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PCOS treatment should be based on pathophysiology. High-mobility-group-box-1 (HMGB1) was shown to increase in PCOS patients as a consequence of reduced cystic-fibrosis-transmembrane-conductance-regulator (CFTR) expression in the ovary, and was associated with insulin resistance and inflammation, both features of PCOS. Inositols and ALA derivatives could have positive effects on insulin sensitivity, reduce androgens, and improve ovulation rhythm. The aim of this study was to verify changes in HMGB1, in metabolic and endocrine parameters in adolescents with PCOS compared with controls and after treatment with a combination of MYO + ALA. Twenty-three PCOS adolescents and 21 controls matched for age and BMI were enrolled. In all subjects, metabolic and hormonal parameters were assayed. Homeostatic index (HOMA-IR) and the triglyceride/HDL-cholesterol ratio were calculated. Ovarian volumes were evaluated. Patients were treated with MYO + ALA for 6 months. HMGB1 was measured using a specific ELISA assay. HMGB1 was increased in PCOS compared with controls (19.76 ± 5.99 versus 5.65 ± 1.88 ng/ml

We previously described increased HMGB1 and reduced FOXO1 dependent on CFTR loss of function in cystic fibrosis (CF) and we showed in vitro that HMGB1 was lowered by insulin. Reduced CFTR g...

In the last few decades, many studies have reported an increasing global incidence of type 1 diabetes. Studies on migrant populations have underlined the importance of both environmental and genetic factors.Evaluate the incidence of type 1 diabetes in North African vs Italian children aged 0-14 years from 1 January 2015, to 31st December 2018, in Emilia-Romagna region, Italy.Clinical and epidemiological data about childhood onset type 1 diabetes in Emilia Romagna region were retrospectively collected by the regional centers of pediatric diabetology and matched using 3 different data sources.365 new cases were diagnosed. Total cumulative incidence was 15.4/100,000/year. North African cases showed a cumulative incidence of 53.8/100,000/year, statistically significant compared to cumulative incidence of the Italian cases alone 13.1/100,000/year (p value 0.001). The annual incidence did not differ in the 4 years for both groups. Conclusion: The incidence of type 1 diabetes in the pediatric age (0 14 years) was significantly higher in the North African population than in the Italian one, suggesting that a mix of genetic and environmental factors may have caused the increase in newly diagnosed cases.• The incidence of type 1 diabetes largely varies worldwide. • Study on immigrants helped to better understand the interplay role between genetics and environment.• This is the first study focused on the incidence of children and adolescents of North African migrants in Italy. • The incidence of children and adolescents of North African migrants in Emilia Romagna region, Italy, seems to be higher than that reported in the host countries, and, above all, than that reported in highest-incidence countries in Europe and in the world.

Metabolic syndrome (MetS) affects the population worldwide and results from several factors such as genetic background, environment and lifestyle. In recent years, an interplay among autophagy, metabolism, and metabolic disorders has become apparent. Defects in the autophagy machinery are associated with the dysfunction of many tissues/organs regulating metabolism. Metabolic hormones and nutrients regulate, in turn, the autophagy mechanism. Autophagy is a housekeeping stress-induced degradation process that ensures cellular homeostasis. High mobility group box 1 (HMGB1) is a highly conserved nuclear protein with a nuclear and extracellular role that functions as an extracellular signaling molecule under specific conditions. Several studies have shown that HMGB1 is a critical regulator of autophagy. This mini-review focuses on the involvement of HMGB1 protein in the interplay between autophagy and MetS, emphasizing its potential role as a promising biomarker candidate for the early stage of MetS or disease’s therapeutic target.

Endocrine disrupting chemicals (EDCs) are exogenous chemicals which can disrupt any action of the endocrine system, and are an important class of substances which play a role in the Developmental Origins of Health and Disease (DOHaD) [...]

Purpose of review Health status is the result of complex interaction between individual factors, general environmental factors and specific factors as nutrition or the presence of chemicals. Aim of this review is to point out the more recent knowledge covering the role of the endocrine disrupting chemical (EDC) on pediatric population wellbeing. Recent findings Prenatal, postnatal life and puberty are the three main temporal windows of susceptibility when EDCs may act. The mechanism is independent from dose or duration of exposition, sex, age or combination of chemicals and may also be transgenerational, affecting both growth and pubertal timing. A window of susceptibility for breast cancer has been detected. Thyroid gland is influenced by environmental chemicals, both in utero and during childhood. Alteration in Thyrotropin stimulating hormone (TSH) levels and neurodevelopmental impairment have been demonstrate. It has been detected a pro-obesogenic action of specific chemicals, impairing also glucose homeostasis during childhood. Summary With a multidisciplinary approach and the use of big data platforms, an attempt has to be made to verify biological variations related to a disease, and how much the risk is influenced by the presence of the endocrine disruptors. This may help the future generation to better interpret uncommunicable diseases.

Coronavirus disease (COVID-19) is an infectious disease caused by the newly discovered coronavirus, Sars-Cov-2. This infection can cause mild to very severe respiratory and systemic illness mainly related with a cytokine storm. The epidemiology of COVID-19 is under continuous evolution, and studies are ongoing aiming at identifying the possible factors facilitating the diffusion of this infection. It is documented that air pollution and smoking are a leading cause of human morbidity and mortality globally, and can increase the risk of many diseases, including respiratory diseases. Overall, a linear relationship between exposure to atmospheric pollutants and diffusion of the Sars-Cov2 virus seems to exist. However, this correlation, cannot be regarded as a cause-effect relationship. The available data show that air pollution is responsible for inflammation and hyper-activation of innate immunity that are associated with the worst outcomes of covid-19 but do not allow to conclude that atmospheric particulate is responsible for increased contagion. As to smoking, nicotine activation of nicotinic receptors leads to enhanced protease activation, apoptosis and inflammatory signaling through the same pathways (Renin-angiotensin system (RAS) and angiotensin-converting enzyme 2 (ACE2)) used by the virus increasing the inflammatory/destructive action of the virus itself. The increase in non-communicable diseases and of chronic inflammatory diseases is in line with environmental pollution, related climate changes, and with an augmented susceptibility to infectious diseases with increased contagiousness and morbidity. Restrictive measures to limit environmental pollution are needed worldwide as this represents a threat for human health.

Context: High mobility group box 1 (HMGB1) is a nuclear constitutive and highly conserved mammalian protein which shows several important physiologic functions, playing a crucial role in local and systemic inflammation. It also seems to be implicated in the development of metabolic syndrome, whereas some in vitro and animal models and recent preliminary human studies suggested its potential role in polycystic ovary syndrome (PCOS) pathophysiology. In particular, some data suggested a potential role of HMGB1 in follicular maturation block. Moreover, increased blood and follicular fluid HMGB1 concentrations have been reported in PCOS women, showing a direct correlation with surrogate indexes of insulin-resistance (IR) (i.e. HOMA-IR). Objective: The purpose of the present study was to investigate the relationships between serum HMGB1 levels and clinical, endocrine and metabolic parameters of PCOS patients. Design and patients: Sixty women with PCOS, 30 with IR and 30 with normal insulin sensitivity (IS), and 30 healthy controls were included in the study. In these subjects, body fat was quantified by bioelectrical impedance; plasma HMGB1 levels were measured using a specific ELISA method (Tecan, Mannedorf, Switzerland); and serum androgens were measured by liquid chromatography/mass spectrometry and equilibrium dialysis. In PCOS women, IR was measured using the gold standard hyperinsulinemic-euglycemic clamp technique, combined with indirect calorimetry. Results: HMGB1 levels did not differ between PCOS women and healthy controls (4.11 ± 3.22 vs 3.77 ± 2.50 ng/mL, respectively; p=0.61). Moreover, HMGB1 levels did not differ between PCOS phenotype subgroups. However, PCOS IR women showed higher levels of this protein as compared with PCOS IS (5.00 ± 3.53 vs 3.16 ± 2.59 ng/mL, respectively; p=0.017). In women with PCOS, HMGB1 levels were associated with several metabolic parameters, including IR measured by glucose utilization during the clamp (rho -0.37, p=0.005). This correlation was preserved after adjusting for potential confounding parameters, such as age, fat mass and serum free testosterone. HMGB1 levels did not change during glucose-clamp induced acute hyperinsulinemia, either in the whole cohort of patients or in IR and IS subgroups analyzed separately. Both in the whole population under study and in PCOS women, HMGB1 levels did not correlate with anthropometric parameters, hormonal features and ovarian morphology. Conclusions: In women with PCOS, HMGB1 blood levels show an independent association with insulin resistance. However, no associations with other typical features of the syndrome were found. Further research is needed in order to establish whether this protein may play a role in the pathogenesis of PCOS.

Fetal growth is regulated by a complex interaction of maternal, placental, and fetal factors. The effects and outcomes that chemicals, widely distributed in the environment, may have on the health status of both the mother and the fetus are not yet well defined. Mainly mixtures of chemical substances are found in the mothers and placenta. Exposure to endocrine-disrupting chemicals (EDCs) can be associated with fetal growth retardation, thyroid dysfunction, and neurological disorders. EDCs mostly interfere with insulin, glucocorticoid, estrogenic, and thyroid pathways, with subsequent effects on normal endocrine and metabolic functions, which cause changes in the epigenome and state of inflammation with life-long effects and consequences. International scientific societies recommend the implementation of research and of all possible preventive measures. This review briefly summarizes all these aspects.

Objective: MicroRNAs (miRNAs) are gene expression regulators. Altered miRNA levels are associated with diabetes, insulin resistance, and inflammation. Insulin resistance and inflammation are both features of Polycystic ovary syndrome (PCOS). The aim of this study was first to assess differences in selected miRNAs (miR-146a, miR-155, miR-320, miR-370, miR-486), involved in insulin sensitivity regulation and inflammation, in women with or without PCOS. Second, to investigate relationships among these miRNAs, insulin, High mobility group box 1 (HMGB1), and IL-6 in follicular fluid (FF), serum 17-beta estradiol (E2), and the number of dominant follicles. Methods: Thirty PCOS and thirty-six non-PCOS women undergoing in vitro fertilization were enrolled. RNA from granulosa cells (GC) and FF was extracted and the specific miRNAs were evaluated using qRT-PCR. HMGB1, insulin, and IL-6 in FF, and serum E2 were assayed using specific kits. Results: MiR-146a, miR-155, miR-486 were upregulated and miR-320 and miR-370 were downregulated in GC from the PCOS patients. In FF, miR-146a, miR-155, and miR-486 showed lower levels in PCOS, whereas miR-320 and miR-370 showed an opposite trend but no significant changes were observed. These miRNAs showed relationships with Body Mass Index (BMI), age, E2, number of dominant follicles, insulin, and HMGB1. Conclusion: In conclusion, the miRNAs analyzed showed changes in PCOS ovaries and had relationships with indices of inflammation and insulin sensitivity within the ovary, providing evidence for new regulatory mechanisms.

Childhood obesity is a major public health problem in industrialized countries. The aim of this study was to estimate the risk of obesity at age 5 based on BMI categories at age 3 and changes in BMI z-score from birth to 3 years of age. In this population-based study BMI data of 5173 children were collected at ages 3 and 5 and were linked to information relative to birth weight. The prevalence of obesity at age 5 was 3.8%. The risk of obesity for children born large for gestational age was 6.5%, while it was 18.6% for children overweight at age 3 and 62% for children who were obese at 3. An increase in BMI z-score from birth to 3 years increases the risk of obesity at age 5 (OR for increase of one standard deviation 2.8%; 95% CI: 2.46–3.20), but adjusting for BMI z-score at age 3, the effect of trajectory disappears (OR 1.08 95% CI: 0.9–1.29). In other words, if one targeted early preventive interventions to 3-year-olds affected by overweight/obesity (only 9.8% of the study cohort), one could possibly address 71% of children potentially affected by obesity at age 5.

Body growth and development are regulated among others by genetic and epigenetic factors. MicroRNAs (miRNAs) are epigenetic regulators of gene expression that act at the post-transcriptional level, thereby exerting a strong influence on regulatory gene networks. Increasing studies suggest the importance of miRNAs in the regulation of the growth plate and growth hormone (GH)-insulin-like growth factor (IGF) axis during the life course in a broad spectrum of animal species, contributing to longitudinal growth. This review summarizes the role of miRNAs in regulating growth in different in vitro and in vivo models acting on GH, GH receptor (GHR), IGFs, and IGF1R genes besides current knowledge in humans, and highlights that this regulatory system is of importance for growth.

Obesity is associated with insulin resistance and low-grade inflammation. Insulin resistance is a risk factor for cancer. A recent chapter in epigenetics is represented by microRNAs (miRNAs), which post-transcriptionally regulate gene expression. Dysregulated miRNA profiles have been associated with diseases including obesity and cancer. Herein we report dysregulated miRNAs in obesity both in animal models and in humans, and we also document dysregulated miRNAs in colorectal cancer (CRC), as example of an obesity-related cancer. Some of the described miRNAs are found to be similarly dysregulated both in obesity, insulin resistance (IR), and CRC. Thus, we present miRNAs as a potential molecular link between obesity and CRC onset and development, giving a new perspective on the role of miRNAs in obesity-associated cancers.

Cystic fibrosis-related diabetes (CFRD) is associated with worsening of inflammation and infections, and the beginning of insulin treatment is debated.To verify high-mobility group box 1 protein (HMGB1) levels in CF patients according to glucose tolerance state, and analyze relationships with insulin secretion and resistance. To verify, in an in vitro model, whether HMGB1 gene expression and protein content were affected by insulin administration and whether these changes were dependent on CF transmembrane conductance regulator (CFTR) loss of function.Forty-three patients in stable clinical conditions and 35 age- and sex-matched controls were enrolled. Glucose tolerance was established in patients based on a 5 point oral glucose tolerance test (OGTT). Fasting glucose to insulin ratio (FGIR), HOMA-IR index, whole-body insulin sensitivity index (WIBISI), and the areas under the curve for glucose (AUCG) and insulin (AUCI) were calculated. HMGB1 was assayed in serum, in cell lysates and conditioned media using a specific ELISA kit. For the in vitro study we used CFBE41o- cells, homozygous for the F508del mutation, and 16HBE14o- as non-CF control. HMGB1 gene expression was studied by real-time RT-PCR. Cells were stimulated with insulin at 2.5 and 5 ng/mL. The CFTR inhibitor 172 and CFTR gene silencing were used to induce CFTR loss of function in 16HBE14o- cells.HMGB1 levels were increased at onset of CFRD (5.04 ± 1.2 vs 2.7 ± 0.3 ng/mL in controls; P.05) and correlated with FGIR (R = +0.43; P = .038), and AUCI (R = +0.43; P = .013). CFTR loss of function in the 16HBE14o- cells increased HMGB1 and was lowered by insulin.HMGB1 was increased in CF patients with deranging glucose metabolism and showed relationships with indexes of glucose metabolism. The increase in HMGB1 was related to CFTR loss of function, and insulin lowered HMGB1. Further research is required to verify whether HMGB1 could potentially be a candidate marker of onset of CFRD and to establish when to start insulin treatment.

To date, 5 cases of 17p13.1 microduplications have been described in the literature. Intellectual disability was reported as the core feature, together with minor facial dysmorphisms and obesity, but a characteristic phenotype for 17p13.1 microduplication has not been delineated. Here, we describe a patient with a 1.56-Mb de novo duplication in 17p13.1, affected by mild intellectual disability, facial dysmorphisms, obesity, and diabetes. By comparing the different phenotypes of currently described cases, we delineated the main clinical features of 17p13.1 microduplication syndrome. All patients described to date had variable facial dysmorphisms; therefore, it was difficult to define a common facial gestalt. Furthermore, we stress endocrinological abnormalities as important features and the need to monitor these over time.

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation.

The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention. The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase. Electronic supplementary material The online version of this article (10.1186/s13052-018-0525-6) contains supplementary material, which is available to authorized users.

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon-intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and highlights the need to search for vertebral anomalies and suspect this condition in the presence of a prominent, elongated coccyx.

Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic.

MicroRNAs are involved in multiple pathophysiological networks and in the pathogenesis of a broad spectrum of human disorders, including cancer and inflammatory diseases. Impaired linear growth is encountered in children with chronic inflammatory conditions such as cystic fibrosis, inflammatory bowel diseases, juvenile idiopathic arthritis, celiac disease and in subjects born intrauterine growth restricted/small for gestational age. Children with inflammatory conditions may also be at risk of developing insulin resistance as a result of the inflammatory process and concurrent therapy. Chronic inflammation may lead to a continuum of abnormalities in the Growth hormone/Insulin-like growth factor 1 (GH/IGF-I) axis, including relative GH insufficiency, GH/IGF-I resistance due to down regulation of GH and IGF-I receptors, changes in GH and IGF-I bioavailability due to modifications of binding proteins, and/or impaired GH/IGF-I signaling. The aim of this review is first to summarize the current knowledge concerning microRNAs involved in inflammation in the most relevant chronic inflammatory diseases in childhood, second to provide new insights into miRNA regulation of growth and insulin sensitivity mediated by the inflammatory processes. We evaluated single microRNAs involved in inflammation in the single conditions mentioned above and verified which had validated and predicted targets within the GH receptor, IGF-I type 1 receptor and insulin receptor interactomes. The findings show a new link among inflammation, growth and insulin sensitivity mediated by miRNAs that warrants further research in the future.

Cystic fibrosis-related diabetes is to date the most frequent complication in cystic fibrosis (CF). The mechanisms underlying this condition are not well understood, and a possible role of insulin resistance is debated. We investigated insulin signal transduction in CF. Total insulin receptor, IRS1, p85 PI3K, and AKT contents were substantially normal in CF cells (CFBE41o-), whereas winged helix forkhead (FOX)O1 contents were reduced both in baseline conditions and after insulin stimulation. In addition, CF cells showed increased ERK1/2, and reduced β2 arrestin contents. No significant change in SOCS2 was observed. By using a CFTR inhibitor and siRNA, changes in FOXO1 were related to CFTR loss of function. In a CF-affected mouse model, FOXO1 content was reduced in the muscle while no significant difference was observed in liver and adipose tissue compared with wild-type. Insulin-like growth factor 1 (IGF-I) increased FOXO1 content in vitro and in vivo in muscle and adipose tissue. In conclusion, we present the first description of reduced FOXO1 content in CF, which is compatible with reduced gluconeogenesis and increased adipogenesis, both features of insulin insensitivity. IGF-I treatment was effective in increasing FOXO1, thereby suggesting that it could be considered as a potential treatment in CF patients possibly to prevent and treat cystic fibrosis-related diabetes.

Background PATRO Children is an ongoing observational, longitudinal, non-interventional, global post-marketing surveillance study, which is investigating the long-term safety and effectiveness of Omnitrope®, a somatropin biosimilar to Genotropin®, in children with growth disturbances. The primary endpoint of PATRO Children is long-term safety and the secondary endpoint is effectiveness, which is assessed by analysing auxological data such as height (HSDS) and height velocity (HVSDS) standard deviation scores. Here, we report the data from the Italian interim analysis of PATRO Children data up to August 2015. Methods PATRO Children is enrolling children who are diagnosed with conditions of short stature requiring GH treatment and are receiving Omnitrope®. Adverse events (AEs) are assessed in all Omnitrope®-treated patients. Height is evaluated yearly to near-adult (final) height, and is herein reported as HSDS; height velocity is also assessed and reported as a standard deviation score (HVSDS). Results Up to August 2015, a total of 186 patients (mean age 10.2 years, 57.5 % males) were enrolled :156 [84 %] had growth hormone deficiency, 12 [6.5 %] were born small for gestational age, seven [3.8 %] had Prader-Willi syndrome, one [0.5 %] had Turner syndrome and one [0.5 %] had chronic renal insufficiency; seven [3.8 %] patients had other indication profiles. The mean treatment duration with Omnitrope® was 28.1 ± 19.1 months. AEs were reported in 35.6 % of patients and included headache, pyrexia, arthralgia, abdominal pain, leg and/or arm pain and increased blood creatine phosphokinase. Two serious AEs in two patients were thought to be drug-related; one patient experienced a minimal increase in a known residual craniopharyngioma, and another a gait disturbance with worsening of walking difficulties. Similar to investigational studies, Omnitrope® treatment was associated with improvements in both HSDS and HVSDS. Conclusions Omnitrope® appears to be well tolerated and effective for the treatment of a wide range of paediatric indications, which is consistent with the outcomes from controlled clinical trials. These results need to be interpreted with caution until the data from the global PATRO Children study are available.

Cystic fibrosis-related diabetes (CFRD) is the most frequent and severe co-morbidity in cystic fibrosis (CF). Presentation and severity are quite variable.To investigate changes in microRNAs (miRNAs) due to CF transmembrane conductance regulator malfunctioning in vitro, to study the circulating levels of selected miRNAs in serum samples from patients, and to assess their relationships in different age groups with genotype, glucose tolerance state, and at onset of CFRD. Design/Setting/Patients/Interventions: Transcriptional profiling of all known miRNAs in CFBE41o- cells, in their normal counterparts (16HBE14o- cells), and in IB3 cells was performed. A set of miRNAs was differentially expressed in the CF cells. By in silico analysis, four miRNAs (miR-146a, miR-155, miR-370, and miR-708) were selected as potential regulators of the FOXO1 gene. Seventy-four CF patients and 50 healthy subjects whose glucose tolerance was characterized by an oral glucose tolerance test were enrolled in the study, and the identified miRNAs were quantified in serum by quantitative RT-PCR. Main Outcome Measurements/Results: A total of 111 miRNAs were differentially expressed in the two CF cell lines. miR-155, miR-370, and miR-708 were up-regulated and miR-146a was down-regulated in vitro, whereas in vivo, miR-146a, miR-155, and miR-370 were up-regulated, and miR-708 was down-regulated. These changes showed relationships with genotype, glucose tolerance state, and onset of CFRD.The data showed significant changes in miRNAs dependent on genotype and glucose tolerance state in CF patients and highlighted some miRNAs of importance in CFRD at onset. miRNAs could explain some of the variability observed in CF.

ObjectivesTo analyze the circulating levels of proinflammatory peptides in healthy prepubertal children in relation to abdominal obesity, measured by waist circumference (WC), and to investigate their interactions with cardiometabolic risk factors.Design and methodsA cross-sectional study of 137 healthy prepubertal children with a mean age of 8.0±0.1 years divided into three groups according to their WC as a measure of abdominal obesity: ‘normal-WC’ children (25th–75th percentile, n=48), ‘children at risk’ (75th–90th percentile, n=39), and ‘abdominally obese’ (≥90th percentile, n=50) children. Auxological measurements and blood pressure (BP) were taken. Fasting levels of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL6), tumor necrosis factor-α (TNF-α), glucose, insulin, and lipid profile were measured. Insulin resistance (IR) was assessed by homeostasis model assessment of IR (HOMA-IR).ResultsAbdominally obese children had significantly higher BP, insulin, HOMA-IR, total cholesterol and triglycerides (TG) compared with their normal-WC counterparts (Pr=0.443, Pr=0.257, P=0.004), TNF-α levels were related to high-density lipoprotein cholesterol (HDL-C; r=−0.216, P=0.016) and TG (r=0.196, P=0.029), whereas the relationship between IL6 and HDL-C reduced its magnitude to an insignificant level (r=−0.173, P=0.055).ConclusionsHealthy prepubertal children with abdominal obesity have associated inflammatory and cardiometabolic alterations, interacting with each other.

ObjectiveIntra-uterine growth restriction (IUGR) is related to a higher incidence of type 2 diabetes mellitus. We previously reported reduced adiponectin and increased interleukin 6 (IL6) concentrations in IUGR placentas, which are features of insulin resistance. We aimed to investigate placental insulin receptor (IR) function and activation in human placenta and subsequently the relationships of insulin signalling peptides with placental protein content in IL6, insulin, resistin and adiponectin, and with parameters of fetal growth.Design and methodsWhole villous tissue was collected from 18 IUGR and 24 appropriate for gestational age (AGA) placentas of comparable gestational age. Insulin signalling peptides, suppressors of cytokine signalling-2 (SOCS2), insulin, adiponectin, resistin, and IL6 concentrations were determined by using western immunoblotting or specific research kits.ResultsThe amount of total IR was similar in both groups but activated IR significantly higher in IUGR. Total IR substrate-1 (IRS1) was increased in IUGR, whereas total IRS2 and activated IRS1 were similar. AKT content was reduced and activated AKT was undetectable in IUGR placentas. c-Jun N-terminal kinase content was reduced in IUGR. Total and activated ERK1/2 was similar in IUGR and AGA groups, and total SOCS2 was increased in IUGR. IL6 lysate concentrations correlated with AKT content and activated IR. Correlations were found also with adiponectin and resistin. SOCS2 correlated negatively with all growth parameters at birth.ConclusionsIR was more activated in placentas of IUGR compared with AGA; however, signal transduction downstream of the receptor was impaired. The increase in activated IR could be in favour of a compensatory mechanism to increase insulin sensitivity. Close relationships of insulin action in placenta with fetal growth were shown.

Objective Intrauterine growth restriction (IUGR) has been related to a higher incidence of insulin resistance in adult life, which is associated with low adiponectin and high resistin, insulin and interleukin (IL)-6 serum concentrations. This study assessed cortisol, insulin, total insulin receptor, resistin, adiponectin and IL-6 concentrations, as markers of insulin sensitivity, in placental lysates and cord serum of IUGR and appropriate for gestational age (AGA) newborns, to establish relationships among peptides and with growth parameters at birth. Design and patients Whole villous tissue and cord serum at birth were collected from 24 AGA and 18 IUGR newborns of comparable gestational age. Measurements Hormonal and peptide concentrations were assayed in placental lysates and cord serum using specific commercial kits. Concentrations in lysates were adjusted per mg of total protein content. Results Cortisol, insulin and resistin concentrations and the total amount of insulin receptor were similar in both groups. IL-6 concentration in lysates was significantly higher in IUGR compared with AGA newborns. Adiponectin was significantly lower in lysates from IUGR compared with AGA newborns. Placental insulin and resistin concentrations were positively correlated. Placental adiponectin concentration was positively correlated with the weight of the placenta, birthweight and head circumference. IL-6 concentration in lysates was negatively correlated with birth length, birthweight and head circumference. Conclusions This study evaluated the markers of insulin sensitivity in the placentas of subjects born IUGR, showing new potential roles for adiponectin and IL-6 in particular, and suggesting a role for the placenta in the programming of these hormones.

Summary Objective Growth delay is a feature of patients with cystic fibrosis (CF). CF is a condition characterized by chronic inflammation that has been shown to modify the IGF system, which is essential for normal growth, and is related to pulmonary function in CF patients. We aimed to verify whether circulating levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6, insulin and the IGF system were related and/or had relationships with linear growth in children with CF. Design and patients Seventeen prepubertal CF patients (nine males and eight females) in a stable clinical condition were enrolled. Auxological parameters, pulmonary function and the Shwachman–Kulczycki (S-K) score were assessed, and serum samples were drawn at baseline and after 12 months. Measurements TNF-α, IL-6, IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 and insulin were assayed using specific commercial kits. Results At baseline, TNF-α serum concentration was related to serum IGF-I concentration (R = 0·53), IGF-II bioactivity (IGF-II/IGFBP-3 molar ratio, R = +0·52) and insulin concentration (R = +0·63). Changes in serum IL-6 and IGFBP-2 concentrations during the 12-month observation were positively correlated (R = +0·63). Changes in height standard deviation score (Ht SDS) were correlated with IGF-I serum concentrations at baseline (R =+0·67) and after 12 months (R = +0·70), with IGF-I bioavailability and with IGFBP-1 serum concentrations (R = –0·88). Body mass index (BMI) SDS correlated with IGF bioavailability. Conclusions This study showed a relationship between inflammatory status and the IGF system, and an effect of these interactions on longitudinal growth. Moreover, a role for insulin in growth was identified. Better control of inflammation and preservation of insulin secretion could benefit these patients.

Summary Objective To evaluate changes and relationships of IGFs and IGFBPs, serum interleukin 6 (IL-6) and tumour necrosis factor (TNF)-α, and auxological parameters at diagnosis of coeliac disease (CD) and at 6 months and 12 months after starting a gluten-free diet (GFD), compared with a control population. Patients Twenty patients were enrolled at diagnosis (9 male, 11 female; age 9·6 ± 0·8 years). A healthy population of 18 subjects (5 male, 13 female; age 11·3 ± 0·6 years) comparable for age, sex and pubertal status served as controls at baseline. Measurements Blood samples were taken at diagnosis, and at 6 months and 12 months after starting the GFD. Serum IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, IL-6 and TNF-α were measured using commercial kits. Height (Ht) standard deviation score (SDS), body mass index (BMI) SDS and Ht velocity SDS were evaluated at diagnosis and at 6 months and 12 months after starting GFD. Results In CD patients, both Ht SDS and BMI SDS increased during the first year of treatment, and Ht velocity SDS increased during the second 6 months of follow-up (P

Adipokines are cytokines produced mainly by adipose tissue, besides many other tissues such as placenta, ovaries, peripheral-blood mononuclear cells, liver, muscle, kidney, heart, and bone marrow. Adipokines play a significant role in the metabolic syndrome and in cardiovascular diseases, have implications in regulating insulin sensitivity and inflammation, and have significant effects on growth and reproductive function. The objective of this review was to analyze the functions known today of adiponectin, leptin, resistin, and visfatin from placenta throughout childhood and adolescence. It is well known now that their serum concentrations during pregnancy and lactation have long-term effects beyond the fetus and newborn. With regard to puberty, adipokines are involved in the regulation of the relationship between nutritional status and normal physiology or disorders of puberty and altered gonadal function, as, for example, premature pubarche and polycystic ovarian syndrome (PCOS). Cytokines are involved in the maturation of oocytes and in the regular progression of puberty and pregnancy.

By retrospectively collecting data from nine Italian centres of pediatric endocrinology, we assessed the different management and final outcome of children with short stature and idiopathic delayed puberty. Data were obtained in 77 patients (54 males, 23 females) diagnosed and followed-up in the various centres during the last 15 years. Inclusion criteria were short stature at initial observation and idiopathic delayed puberty diagnosed during follow-up. At first observation, age was 13.8 +/- 1.0 years and height standard deviation score (SDS) was -2.6 +/- 0.6 in males. In females age was 13.1 +/- 0.9 years and height SDS -2.6 +/- 0.4. Local diagnostic and therapeutic protocols included testing for growth-hormone deficiency (six centres) and treatment in case of deficiency or, in the remaining centres, testosterone or no treatment in males, and no treatment in females. At diagnosis, both in males and in females, the auxological features (height SDS, target height SDS and bone age delay) were similar in the patients treated with growth hormone, testosterone or not treated. Overall 32 patients received growth hormone (25 males, 7 females), 33 no treatment (17 males, 16 females) and 12 testosterone. There was no difference in the adult height of males and females in the different treatment groups. In males there were no differences between adult and target height SDSs (growth hormone-treated 0.31 +/- 0.79, untreated 0.10 +/- 0.82, testosterone-treated 0.05 +/- 0.95), between adult and initial height SDSs (growth hormone-treated 1.70 +/- 0.93, untreated 1.55 +/- 0.92, testosterone-treated 1.53 +/- 1.43) and percentage of subjects with adult height above target height. In females, there were no differences between adult and target height SDSs (growth hormone-treated -0.49 +/- 1.13; untreated 0.10 +/- 0.97) and between adult and initial height SDSs (growth hormone-treated 1.76 +/- 0.92; untreated 1.77 +/- 0.98), whereas a significantly higher percentage of patients remained below target height in the growth hormone-treated group (6/7, 85.7% vs 5/11, 31.3%) (P = 0.02). In conclusion, the diagnostic and therapeutic management of the patients with short stature and delayed puberty is different among Italian pediatric endocrinologists. Our data do not support the usefulness of growth-hormone therapy in improving adult height in subjects with short stature and delayed puberty, particularly in the female sex.

© 2015 Heindel et al. A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16-18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as "metabolic disruptors", in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.

Objectives: The IGF system is central to fetal growth. Recently, the relationships between cytokines and the IGF system have been shown in specific tissues. It is unknown whether these occur in the placenta. The aim of this study was to assess whether interleukin-6 (IL-6) modulated the IGF system. Methods: Whole villous tissue and cord serum were collected from fetal growth restriction (FGR) neonates diagnosed before birth with altered Doppler velocimetry and controls. Sixteen FGR and 20 controls, born after week 32 of gestation from elective Caesarean sections, were compared. Total RNA was extracted from the placenta samples, reverse transcribed, and real-time quantitative reverse transcriptase (RT)-PCR was performed to quantify cDNA for IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-2, and IL-6. The same proteins were assayed in placenta lysates and cord serum using specific commercial kits and western immunoblotting. Results: FGR subjects had significantly more IGFBPs-1 and -2, and IL-6 mRNA and corresponding proteins in the placenta. In particular, the less phosphorylated isoforms of IGFBP-1 were highly increased. IL-6 and IGFBPs-2 mRNA, and IL-6 and IGFBP-1 peptides were positively and significantly correlated in the placenta. The IGF-II peptide was also significantly increased in FGR placentas. In cord serum, IGFBPs-1 and -2 were significantly more elevated in the FGR neonates. Serum IL-6 was significantly and positively correlated with both IGFBP-1 and IGFBP-2. Conclusions: The placenta of FGR neonates has higher IGF-II, IGFBP-1, IGFBP-2, and IL-6 contents compared with controls. At birth, IGFBPs-1 and -2 are increased in the cord blood of FGR neonates. IL-6 and IGFBP-2 gene expressions are closely related in the placenta. We suggest that the increase in IL-6 and IGFBP-2 could be subsequent to hypoxia and nutrient deficiency. As IGFBP-2 has a strong affinity for IGF-II, which is crucial for fetal growth, it could be an important bioregulator of IGF-II in the placenta.