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1.
Acta Diabetol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570993

RESUMO

AIMS: The development of the immune phenotype in patients with type 1 diabetes (T1D) during the first year following disease onset remains poorly described, and studies analysing the longitudinal development of a complex set of immunological and metabolic parameters are missing. Thus, we aim to provide such complex view in a cohort of 38 children with new onset T1D who were prospectively followed for 1 year. METHODS: All subjects were tested for a set of immunological parameters (complete blood count; serum immunoglobulins; and T, B and dendritic cells), HbA1c and daily insulin dose at baseline and at 6 and 12 months after T1D diagnosis. A mixed meal tolerance test was administered to each of the subjects 12 months after diagnosis, and the C-peptide area under the curve (AUC) was noted and was then tested for association with all immunological parameters. RESULTS: A gradual decrease in leukocytes (adjusted p = 0.0012) was reflected in a significant decrease in neutrophils (adjusted p = 0.0061) over the post-onset period, whereas Tregs (adjusted p = 0.0205) and originally low pDCs (adjusted p < 0.0001) increased. The expression of the receptor for BAFF (BAFFR) on B lymphocytes (adjusted p = 0.0127) markedly increased after onset. No immunological parameters were associated with C-peptide AUC; however, we observed a linear increase in C-peptide AUC with the age of the patients (p < 0.0001). CONCLUSIONS: Our study documents substantial changes in the innate and adaptive immune system over the first year after disease diagnosis but shows no association between immunological parameters and residual beta-cell activity. The age of patients remains the best predictor of C-peptide AUC, whereas the role of the immune system remains unresolved.

2.
J Pediatr Endocrinol Metab ; 32(10): 1147-1153, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31483759

RESUMO

Background Paediatric type 1 diabetes (T1D) and rare syndromes of monogenic multi-organ autoimmunity share basic features such as full insulin dependency and the presence of circulating beta-cell autoantibodies. However, the aetiopathogenesis, natural course and treatment of these conditions differ; therefore, monogenic multi-organ autoimmunity requires early recognition. We aimed to search for these monogenic conditions among a large cohort of children with T1D. Methods Of 519 children with T1D followed-up in a single centre, 18 had multiple additional autoimmune conditions - either autoimmune thyroid disease (AITD) and coeliac disease (CD) or at least one additional organ-specific autoimmune condition in addition to AITD or CD. These 18 children were tested by direct Sanger sequencing (four patients with a suggestive phenotype of immune dysregulation, polyendocrinopathy, enteropathy, X-linked [IPEX] or signal transducer and activator of transcription 3 [STAT3]- and cytotoxic T-lymphocyte protein 4 [CTLA4]-associated syndromes) or by whole-exome sequencing (WES) focused on autoimmune regulator (AIRE), forkhead box protein 3 (FOXP3), CTLA4, STAT3, signal transducer and activator of transcription 1 (STAT1), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) and interleukin-2 receptor subunit α (IL2RA) genes. In addition, we assessed their T1D genetic risk score (T1D-GRS). Results We identified novel variants in FOXP3, STAT3 and CTLA4 in four cases. All patients had a severe phenotype suggestive of a single gene defect. No variants were identified in the remaining 14 patients. T1D-GRS varied among the entire cohort; four patients had scores below the 25th centile including two genetically confirmed cases. Conclusions A monogenic cause of autoimmune diabetes was confirmed only in four patients. Genetic screening for monogenic autoimmunity in children with a milder phenotype and a combination of AITD and CD is unlikely to identify a monogenic cause. In addition, the T1D-GRS varied among individual T1D patients.

3.
J Autoimmun ; : 102294, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31256920

RESUMO

BACKGROUND: The aberrant recognition of self-nucleic acids by the innate immune system contributes to the pathology of several autoimmune diseases. Although microbial DNA and, in certain instances, self-DNA that is released from damaged cells are primarily recognized by Toll-like receptor 9 (TLR9), recent evidence suggests that other cytosolic sequence-nonspecific DNA sensors contribute to DNA recognition. In this study, we focused on the sensing of microbial and host DNA in type 1 diabetes (T1D) patients. METHODS: Peripheral blood mononuclear cells (PBMCs) and monocytes from pediatric patients with T1D and from healthy donors were stimulated with microbial DNA (CpG) or with self-DNA (DNA contained within neutrophil extracellular traps, NETs). The production of cytokines was measured by flow cytometry and multiplex bead assays. The internalization of microbial DNA and its colocalization with STING was detected by image cytometry. Furthermore, the involvement of the TBK1 kinase was investigated by detecting its phosphorylation with phospho-flow cytometry or by using a TBK1 inhibition assay. RESULTS: We observed a prominent proinflammatory response in T1D PBMCs, especially pDCs and monocytes, to microbial DNA in comparison to that in controls. We further confirmed that monocytes could bind and internalize DNA and respond by releasing proinflammatory cytokines in a more pronounced manner in T1D patients than those in controls. Surprisingly, this cytokine production was not affected by TLR9 blockade, suggesting the involvement of intracellular receptors in DNA recognition. We further identified TBK1 and STING as two crucial molecules in the DNA-sensing pathway that were involved in CpG-DNA sensing by T1D cells. A similar DNA-sensing pathway that was dependent on intracellular DNA sensors and the STING-TBK1 interaction was employed in response to NETs, which were used to model self-DNA. CONCLUSIONS: Here, we show that there were significant differences in DNA sensing in T1D patients compared to that in controls. We demonstrate that monocytes from T1D patients are able to sense microbial- and self-DNA, leading to proinflammatory cytokine secretion through the adaptor protein STING and the TBK1 kinase.

4.
Diabetologia ; 62(7): 1291-1296, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31025045

RESUMO

AIMS/HYPOTHESIS: This study aimed to assess the ability of human gut microbiota to delay the onset of type 1 diabetes when transferred into germ-free NOD mice. METHODS: Two children with rapid and three children with slow beta cell function loss (as assessed by C-peptide AUC change in the mixed-meal tolerance tests performed 1 and 12 months after type 1 diabetes onset), participating in an ongoing trial with gluten-free diet, donated faeces, which were transferred into germ-free NOD mice. The mice were subsequently followed for diabetes incidence. RESULTS: The bacterial profiles of bacteriome-humanised mice had significantly (p < 10-5) lower alpha diversity than the donor material, with marked shifts in ratios between the main phyla. Diabetes onset was significantly delayed in all bacteriome-humanised colonies vs germ-free NOD mice, but the pace of beta cell loss was not transferable to the mouse model. CONCLUSIONS/INTERPRETATION: Germ-free NOD mice colonised with human gut microbiome are able to adopt a large proportion of transferred bacterial content, although the ratios of main phyla are reproduced only suboptimally. The recipient mice did not replicate the phenotype of the stool donor in relation to the pace towards type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02867436.

5.
J Clin Endocrinol Metab ; 104(10): 4273-4281, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753492

RESUMO

CONTEXT: Familial short stature (FSS) is a term describing a growth disorder that is vertically transmitted. Milder forms may result from the combined effect of multiple genes; more severe short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not been thoroughly elucidated to date. OBJECTIVES: To identify the genetic etiology of severe FSS in children treated with GH because of the diagnosis of small for gestational age or GH deficiency (SGA/GHD). DESIGN, SETTINGS, AND PATIENTS: Of 736 children treated with GH because of GHD/SGA, 33 with severe FSS (life-minimum height -2.5 SD or less in both the patient and shorter parent) were included in the study. The genetic etiology was known in 5 of 33 children prior to the study [ACAN (in 2], NF1, PTPN11, and SOS1). In the remaining 28 of 33, whole-exome sequencing was performed. The results were evaluated using American College of Medical Genetics and Genomics standards and guidelines. RESULTS: In 30 of 33 children (90%), we found at least one variant with potential clinical significance in genes known to affect growth. A genetic cause was elucidated in 17 of 33 (52%). Of these children, variants in growth plate-related genes were found in 9 of 17 [COL2A1, COL11A1, and ACAN (all in 2), FLNB, FGFR3, and IGF1R], and IGF-associated proteins were affected in 2 of 17 (IGFALS and HMGA2). In the remaining 6 of 17, the discovered genetic mechanisms were miscellaneous (TRHR, MBTPS2, GHSR, NF1, PTPN11, and SOS1). CONCLUSIONS: Single-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.

6.
Pediatr Diabetes ; 20(4): 434-443, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30773756

RESUMO

BACKGROUND: Frequent use of modern diabetes technologies increases the chance for optimal type 1 diabetes (T1D) control. Limited reimbursement influences the access of patients with T1D to these modalities and could worsen their prognosis. We aimed to describe the situation of reimbursement for insulins, glucometers, insulin pumps (CSII) and continuous glucose monitoring (CGM) for children with T1D in European countries participating in the SWEET Project and to compare data from EU countries with data from our previous study in 2009. METHODS: The study was conducted between March 2017 and August 2017. First, we approached diabetes technology companies with a survey to map the reimbursement of insulins and diabetic devices. The data collected from these companies were then validated by members of the SWEET consortium. RESULTS: We collected data from 29 European countries, whereas all types of insulins are mostly fully covered, heterogeneity was observed regarding the reimbursement of strips for glucometers (from 90 strips/month to no limit). CSII is readily available in 20 of 29 countries. Seven countries reported significant quota issues or obstacles for CSII prescription, and two countries had no CSII reimbursement. CGM is at least partially reimbursed in 17 of 29 countries. The comparison with the 2009 study showed an increasing availability of CSII and CGM across the EU. CONCLUSIONS: Although innovative diabetes technology is available, a large proportion of children with T1D still do not benefit from it due to its limited reimbursement.

7.
Eur J Endocrinol ; 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30407922

RESUMO

OBJECTIVE: To identify cross-border international registries for rare endocrine conditions that are led from Europe and understand the extent of engagement with these registries within a network of reference centres (RC) for rare endocrine conditions. METHODS: Database search of international registries and a survey of RCs in the European Reference Network for rare endocrine conditions (Endo-ERN) with an overall response rate of 82%. RESULTS: Of the 42 conditions with orphacodes currently covered within Endo-ERN, international registries exist for 32 (76%). Of 27 registries identified in the Orphanet and RD-Connect databases, Endo-ERN RC were aware of 11 (41%). Of 21 registries identified by the RC, RD-Connect and Orphanet did not have a record of 10 (48%). Of the 29 glucose RC, the awareness and participation rate in an international registry was highest for rare diabetes at 75% and 56%, respectively. Of the 37 sex development RC, the corresponding rates were highest for disorders of sex development at 70% and 52%. Of the 33 adrenal RC, the rates were highest for adrenocortical tumours at 68% and 43%. Of the 43 pituitary RC, the rates were highest for pituitary adenomas at 43% and 29%. Of the 31 genetic tumour RC, the rates were highest for MEN1 at 26% and 9%. For the remaining conditions, awareness and participation in registries was less than 25%. CONCLUSION: Although there is a need to develop new registries for rare endocrine conditions, there is a more immediate need to improve the awareness and participation in existing registries.

8.
Diabetes Technol Ther ; 20(11): 744-750, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30285476

RESUMO

OBJECTIVE: Officially licensed hybrid closed-loop systems are not currently available worldwide; therefore, open-source systems have become increasingly popular. Our aim was to assess the safety, feasibility, and efficacy of an open-source hybrid closed-loop system (AndroidAPS) versus SmartGuard® technology for day-and-night glucose control in children under extreme sports conditions. RESEARCH DESIGN AND METHODS: Twenty-two children (16 girls, 6-15 years of age, median HbA1c 56 ± 9 mmol/mol) were enrolled in this pivotal winter sports camp study. The participants were divided into two groups using either the AndroidAPS or SmartGuard technology. Physical exertion was represented by all-day alpine skiing. The primary endpoints were mean glucose level, time below the threshold of 3.9 mmol/L, and time within the target range of 3.9 to 10 mmol/L. RESULTS: The children using the AndroidAPS had significantly lower mean glycemia levels (7.2 ± 2.7 vs. 7.7 ± 2.8 mmol/L; 129.6 ± 49 vs. 138.6 ± 50 mg/dL, P < 0.042) than the children using the SmartGuard. The proportion of time below the target (median 5.0% ± 2.5% vs. 3.0% ± 2.3%, P = 0.6) and in the target zone (63% ± 9.5% vs. 63% ± 18%, P = 0.5) did not significantly differ. The AndroidAPS group experienced more frequent malfunctions of the cannula set (median 0.8 ± 0.4 vs. 0.2 ± 0.4, P = 0.02), which could have affected the results. No significant difference was found in the amount of carbohydrates consumed for the prevention and treatment of hypoglycemia [median 40 ± 23 vs. 25 ± 29 g/(patient ·3 days)]. No episodes of severe hypoglycemia or other serious adverse events were noted. CONCLUSIONS: This pilot study showed that the AndroidAPS system was a safe and feasible alternative to the SmartGuard Technology.

9.
Pediatr Diabetes ; 19(8): 1441-1450, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30105887

RESUMO

OBJECTIVE: To describe the association between height, demographics, and treatment in youths with type 1 diabetes participating in an international network for pediatric diabetes centers (SWEET). METHODS: Data were collected from 55 centers with documented patients' height. All subjects below 20 years of age, diabetes duration >1 year, and without celiac disease were included. World Health Organization growth charts were used to calculate height and body mass index z-scores. Multiple hierarchic regression models adjusting for known confounders were applied. RESULTS: Data on 22 941 subjects (51.8% male) were analyzed with a median and interquartile range for age 14.8 years (11.2, 17.6), diabetes duration 5.6 years (3.1, 8.9), and height z-score 0.34 (-0.37, 1.03). Children were taller in the youngest age groups: adjusted height z-scores of 0.31 (±0.06) and 0.39 (±0.06), respectively; with shorter diabetes duration (<2 years: 0.36 [±0.06]; 2-<5 years: 0.34 [±0.06]; ≥5 years: 0.21 [±0.06]) and if they were pump users: 0.35 ± 0.05 vs 0.25 ± 0.05 (>three injections/day and 0.19 ± 0.06 [0-3 injections daily]), respectively. High hemoglobin A1c (HbA1c) and low to normal weight were associated with a lower height z-score. Trends were identical in all models except for gender. No gender differences were found except in the final height model where females exhibited higher z-score than males. CONCLUSION: For youths treated at centers offering modern diabetes management, major growth disturbances are virtually eliminated. For children with a young age at onset, high HbA1c, injections, and/or non-intensive diabetes, treatment still requires attention in order to attain normal growth.

10.
Pediatr Diabetes ; 19(7): 1211-1220, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30033651

RESUMO

OBJECTIVE: To assess the prevalence of underweight (UW), overweight (OW), and obesity in children and adolescents with type 1 diabetes (T1D). METHODS: An international cross-sectional study including 23 026 T1D children (2-18 years, duration of diabetes ≥1 year) participating in the SWEET prospective, multicenter diabetes registry. Body mass index SD score (BMI-SDS) was calculated using the World Health Organization BMI charts. Children were categorized as UW (BMI-SDS < -2SD), OW (+1SD < BMI-SDS ≤ +2SD), and obese (OB) (BMI-SDS > +2SD). Hierarchic regression models were applied with adjustment for sex, age, and duration of diabetes. RESULTS: The prevalence of UW, OW, and obesity was: 1.4%, 22.3%, and 7.3% in males and 0.6%, 27.2%, and 6.8% in females. Adjusted BMI-SDS was significantly higher in females than in males (mean ± SEM: 0.54 ± 0.05 vs 0.40 ± 0.05, P < 0.0001). In males, BMI-SDS significantly decreased by age (P < 0.0001) in the first three age categories 0.61 ± 0.06 (2 to <10 years), 0.47 ± 0.06 (10 to <13 years), 0.34 ± 0.05 (13 to <16 years). In females, BMI-SDS showed a U-shaped distribution by age (P < 0.0001): 0.54 ± 0.04 (2 to <10 years), 0.39 ± 0.04 (10 to <13 years), 0.55 ± 0.04 (13 to <16 years). BMI-SDS increased by diabetes duration (<2 years: 0.38 ± 0.05, 2 to <5 years: 0.44 ± 0.05, and ≥5 years: 0.50 ± 0.05, P < 0.0001). Treatment modality did not affect BMI-SDS. Adjusted HbA1c was significantly higher in females than in males (8.20% ± 0.10% vs 8.06% ± 0.10%, P < 0.0001). In both genders, the association between HbA1c and BMI-SDS was U-shaped with the highest HbA1c in the UW and obesity groups. CONCLUSIONS: The high rate of OW and obesity (31.8%) emphasize the need for developing further strategies to prevent and treat excess fat accumulation in T1D.

11.
Artigo em Inglês | MEDLINE | ID: mdl-29729943

RESUMO

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

12.
J Clin Endocrinol Metab ; 103(3): 1188-1197, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29300907

RESUMO

Context: Patients with Turner syndrome (TS) are at risk for osteoporotic fractures. Objective: The aims of this study were to assess the incidence of clinically important fractures in girls with TS and prospectively describe the development of volumetric bone mineral density (BMD). Design: Peripheral quantitative computerized tomography (pQCT) of the radius every other year over the 6 years of observation. Setting: Government-funded university referral center. Participants: Thirty-two girls with TS, aged 6 to 16 years, were included in the analyses. Fracture incidence was compared with the data in the general population. Bone density and strength were compared with data from 185 healthy girls. Outcomes: The main clinical outcome was the fracture occurrence. The secondary outcomes were the changes in Z-scores of the bone parameters. Results: Three girls with TS sustained four fractures during 6 years of observation. The fracture rate in TS was not substantially higher than the downward-biased fracture-rate estimate from age-matched, healthy controls (P = 0.48). Whereas the trabecular BMD Z-score decreased with age (ß estimate -0.21 ± 0.04, P < 0.001), total bone cross-sectional area correspondingly increased (+0.16 ± 0.04, P < 0.001), which led to normal bone strength. A positive history of incident fractures was not significantly associated with any of the pQCT-derived bone parameters. Conclusions: Current pediatric TS patients that are treated with growth hormone and estrogens are not at risk for osteoporotic fractures. Low BMD in TS may be counterweighted by enlarged bone radius, which leads to normal bone strength at the appendicular skeleton.


Assuntos
Densidade Óssea/efeitos dos fármacos , Estrogênios/uso terapêutico , Hormônio do Crescimento/uso terapêutico , Fraturas por Osteoporose/epidemiologia , Síndrome de Turner/fisiopatologia , Adolescente , Criança , Feminino , Seguimentos , Humanos , Incidência , Fraturas por Osteoporose/etiologia , Rádio (Anatomia)/diagnóstico por imagem , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X/métodos , Síndrome de Turner/complicações , Síndrome de Turner/tratamento farmacológico
13.
Pediatr Diabetes ; 19(3): 578-585, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28880485

RESUMO

BACKGROUND: Training for healthcare professionals (HCPs) in Europe who care for children and young people (CYP) with type 1 diabetes and their families is variable depending on the country. Building on the work of SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) and using the German Certified Diabetes Educators (CDEs) curriculum, a European collaboration of pediatric diabetes experts aimed to (1) establish current core elements that should be included in a pediatric diabetes education training course and (2) create a template for a European CDE's training curriculum. METHODS: A qualitative methodology incorporating a survey questionnaire, focus group discussions, individual semi-structured interviews and workshops was employed to explore participants' experiences and opinions. HCPs-pediatric consultants, diabetes nurses, dietitians and psychologists, national and local diabetes leads, academic and education leads and children, and young people with diabetes and families took part in the study. The total number of participants equaled 186. RESULTS: A template for a European Certified Diabetes Educator Curriculum (EU-CDEC) was developed based on the themes that emerged from the participants' expertise and experiences. This provides a model for HCPs' pediatric diabetes training provision. CONCLUSIONS: There is a severe shortage of high quality, standardized training for HCPs across the majority of European countries. Lack of trained HCPs for CYP with diabetes will result in the delivery of suboptimal care and impact on health, wellbeing and clinical and psychological outcomes. The EU-CDEC template can be used to increase access to high quality training provision for all HCPs across Europe and worldwide.

14.
Bone ; 106: 22-27, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29017892

RESUMO

BACKGROUND: Sarcopenia and osteoporosis are among the late complications of type 1 diabetes (T1D) in adults. Whether and to what extent musculoskeletal impairment is present in childhood and adolescence has yet to be determined. The aim of this study was to assess volumetric bone mineral density (BMD) and dynamic muscle function in adolescents with T1D and to assess the clinical and biochemical predictors of their musculoskeletal system. METHODS: Ninety-five children and adolescents (59 boys and 36 girls, mean age 16.2±1.2years) with T1D were included in this cross-sectional study. Study participants were divided into two groups according to the duration of the disease (<6years and >9years, respectively). Volumetric BMD of the non-dominant tibia was assessed using peripheral quantitative computed tomography (pQCT). Dynamic muscle function was evaluated using jumping mechanography. Gender- and height-specific Z-scores were calculated using published reference data. HbA1c was evaluated retrospectively as an average over the past 5years. RESULTS: Relative muscle power (Pmax/mass) and force (Fmax/body weight) were significantly decreased in T1D subjects (mean Z-scores -0.4±1.0; p<0.001, and -0.3±1.1; p<0.01, respectively). The duration of T1D negatively affected Pmax/mass (p<0.01) but not Fmax/body weight (p=0.54). Patients with T1D had also decreased trabecular BMD, the Strength-Strain Index and cortical thickness (mean Z-scores -0.8±1.3; -0.5±0.8 and -1.1±0.8, respectively, p<0.001 for all) whereas cortical BMD was increased when compared to controls (Z-score 1.2±0.90, p<0.001). No association was observed between the HbA1c and 25-hydroxyvitamin D levels and bone or muscle parameters. CONCLUSION: T1D influences the musculoskeletal system in adolescence. Decreased muscle function could contribute to the osteoporosis reported in adult diabetic patients.


Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Adolescente , Adulto , Antropometria , Densidade Óssea/fisiologia , Osso e Ossos/fisiologia , Estudos Transversais , Feminino , Humanos , Masculino , Tomografia Computadorizada por Raios X , Adulto Jovem
15.
J Pediatr Endocrinol Metab ; 30(12): 1311-1315, 2017 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-29127764

RESUMO

BACKGROUND: Congenital hyperinsulinism (CHI) is frequently caused by mutations in one of the KATP channel subunits encoded by the genes ABCC8 and KCNJ11. The effect of simultaneous mutations in both of these genes on the pancreatic ß-cell function is not known and patients with CHI carrying both ABCC8 and KCNJ11 mutations have not yet been reported. We questioned if a combination of heterozygous mutations in the ABCC8 and KCNJ11 genes could also lead to ß-cell dysfunction presenting as CHI. METHODS: As a model, we used a patient with transient CHI that paternally inherited novel heterozygous mutations in ABCC8 (p.Tyr1293Asp) and KCNJ11 (p.Arg50Trp) genes. The pathogenic effects on the pancreatic ß-cells function were examined in an in vitro functional study using radioactive rubidium efflux assay. RESULTS: We showed that the activation of the mutated KATP channels by diazoxide was decreased by 60.9% in the channels with the heterozygous combination of both mutations compared to the wild type channels. This could indicate the pathogenic effect on the pancreatic ß-cell function leading to CHI although conclusive evidence is needed to be added. CONCLUSIONS: Our findings may widen the spectrum of genetic causes of CHI and suggest a novel pathogenic mechanism of CHI that must however, be further investigated.


Assuntos
Hiperinsulinismo Congênito/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores Sulfonilureia/genética , Adulto , Idoso , Criança , Pré-Escolar , Hiperinsulinismo Congênito/fisiopatologia , Epistasia Genética/fisiologia , Família , Heterozigoto , Humanos , Recém-Nascido , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Mutação , Linhagem
16.
Eur J Pediatr ; 176(10): 1355-1363, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28840427

RESUMO

Low bone mineral density (BMD) and an increased fracture incidence are two extraintestinal complications associated with inflammatory bowel disease (IBD). We aimed to evaluate musculoskeletal traits and assess vertebral fracture (VF) rate in children and adolescents with IBD. Seventy patients with IBD with a median age of 13.8 years were included. The BMD and geometric parameters of the non-dominant tibia were assessed using pQCT. Dynamic muscle functions were evaluated using jumping mechanography. VFs were assessed according to the semiquantitative standardized method by Genant. The muscle functions adjusted for the patients' weight did not differ from the reference population. A low trabecular BMD (Z-score - 1.6; p < 0.001) and cortical thickness (Z-score - 0.7; p < 0.001) were found in children and adolescents with IBD. Conversely, an increased cortical BMD (Z-score 1.1; p < 0.001) was noted. No significant association was found between the 25-OHD serum levels and the bone or muscle measurements. One patient with asymptomatic VF was identified. CONCLUSION: IBD in childhood or adolescents affects bones but not muscles. Bone changes are independent of the 25-OHD serum level. A thoracolumbar spine X-ray should not be routinely recommended in children with IBD. What is Known: • Low bone mineral density and an increased fracture rate are the complications associated with IBD. • Bone strength and structural development is strongly dependent on skeletal muscle stimulation. What is New: • Children with IBD have altered bone density and geometry but normal dynamic muscle functions. • Thoracolumbar spine X-ray should be indicated on an individual basis in children with IBD.


Assuntos
Densidade Óssea , Osso Esponjoso/fisiopatologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/fisiopatologia , Força Muscular , Fraturas da Coluna Vertebral/etiologia , Absorciometria de Fóton , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Prevalência , Radiografia , Fatores de Risco , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/epidemiologia , Adulto Jovem
17.
Endocrinology ; 158(7): 2058-2065, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28525638

RESUMO

Detection and quantification of unmethylated circulating insulin (INS) DNA presumably released from ß cells has been previously used for assessing their destruction. As the targets within the INS gene suffer from suboptimal specificity, we sought to improve the assay parameters by using the glucokinase gene (GCK) tissue-specific pancreatic promoter. The amount of methylated and unmethylated GCK DNA was measured using a droplet polymerase chain reaction assay and compared with the previously published INS-targeted assay. The method was tested using synthetic target sequences and DNA from pancreatic islets, blood, brain, kidney, large intestine, liver, lung, small intestine, and stomach. Circulating serum DNA was obtained from children with recent-onset type 1 diabetes (T1D) (n = 25), autoantibody-positive first-degree relatives of T1D patients (n = 14), and healthy controls (n = 20). The unmethylated GCK DNA was found to be more islet specific than unmethylated INS DNA. The proportion of the unmethylated GCK DNA was lower than INS in all tested extrapancreatic tissues, except kidney. Although the amounts of methylated DNA measured by the two assays were similar, the INS assay detected considerably more unmethylated DNA. Whereas none of the assays showed significant increase in the amount of unmethylated DNA, the ratio of unmethylated/methylated GCK DNA was borderline significantly increased in autoantibody-positive relatives compared with T1D patients (P = 0.04) and controls (P = 0.06). Targeting the assay into the GCK gene improved analytical parameters of the assay. As the amount of unmethylated target DNA in properly treated samples is very low, the clinical utility of this method remains to be evaluated.


Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Glucoquinase/genética , Células Secretoras de Insulina/fisiologia , Insulina/genética , Adolescente , Adulto , Estudos de Casos e Controles , Morte Celular/genética , Criança , Pré-Escolar , Metilação de DNA , Análise Mutacional de DNA/métodos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Feminino , Glucoquinase/análise , Humanos , Lactente , Insulina/análise , Células Secretoras de Insulina/patologia , Masculino , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Adulto Jovem
18.
Mol Cell Endocrinol ; 452: 64-73, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28501574

RESUMO

Children with adrenocortical tumors (ACTs) often present with virilization due to high tumoral androgen production, with dihydrotestosterone (DHT) as most potent androgen. Recent work revealed two pathways for DHT biosynthesis, the classic and the backdoor pathway. Usage of alternate routes for DHT production has been reported in castration-resistant prostate cancer, CAH and PCOS. To assess whether the backdoor pathway may contribute to the virilization of pediatric ACTs, we investigated seven children suffering from androgen producing tumors using steroid profiling and immunohistochemical expression studies. All cases produced large amounts of androgens of the classic and/or backdoor pathway. Variable expression of steroid enzymes was observed in carcinomas and adenomas. We found no discriminative pattern. This suggests that enhanced androgen production in pediatric ACTs is the result of deregulated steroidogenesis through multiple steroid pathways. Thus future treatments of ACTs targeting androgen overproduction should consider these novel steroid production pathways.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Androgênios/biossíntese , Neoplasias Ovarianas/metabolismo , Virilismo/metabolismo , Adolescente , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Androgênios/sangue , Criança , Di-Hidrotestosterona/sangue , Feminino , Humanos , Imuno-Histoquímica , Lactente , Síndrome de Li-Fraumeni/genética , Masculino , Neoplasias Ovarianas/patologia , Proteína Supressora de Tumor p53/genética , Virilismo/patologia
19.
Diabetes Technol Ther ; 19(5): 299-304, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28520532

RESUMO

BACKGROUND: The prevention of postexercise nocturnal hypoglycemia after prolonged physical activity using sensor-augmented pump (SAP) therapy with predictive low-glucose management (PLGM) has not been well studied. We conducted a study at a pediatric diabetes camp to determine whether a SAP with PLGM reduces the frequency of nocturnal hypoglycemia after prolonged physical activity more effectively than a SAP with a carbohydrate intake algorithm. METHODS: During a 1-week sport camp, 20 children (aged 10-13 years) with type 1 diabetes (T1D) managed by SAP therapy either with (n = 7) or without PLGM (n = 13) were studied. The hypoglycemia management strategy and the continuous glucose monitoring (CGM)/PLGM settings were standardized. The incidence, severity, and duration of hypoglycemia and carbohydrate intake were documented and compared. RESULTS: The PLGM system was activated on 78% of all nights (once per night on average). No difference was found between the SAP and PLGM groups in the mean overnight glucose curve or mean morning glucose (7.8 ± 2 mmol/L vs. 7.4 ± 3 mmol/L). There was no difference in the frequency and severity of hypoglycemia. However, the SAP group consumed significantly more carbohydrates to prevent and treat hypoglycemia than those in the PLGM group; the values were 10 ± 2 and 1 ± 2 gS (P < 0.0001) in the SAP and PLGM groups, respectively. Moreover, the SAP group spent a significantly longer time in hypoglycemia (64 ± 2 min vs. 38 ± 2 min, P < 0.05). We observed a difference in the time distribution of nocturnal hypoglycemia (10 to 12 p.m. in the PLGM group and 3 to 7 a.m. in the SAP group, P < 0.05). CONCLUSION: With PLGM system, euglycemia after prolonged physical activity was largely maintained with a minimal carbohydrate intake.


Assuntos
Comportamento Infantil , Diabetes Mellitus Tipo 1/tratamento farmacológico , Exercício , Hipoglicemia/prevenção & controle , Sistemas de Infusão de Insulina , Monitorização Ambulatorial , Esportes , Atividades Cotidianas , Adolescente , Algoritmos , Glicemia/análise , Criança , Terapia Combinada/efeitos adversos , República Tcheca/epidemiologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/dietoterapia , Diabetes Mellitus Tipo 1/metabolismo , Dieta para Diabéticos/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Carboidratos da Dieta/metabolismo , Feminino , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/epidemiologia , Hipoglicemia/etiologia , Incidência , Sistemas de Infusão de Insulina/efeitos adversos , Masculino , Teste de Materiais , Monitorização Ambulatorial/efeitos adversos
20.
Immunol Lett ; 189: 94-100, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28414179

RESUMO

BACKGROUND: Lately, mounting evidence has shown that B cells play an important role in the pathogenesis of type 1 diabetes (T1D). Here, we present alterations in B cell subsets including BAFF receptor (BAFFR) expression in cohorts of patients with type 1 diabetes (T1D) and their relatives. PATIENTS AND METHODS: B cells were studied in 438 patients with T1D (158 at disease onset and 280 with long-term disease), 136 first-degree relatives and 53 healthy controls. The B cell panel included transitional, naïve, MZ-like, switched memory B cells and plasmablasts. We also measured serum BAFF levels as well as BAFFR expression on both B and T cells. Moreover, the effect of BAFF on T and B lymphocytes was analysed in vitro. RESULTS: We observed a significant decrease in the proportion of transitional B cells in the patients with T1D, accompanied by an increased proportion of plasmablasts, especially in recent-onset patients and their relatives. While the BAFF serum levels did not differ in the patients with T1D, BAFFR-expressing B and especially T cell numbers were reduced in the T1D cohort, with the exception of patients with recent-onset disease who exhibited a significant increase in the number of BAFFR-expressing T cells. T cell activation and B cell proliferation were more pronounced after activation with BAFF in the T1D cohort compared to controls. CONCLUSION: The B cell panel in patients with T1D is characterized by significantly reduced populations of B cells in their early stages of development with a shift towards plasma cells. The dynamics of BAFFR-expressing B and T cells and the more pronounced responsiveness of the T1D T cells to BAFF point to the role of BAFF and T and B cell cooperation in the development of T1D.


Assuntos
Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Subpopulações de Linfócitos B/imunologia , Diferenciação Celular , Diabetes Mellitus Tipo 1/imunologia , Plasmócitos/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Receptor do Fator Ativador de Células B/genética , Comunicação Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Adulto Jovem
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