Prenatal Betamethasone Exposure and its Impact on Pediatric Type 1 Diabetes Mellitus : A Preliminary Study in a Spanish Cohort

Betamethasone, a glucocorticoid used to induce lung maturation when there is a risk of preterm delivery, can affect the immune system maturation and type 1 diabetes (T1D) incidence in the progeny. It has been described that prenatal betamethasone protects offspring from experimental T1D development. The main aim of this study was to evaluate the possible association between betamethasone prenatal exposure and T1D in humans. Research Design and Methods. A retrospective case-control study with a total of 945 children, including 471 patients with T1D and 474 healthy siblings, was performed. Participants were volunteers from the Germans Trias i Pujol Hospital and DiabetesCero Foundation. Parents of children enrolled in the study completed a questionnaire that included questions about weeks of gestation, preterm delivery risk, weight at birth, and prenatal betamethasone exposure of their children. Multiple logistic regression was used to detect the association between betamethasone exposure and T1D. We compared T1D prevalence between subjects prenatally exposed or unexposed to betamethasone. The percent of children with T1D in the exposed group was 37.5% (21 of 56), and in the unexposed group was 49.52% (410 of 828) (p = 0.139). The percentage of betamethasone-treated subjects with T1D in the preterm group (18.05%, 13 of 72) was significantly higher than that found in the control group (12.5%, 9 of 72) (p = 0.003). The odds ratio for T1D associated with betamethasone in the univariate logistic regression was 0.59 (95% confidence interval, 0.33; 1.03 [ p = 0.062]) and in the multivariate logistic regression was 0.83 (95% confidence interval, 0.45; 1.52 [ p = 0.389]). The results demonstrate that the prenatal exposure to betamethasone does not increase T1D susceptibility, and may even be associated with a trend towards decreased risk of developing the disease. These preliminary findings require further prospective studies with clinical data to confirm betamethasone exposure effect on T1D risk

Subclinical hypothyroidism in childhood, treatment or only follow-up?

Subclinical hypothyroidism (SH) is defined as serum levels of thyroid-stimulating hormone (TSH) above the upper limit with normal concentrations of free T4 (fT4). Its management remains challenging. The aim of the study was to evaluate clinical and laboratory findings as well as the clinical course of children with SH followed in a third level hospital. Sixty-five patients aged between 2 and 18 years old were retrospectively studied. The patients were followed for a median period of 9 months (range 6 months to 24 months). Those who normalized TSH levels were discharged (Group 1). If TSH persisted mildly elevated (5-10μUI/mL) with normal fT4 and negative TPOAb/TgAb, they were classified as Group 2 and followed semi-annually without treatment. Those patients whose TSH raised ≥10μUI/mL or who maintained TSH 5-10μUI/mL and positive TPOAb/TgAb were considered suitable for thyroxin therapy (Group 3, G3). In 89% of our patients, TSH concentrations spontaneously reverted to normality or remained stable without treatment (Groups 1 and 2), whereas less than 11% progressed to clinical hypothyroidism (Group 3). Baseline TSH was significantly lower in group 1 than in group 3. In group 3 the prevalence of female sex (71%) was higher and TPO antibodies were present in 85% of patients. The risk of developing overt hypothyroidism in patients with positive anti-thyroid antibodies respect to those who normalized TSH was 45 (95%CI 6.5-312.5). Baseline TSH, female sex and the presence of thyroid autoimmunity were the best predictors of the evolution to SH over time

Immunoregulatory Biomarkers of the Remission Phase in Type 1 Diabetes : miR-30d-5p Modulates PD-1 Expression and Regulatory T Cell Expansion

The partial remission (PR) phase of type 1 diabetes (T1D) is an underexplored period characterized by endogenous insulin production and downmodulated autoimmunity. To comprehend the mechanisms behind this transitory phase and develop precision medicine strategies, biomarker discovery and patient stratification are unmet needs. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression and modulate several biological processes, functioning as biomarkers for many diseases. Here, we identify and validate a unique miRNA signature during PR in pediatric patients with T1D by employing small RNA sequencing and RT-qPCR. These miRNAs were mainly related to the immune system, metabolism, stress, and apoptosis pathways. The implication in autoimmunity of the most dysregulated miRNA, miR-30d-5p, was evaluated in vivo in the non-obese diabetic mouse. MiR-30d-5p inhibition resulted in increased regulatory T cell percentages in the pancreatic lymph nodes together with a higher expression of CD200. In the spleen, a decrease in PD-1 + T lymphocytes and reduced PDCD1 expression were observed. Moreover, miR-30d-5p inhibition led to an increased islet leukocytic infiltrate and changes in both effector and memory T lymphocytes. In conclusion, the miRNA signature found during PR shows new putative biomarkers and highlights the immunomodulatory role of miR-30d-5p, elucidating the processes driving this phase

NK Cell Subsets Changes in Partial Remission and Early Stages of Pediatric Type 1 Diabetes

Type 1 diabetes (T1D) is a chronic metabolic disease characterized by the autoimmune destruction of β-cells in the pancreatic islets. T1D is preceded by islet-specific inflammation led by several immune cells. Among them, natural killer (NK) cells are emerging as important players in T1D development. Human NK cells are characterized by CD56 and CD16 expression, which allows classifying NK cells into four subsets: 1) CD56 dim CD16 + or effector NK cells (NK); 2) CD56 bright CD16 − or regulatory NK cells (NK); 3) intermediate CD56 bright CD16 + NK cells; and 4) CD56 dim CD16 − NK cells, whose function is not well determined. Since many studies have shown that T1D progression is associated with changes in various immune cell types, we hypothesize that the kinetics of NK cell subsets in the blood could correlate with different stages of T1D. To that aim, pediatric patients newly diagnosed with T1D were recruited, and peripheral NK cell subsets were analyzed by flow cytometry at several disease checkpoints: disease onset, partial remission (PR), 8 months (for non-remitters), and 12 months of progression. Our results showed that total NK cells and their four subsets are altered at the early stages of T1D. A decrease in the counts and percentage of total NK cells and NK cells at the different disease stages was found when compared to controls. These results suggest the extravasation of these cells into the islets at disease onset, which is maintained throughout the follow-up. By contrast, NK cells increased during the early stages after T1D onset, and both intermediate NK cells and CD56 dim CD16 - NK cells diminished at the PR stage, which might reflect the immunoregulatory attempts and could be candidate biomarkers for this stage. Also, CD56 dim CD16 - NK cells increased during T1D progression. Finally, changes in CD16 expression were identified in the different T1D stages, highlighting a CD16 expression reduction in total NK cells and NK cells 1 year after diagnosis. That may reflect a state of exhaustion after multiple cell-to-cell interactions. Altogether, our preliminary data provide a longitudinal picture of peripheral NK cell subpopulations during the different T1D stages, which could be potential candidate biomarkers indicators of disease progression

Partial remission and early stages of pediatric type 1 diabetes display immunoregulatory changes. A pilot study

Altres ajuts: This work has been funded by the European Regional Development funds (FEDER), and by DiabetesCero Foundation. CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from Instituto de Salud Carlos III (Spain). SRF is supported by the Agency for Management of University and Research Grants (AGAUR) of the Generalitat de Catalunya.Type 1 diabetes (T1D) is a chronic metabolic disease of unknown etiology that results from β-cell destruction. The onset of the disease, which arises after a long asymptomatic period of autoimmune attack, may be followed by a relapsing and remitting progression, a phenomenon that is most evident during the partial remission phase (PR). This stage lasts for a few months, shows minor requirements of exogenous insulin and could be explained by a recovery of immunological tolerance. This study aims to identify new biomarkers at early stages of pediatric T1D that reflect immunoregulatory changes. To that end, pediatric patients with T1D (n = 52) and age-related control subjects (n = 30) were recruited. Immune response-related molecules and lymphocyte subsets were determined starting at T1D onset and until the second year of progression. Results showed that circulating TGF-β levels decreased during PR, and that betatrophin concentration was increased in all the considered stages without differing among studied checkpoints. Moreover, an increase of regulatory T, B and NK subsets was found during T1D progression, probably reflecting an attempt to restore self-tolerance. By contrast, a reduction in monocyte levels was observed at the early stages of diabetes. The results reveal significant changes in immunological parameters during the different early stages of T1D in children, which could ultimately serve as potential biomarkers to characterize the progression of T1D

Differential association between S100A4 levels and insulin resistance in prepubertal children and adult subjects with clinically severe obesity

Objectives: S100A4 has been recently identified as an adipokine associated with insulin resistance (IR) in adult subjects with obesity. However, no data about its levels in children with obesity and only a few approaches regarding its potential mechanism of action have been reported. To obtain a deeper understanding of the role of S100A4 in obesity, (a) S100A4 levels were measured in prepubertal children and adult subjects with and without obesity and studied the relationship with IR and (b) the effects of S100A4 in cultured human adipocytes and vascular smooth muscle cells (VSMCs) were determined. Methods: Sixty-five children (50 with obesity, age 9.0 ±1.1 years and 15 normal weight, age 8.4 ±0.8 years) and fifty-nine adults (43 with severe obesity, age 46 ±11 years and 16 normal weight, age 45 ±9 years) were included. Blood from children and adults and adipose tissue samples from adults were obtained and analysed. Human adipocytes and VSMC were incubated with S100A4 to evaluate their response to this adipokine. Results: Circulating S100A4 levels were increased in both children (P =.002) and adults (P <.001) with obesity compared with their normal-weight controls. In subjects with obesity, S100A4 levels were associated with homeostatic model assessment-insulin resistance (HOMA-IR) in adults (βstd =.42, P =.008) but not in children (βstd =.12, P =.356). Human adipocytes were not sensitive to S100A4, while incubation with this adipokine significantly reduced inflammatory markers in VSMC. Conclusions: Our human data demonstrate that higher S100A4 levels are a marker of IR in adults with obesity but not in prepubertal children. Furthermore, the in vitro results suggest that S100A4 might exert an anti-inflammatory effect. Further studies will be necessary to determine whether S100A4 can be a therapeutic target for obesity

Impacto del uso de cuestionarios de calidad de vida relacionada con la salud vía internet en la práctica clínica en niños y adolescentes con diabetes mellitus tipo 1

La DM1 es una enfermedad crónica que conlleva gran afectación en la vida diaria. El presente trabajo analiza el impacto de la valoración de la CVRS medida vía internet en la práctica clínica habitual en niños y adolescentes con DM1. Para ello se diseñó un estudio multicéntrico de seguimiento sobre 136 pacientes controlados en 5 hospitales del área de Barcelona (72 niñas, edad media de 13,4 años y rango 8-19 años, HbA1c media: 7,5±1%). Se recogieron una serie de variables sociodemográficas y de salud mental además de las variables clínicas propias de la enfermedad. La calidad de vida se evaluó mediante los índices EuroQol-5D y KIDSCREEN recogidos online. Durante el año de seguimiento se dividió a los pacientes en dos grupos y sólo en uno de ellos se discutieron los resultados de la CVRS con el médico en cada visita (grupo intervención, n: 70). Completaron el estudio a 1 año 119 pacientes (87,5%). Al inicio del estudio se realizó un trabajo descriptivo concluyendo que los pacientes diabéticos presentaban una CVRS similar a la población general con peor sensación de bienestar físico (puntuación <50). La CVRS mostró correlación con la edad, la Hemoglobina glicosilada (HbA1c) y la salud mental, siendo la edad (coeficiente B= -0,93), las familias monoparentales (B= -15,2), la adherencia al tratamiento (B= 4,34) y la salud mental (B= -0,7) los factores más influyentes. Con el paso del tiempo, al final del estudio, se observaron puntuaciones de CVRS mejores (Effect size, ES= 0,56) en el grupo de intervención especialmente en las dimensiones de bienestar psicológico (B= 4,32) y ambiente escolar (B= 4,64), siendo la salud mental (B= -0,78 [bienestar psicológico] y -0,43 [ambiente escolar]), la disfunción familiar (B= -2,99 y –3,7, respectivamente) y la adherencia al tratamiento (B= 3,7) los factores más influyentes. No hubo mejoría en el control metabólico. El estudio muestra algunos factores que deben tenerse en cuenta para mejorar la CVRS en esta población y también la factibilidad de utilizar internet para recopilar esta información en la práctica clínica.Type 1 diabetes mellitus (T1DM) is a chronic disease that affects all aspects of patient’s life. This study assesses the impact of systematic monitoring of health-related quality of life (HRQOL) via Internet in clinical practice in children and adolescents with T1DM. A multicenter longitudinal study was designed on 136 patients recruited from five hospitals Barcelona (72 girls, mean age 13.4 years and range 8-19 years, average HbA1c: 7.5 ± 1%). Sociodemographic and mental health variables were collected in addition to the clinical variables. HRQOL was assessed using the EuroQol-5D and KIDSCREEN indexes collected online. During the follow-up year, the patients were divided into two groups and only the intervention group discussed the results of the HRQOL with the physician at each visit (intervention group, n: 70). Complete data were collected for 119 patients (87.5%). At baseline, a descriptive study was carried out concluding that diabetic patients report similar HRQOL than the general population with worse physical well-being (score <50). HRQOL correlated with age, HbA1c and mental health; and age (coefficient B= -0.93), single-parent families (B= -15.2), adherence to treatment (B= 4.34) and mental health (B= -0.7) were the most influential factors. Over time, at the end of the study, better HRQOL scores (Effect size, ES= 0.56) were seen in the intervention group, especially in the dimensions of psychological well-being (B= 4.32) and school environment (B= 4.64); mental health (B= -0.78 [psychological well-being] and -0.43 [school environment]), family dysfunction (B= -2.99 and -3.7, respectively) and adherence to treatment (B = 3.7) were the most influential factors. There was no improvement in metabolic control. The study shows some factors to be taken into account to improve HRQOL in this population and also the feasibility of using Internet to collect this information in clinical practice

Impacto del uso de cuestionarios de calidad de vida relacionada con la salud vía Internet en la práctica clínica en niños y adolescentes con diabetes mellitus tipo 1 /

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2017-2018La DM1 es una enfermedad crónica que conlleva gran afectación en la vida diaria. El presente trabajo analiza el impacto de la valoración de la CVRS medida vía internet en la práctica clínica habitual en niños y adolescentes con DM1. Para ello se diseñó un estudio multicéntrico de seguimiento sobre 136 pacientes controlados en 5 hospitales del área de Barcelona (72 niñas, edad media de 13,4 años y rango 8-19 años, HbA1c media: 7,5±1%). Se recogieron una serie de variables sociodemográficas y de salud mental además de las variables clínicas propias de la enfermedad. La calidad de vida se evaluó mediante los índices EuroQol-5D y KIDSCREEN recogidos online. Durante el año de seguimiento se dividió a los pacientes en dos grupos y sólo en uno de ellos se discutieron los resultados de la CVRS con el médico en cada visita (grupo intervención, n: 70). Completaron el estudio a 1 año 119 pacientes (87,5%). Al inicio del estudio se realizó un trabajo descriptivo concluyendo que los pacientes diabéticos presentaban una CVRS similar a la población general con peor sensación de bienestar físico (puntuación 50). La CVRS mostró correlación con la edad, la Hemoglobina glicosilada (HbA1c) y la salud mental, siendo la edad (coeficiente B= -0,93), las familias monoparentales (B= -15,2), la adherencia al tratamiento (B= 4,34) y la salud mental (B= -0,7) los factores más influyentes. Con el paso del tiempo, al final del estudio, se observaron puntuaciones de CVRS mejores (Effect size, ES= 0,56) en el grupo de intervención especialmente en las dimensiones de bienestar psicológico (B= 4,32) y ambiente escolar (B= 4,64), siendo la salud mental (B= -0,78 [bienestar psicológico] y -0,43 [ambiente escolar]), la disfunción familiar (B= -2,99 y -3,7, respectivamente) y la adherencia al tratamiento (B= 3,7) los factores más influyentes. No hubo mejoría en el control metabólico. El estudio muestra algunos factores que deben tenerse en cuenta para mejorar la CVRS en esta población y también la factibilidad de utilizar internet para recopilar esta información en la práctica clínica.Type 1 diabetes mellitus (T1DM) is a chronic disease that affects all aspects of patient's life. This study assesses the impact of systematic monitoring of health-related quality of life (HRQOL) via Internet in clinical practice in children and adolescents with T1DM. A multicenter longitudinal study was designed on 136 patients recruited from five hospitals Barcelona (72 girls, mean age 13.4 years and range 8-19 years, average HbA1c: 7.5 ± 1%). Sociodemographic and mental health variables were collected in addition to the clinical variables. HRQOL was assessed using the EuroQol-5D and KIDSCREEN indexes collected online. During the follow-up year, the patients were divided into two groups and only the intervention group discussed the results of the HRQOL with the physician at each visit (intervention group, n: 70). Complete data were collected for 119 patients (87.5%). At baseline, a descriptive study was carried out concluding that diabetic patients report similar HRQOL than the general population with worse physical well-being (score 50). HRQOL correlated with age, HbA1c and mental health; and age (coefficient B= -0.93), single-parent families (B= -15.2), adherence to treatment (B= 4.34) and mental health (B= -0.7) were the most influential factors. Over time, at the end of the study, better HRQOL scores (Effect size, ES= 0.56) were seen in the intervention group, especially in the dimensions of psychological well-being (B= 4.32) and school environment (B= 4.64); mental health (B= -0.78 [psychological well-being] and -0.43 [school environment]), family dysfunction (B= -2.99 and -3.7, respectively) and adherence to treatment (B = 3.7) were the most influential factors. There was no improvement in metabolic control. The study shows some factors to be taken into account to improve HRQOL in this population and also the feasibility of using Internet to collect this information in clinical practice

Subclinical hypothyroidism in childhood, treatment or only follow-up?

Subclinical hypothyroidism (SH) is defined as serum levels of thyroid-stimulating hormone (TSH) above the upper limit with normal concentrations of free T4 (fT4). Its management remains challenging. The aim of the study was to evaluate clinical and laboratory findings as well as the clinical course of children with SH followed in a third level hospital. Sixty-five patients aged between 2 and 18 years old were retrospectively studied. The patients were followed for a median period of 9 months (range 6 months to 24 months). Those who normalized TSH levels were discharged (Group 1). If TSH persisted mildly elevated (5-10μUI/mL) with normal fT4 and negative TPOAb/TgAb, they were classified as Group 2 and followed semi-annually without treatment. Those patients whose TSH raised ≥10μUI/mL or who maintained TSH 5-10μUI/mL and positive TPOAb/TgAb were considered suitable for thyroxin therapy (Group 3, G3). In 89% of our patients, TSH concentrations spontaneously reverted to normality or remained stable without treatment (Groups 1 and 2), whereas less than 11% progressed to clinical hypothyroidism (Group 3). Baseline TSH was significantly lower in group 1 than in group 3. In group 3 the prevalence of female sex (71%) was higher and TPO antibodies were present in 85% of patients. The risk of developing overt hypothyroidism in patients with positive anti-thyroid antibodies respect to those who normalized TSH was 45 (95%CI 6.5-312.5). Baseline TSH, female sex and the presence of thyroid autoimmunity were the best predictors of the evolution to SH over time

Partial remission and early stages of pediatric type 1 diabetes display immunoregulatory changes. A pilot study

Altres ajuts: This work has been funded by the European Regional Development funds (FEDER), and by DiabetesCero Foundation. CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from Instituto de Salud Carlos III (Spain). SRF is supported by the Agency for Management of University and Research Grants (AGAUR) of the Generalitat de Catalunya.Type 1 diabetes (T1D) is a chronic metabolic disease of unknown etiology that results from β-cell destruction. The onset of the disease, which arises after a long asymptomatic period of autoimmune attack, may be followed by a relapsing and remitting progression, a phenomenon that is most evident during the partial remission phase (PR). This stage lasts for a few months, shows minor requirements of exogenous insulin and could be explained by a recovery of immunological tolerance. This study aims to identify new biomarkers at early stages of pediatric T1D that reflect immunoregulatory changes. To that end, pediatric patients with T1D (n = 52) and age-related control subjects (n = 30) were recruited. Immune response-related molecules and lymphocyte subsets were determined starting at T1D onset and until the second year of progression. Results showed that circulating TGF-β levels decreased during PR, and that betatrophin concentration was increased in all the considered stages without differing among studied checkpoints. Moreover, an increase of regulatory T, B and NK subsets was found during T1D progression, probably reflecting an attempt to restore self-tolerance. By contrast, a reduction in monocyte levels was observed at the early stages of diabetes. The results reveal significant changes in immunological parameters during the different early stages of T1D in children, which could ultimately serve as potential biomarkers to characterize the progression of T1D