are of foremost importance in paediatric diabetes care. Early detection of diabetic microangiopathy and timely treatment of early signs of these complications have a pivotal role in prevention of blindness and end-stage renal failure in children and adolescents with diabetes.     

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.     

Long-lasting immune responses 4 years after GAD-alum treatment in children with type 1 diabetes

A phase II clinical trial with glutamic acid decarboxylase (GAD) 65 formulated with aluminium hydroxide (GAD-alum) has shown efficacy in preserving residual insulin secretion in children and adolescents with recent-onset type 1 diabetes (T1D). We have performed a 4-year follow-up study of 59 of the original 70 patients to investigate long-term cellular and humoral immune responses after GAD-alum-treatment. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with GAD₆₅. Frequencies of naïve, central and effector memory CD4+ and CD8+ T cells were measured, together with cytokine secretion, proliferation, gene expression and serum GAD₆₅ autoantibody (GADA) levels. We here show that GAD-alum-treated patients display increased memory T-cell frequencies and prompt T-cell activation upon in vitro stimulation with GAD₆₅, but not with control antigens, compared with placebo subjects. GAD₆₅-induced T-cell activation was accompanied by secretion of T helper (Th) 1, Th2 and T regulatory cytokines and by induction of T-cell inhibitory pathways. Moreover, post-treatment serum GADA titres remained persistently increased in the GAD-alum arm, but did not inhibit GAD₆₅ enzymatic activity. In conclusion, memory T- and B-cell responses persist 4 years after GAD-alum-treatment. In parallel to a GAD₆₅-induced T-cell activation, our results show induction of T-cell inhibitory pathways important for regulating the GAD₆₅ immunity.     

General screening for celiac disease is advisable in children with type 1 diabetes.

The association between celiac disease (CD) and diabetes mellitus type 1 is well known. Only about one-third of all patients with CD are diagnosed in childhood as a result of typical gastrointestinal symptoms or growth retardation. To evaluate the feasibility of CD screening in diabetic children, we tested autoantibodies to tissue transglutaminase (tTGA) in all children with type 1 diabetes from our pediatric department during a 12-month period. In antibody-positive cases, we analyzed the clinical presentation and offered a duodenal biopsy to confirm the diagnosis and grade the severity of the inflammatory process. Of 205 children, 13 (6.3 %) were tTGA-positive. In seven of eight children who agreed to perform a biopsy, CD typical histological signs were detected (Marsh 1: n = 1, Marsh 3: n = 6). In three patients with confirmed disease, symptoms (iron deficiency, recurrent abdominal pain) remained undiscovered up to time of screening (latent form); in four, the disease was asymptomatic (silent form). Since clinical symptoms are mostly mild or absent in spite of severe signs of duodenal inflammation, we recommend tTGA screening in all diabetic children. This strategy may allow the identification of patients in an early stage in respect of prevention of long-term complications.     

The proinsulin level in blood of children with type 1 diabetes mellitus of various duration

Proinsulin content was measured in the serum of 82 children (aged from 3 to 14 years) with type 1 diabetes mellitus of various duration. Three groups of patients characterized by low (54%), normal (42%) and high (4%) levels of this prohormone were recognized. No dependence between the proinsulin level and duration of this disease term was found. The serum proinsulin level may be used as a parameter specifying pathogenesis of type 1 diabetes mellitus.     

Screening for associated autoimmunity in type 1 diabetes mellitus with respect to diabetes control

As an autoimmune disease, type 1 diabetes mellitus (DM) can be associated with other autoimmune disorders. The aim of this study was to detect subclinically associated autoimmune thyroid disease, coeliac disease, and Addison's disease. The presence of autoantibodies was evaluated with special regard to the control of diabetes and to the clinical status of the patient. Fifty-one type 1 diabetic patients (22 men, 29 women, mean age 37+/-11 years, mean duration of diabetes 16+/-13 years) were included into this study. Specific antibodies to islet antigens--glutamic acid decarboxylase (GAD65), protein thyrosine phosphatase IA-2alpha, and to thyroid autoantigens--thyroid microsomal peroxidase (TPO) and thyroglobulin (TG) and also thyroid stimulating hormone (TSH) were measured by RIA. Autoantigens of the small intestine--tissue transglutaminase autoantibodies (ATTG), IgA and IgG antibodies to gliadin (AGA-IgA, AGA-IgG) were evaluated by ELISA. Endomysial autoantibodies (EMA) and adrenal cortex antibodies (ACA) were detected by indirect immunofluorescence microscopy. Eleven new cases of thyreopathy (22 % of patients) were detected by the assessment of thyroid autoantibodies and TSH. Two new cases of thyreotoxicosis were diagnosed during the study. Coeliac disease was diagnosed in at least two cases. Addison's disease was not diagnosed, although the ACA were positive in two patients. No influence of single or combined autoantibody positivity on the control of diabetes was found if normal organ function was preserved. In both patients with thyreotoxicosis the control of diabetes was worsened and improved after treatment. The screening of autoantibodies in type 1 diabetic patients could reveal subclinical cases of AITD or coeliac disease. Subclinical forms of these disorders have no influence on diabetes control. However, impaired organ function may be associated with the worsened control of diabetes as we demonstrated on two newly diagnosed cases of thyreotoxicosis. We suggest the need for the follow-up of patients with positive autoantibodies because further deterioration of the respective organs can be expected.     

Increased frequency of islet cell antibodies in unaffected brothers of children with type 1 diabetes

AIM: To assess the relation between islet cell antibody (ICA) positivity and demographic characteristics in an extensive series of first-degree relatives of children with type 1 diabetes (T1D). METHODS: Family members of children diagnosed with T1D before the age of 16 years and attending one of 27 participating paediatric units in Finland taking care of children with diabetes were invited to volunteer for an ICA screening program aimed at identifying individuals eligible for inclusion in the European Nicotinamide Diabetes Intervention Trial (ENDIT). The final series comprised 2,522 first-degree relatives (1,107 males) with a mean age of 20.4 (range 0.1-51.9) years, out of whom 390 were fathers, 622 mothers, 717 brothers, and 793 sisters of affected cases. RESULTS: Two hundred and four family members (8.1%) tested positive for ICA with levels ranging from 3 to 564 (median 18) Juvenile Diabetes Foundation (JDF) units. One hundred and five relatives (4.2%) had an ICA level of 18 JDF units or more. Males had detectable ICA more often than females (9.6 vs. 6.9%; p = 0.02). Antibody-positive family members under the age of 20 years had higher ICA levels than the older ones [median 18 (range 3-514) JDF units vs. 10 (range 3-564) JDF units; p = 0.008]. Among the adult relatives (>or=20 years of age) antibody-positive females had higher ICA levels than the males [median 10 (range 5-564) JDF units vs. 9 (range 3-130) JDF units; p = 0.04]. Siblings had an increased frequency of high-titre ICA (>or=18 JDF units) when compared to the parents (4.8 vs. 3.2%; p = 0.05). Among siblings, we found a higher frequency of ICA positivity in brothers than in sisters (10.8 vs. 6.9%; p = 0.01), and this was also true for high-titre ICA (6.0 vs. 3.8 %; p = 0.04). Geographically, the highest ICA prevalence was seen among relatives living in the middle of Finland (10.4 vs. 7.2% in the other parts of Finland; p = 0.01). CONCLUSIONS: These results imply that male gender and young age favour positive ICA reactivity among family members of children with T1D. Siblings test positive for high ICA titres (>or=18 JDF units) more frequently than parents. Accordingly, judged from demographic characteristics, the yield of ICA screening in first-degree relatives would be maximized by targeting young brothers of affected cases.     

Humoral response to oligomeric human immunodeficiency virus type 1 envelope protein.

The humoral immune response to human immunodeficiency virus type 1 (HIV-1) is often studied by using monomeric or denatured envelope proteins (Env). However, native HIV-1 Env complexes that maintain quaternary structure elicit immune responses that are qualitatively distinct from those seen with monomeric or denatured Env. To more accurately assess the levels and types of antibodies elicited by HIV-1 infection, we developed an antigen capture enzyme-linked immunosorbent assay using a soluble, oligomeric form of HIV-1IIIB Env (gp140) that contains gp120 and the gp41 ectodomain. The gp140, captured by various monoclonal antibodies (MAbs), retained its native oligomeric structure: it bound CD4 and was recognized by MAbs to conformational epitopes in gp120 and gp41, including oligomer-specific epitopes in gp41. We compared the reactivities of clade B and clade E serum samples to captured Env preparations and found that while both reacted equally well with oligomeric gp140, clade B seras reacted more strongly with monomeric gp120 than did clade E samples. However, these differences were minimized when gp120 was captured by a V3 loop MAb, which may lead to increased exposure of the CD4 binding site. We also measured the ability of serum samples to block binding of MAbs to epitopes in gp120 and gp41. Clade B serum samples consistently blocked binding of oligomer-dependent MAbs to gp41 and, to a slightly lesser extent, MAbs to the CD4 binding site in gp120. Clade E serum samples showed equivalent or greater blocking of oligomer-dependent gp41 antibodies and considerably less blocking of CD4-binding-site MAbs. Finally, we found that < 5% of the antibodies in clade B sera bound to epitopes present only in monomeric gp120, 30% bound to epitopes present in both monomeric gp120 and oligomeric gp140, and 70% bound to epitopes present in oligomeric gp140, which includes gp41. Thus, captured oligomeric Env closely reflects the antigenic characteristics of Env protein on the surface of virions and infected cells, retains highly conserved epitopes that are recognized by antibodies raised against different clades, and makes it possible to detect a much greater fraction of total anti-HIV-1 Env activity in sera than does native monomeric gp120.     

Evaluation of renal blood flow by Doppler study in children and adolescents with type 1 diabetes

Renal blood flow was ultrasonographically studied in 220 children, adolescents, and young, postpubertal patients who had fell ill with type 1 diabetes mellitus (DM) in childhood (of them there were 111 (49.8%) males and 112 (50.2%) females with a disease history of 1 to 27 years (73 patients with diabetic nephropathy (DN) and 150 without DN). Thirty apparently healthy children and adolescents made up a comparison group. Doppler duplex scanning and Doppler pulse-wave study (DPWS) were made at the level of the great renal artery, segmental, interlobar, and arcuate arteries. With DPWS, the values of peripheral resistance were lower than the normal values at the level of interlobar and arcuate arteries in all patients with microangiopathies. There were significant differences between the groups of patients with different types of microangiopathies, the group of patients with DM without DMA, and the control group. Echography was used to determine the volumes of the kidneys in 220 patients. In patients with DM, renal volume was significantly greater than that in the control patients (p<0.05).     

Antibiotic therapy in children with pertussis]

The data accumulated within the last years required revision of the indications to the use of antibiotics in treatment of pertussis. One of the aims of antibiotic therapy in pertussis was to prevent colonization of B. pertussis in the respiratory tracts. With that end in view the choice of antibiotics should be limited by those, to which the pathogen is the most sensitive i.e. erythromycin, ampicillin and augmentin. Comparative efficacy of erythromycin and ampicillin during the first 2 weeks of the disease was studied in 79 infants at the age not older than 1 year with pertussis and it was shown that erythromycin was advantageous by its therapeutic activity and less side effects. Expedience of the antibiotic therapy during the spastic period for providing a preventive effect on development of bronchopulmonary complications was studied in 201 patients with pertussis. No preventive effect of the antibiotics on development of the bronchopulmonary complications defined by the secondary bacterial flora was recorded. In the group of the patients treated with the antibiotics prophylactically (group 1) the complications were 2.6 times more frequent than in the patients treated with pathogenetic agents alone (group 2). Intrahospital pneumonia developed in 8.9 per cent of the patients in group 1 and in 1.5 per cent of the patients in group 2. Therefore, antibiotics should not be used at the late periods of pertussis for prophylaxis of secondary bacterial complications.     

The progress and potential of proteomic biomarkers for type 1 diabetes in children

Introduction: Although it is possible to identify the genetic risk for type 1 diabetes (T1D), it is not possible to predict who will develop the disease. New biomarkers are needed that would help understand the mechanisms of disease onset and when to administer targeted therapies and interventions.

Areas covered: An overview is presented of international study efforts towards understanding the cause of T1D, including the collection of several extensive temporal sample series that follow the development of T1D in at risk children. The results of the proteomics analysis of these materials are presented, which have included bodily fluids, such as serum or plasma and urine, as well as tissue samples from the pancreas.

Expert commentary: Promising recent reports have indicated detection of early proteomic changes in the serum of patients prior to diagnosis, potentially providing new measures for risk assessment. Similarly, there has been evidence that post-translational modification (PTM) may result in the recognition of islet cell proteins as autoantigens; modified proteins could thus be used as targets for immunomodulation to overcome the threat of the autoimmune response.     

Thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus. Effect of age, gender and HLA type

Type 1 diabetes is often associated with additional autoimmune phenomena. However, data reported on the frequency of thyroid autoimmunity differ vastly. Therefore, the prevalence of thyroid autoantibodies was evaluated at a large pediatric diabetes center in Southern Germany. 2,305 determinations (TPO and TG, ELISA) were performed in 495 patients with type 1 diabetes (234 boys, 261 girls; age at last measurement: 15.4 +/- 0.3 years, duration of diabetes 7. 5 +/- 0.2 years). The prevalence of elevated thyroid antibodies increased dramatically with age: from 3.7% in patients less than 5 years of age up to 25.3% in the age group 15-20 years (p < 0.0001). For children older than 10 years, girls were significantly more affected than boys (p < 0.0001). Thyroid autoimmunity tended to be more prevalent in the subgroup of patients with the HLA type DR3/DR4 compared to patients with other HLA types (p = 0.08). In children older than 10 years, basal TSH concentrations were significantly elevated in antibody-positive patients (p < 0.05). In conclusion, thyroid autoimmunity is prevalent in children and adolescents with type 1 diabetes. Adolescent girls and young women are especially affected. Yearly routine determinations of thyroid antibodies are therefore recommended.