This review focuses on the current knowledge of the effects of thyroid hormones on central nervous system differentiation and development in animals and the human fetal brain. The outcomes of ...children with congenital hypothyroidism and of newborns with hypothyroid pregnant mothers are emphasized, focusing on how therapies could affect and especially improve the outcomes.
Insulin Resistance in Children Tagi, Veronica Maria; Giannini, Cosimo; Chiarelli, Francesco
Frontiers in endocrinology (Lausanne),
06/2019, Letnik:
10
Journal Article
Recenzirano
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Insulin resistance (IR) is a pathological condition strongly associated with obesity. However, corticosteroids or growth hormone therapy and genetic diseases may affect insulin sensitivity lifelong. ...In obese children and adolescents of any age there is an evident association between IR and an increased prevalence of type 2 diabetes (T2D) and other elements contributing to the metabolic syndrome, leading to a higher cardiovascular risk. Therefore, early diagnosis and interventions in the attempt to prevent T2D when glycemia values are still normal is fundamental. The gold standard technique used to evaluate IR is the hyperinsulinemic euglycemic clamp, however it is costly and difficult to perform in clinical and research sets. Therefore, several surrogate markers have been proposed. Although the treatment of insulin resistance in children is firstly targeted to lifestyle interventions, in selected cases the integration of a pharmacological intervention might be taken into consideration. The aim of this review is to present the current knowledge on IR in children, starting with an outline of the recent evidences about the congenital forms of deficiency in insulin functioning and therefore focusing on the physiopathology of IR, its appropriate measurement, consequences, treatment options and prevention strategies.
Prediction and Prevention of Type 1 Diabetes Primavera, Marina; Giannini, Cosimo; Chiarelli, Francesco
Frontiers in endocrinology (Lausanne),
06/2020, Letnik:
11
Journal Article
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Type 1 Diabetes (T1D) is one of the most common chronic autoimmune diseases in children. The disease is characterized by the destruction of beta cells, leading to hyperglycemia, and to a lifelong ...insulin-dependent state. Although several studies in the last decades have added relevant insights, the complex pathogenesis of the disease is not yet completely understood. Recent studies have been focused on several factors, including family history and genetic predisposition (HLA and non-HLA genes) as well as environmental and metabolic biomarkers, with the aim of predicting the development and progression of T1D. Once a child becomes symptomatic, beta cell mass has already reached a critical threshold (usually a residual of 20–30% of normal amounts), thus representing only the very late phase of the disease. In particular, this final stage follows two preceding asymptomatic stages, which have been precisely identified. In view of the long natural history and complex pathogenesis of the disease, many strategies may be proposed for primary, secondary, and tertiary prevention. Strategies of primary prevention aim to prevent the onset of autoimmunity against beta cells in asymptomatic individuals at high risk for T1D. In addition, the availability of novel humoral and metabolic biomarkers that are able to characterize subjects at high risk of progression, have stimulated several studies on secondary and tertiary prevention, aimed to preserve residual beta cell destruction and/or to prolong the remission phase after the onset of T1D. This review focuses on the major current knowledge on prediction and prevention of T1D in children.
MAFLD and Celiac Disease in Children Scapaticci, Serena; Venanzi, Annamaria; Chiarelli, Francesco ...
International journal of molecular sciences,
01/2023, Letnik:
24, Številka:
2
Journal Article
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Celiac disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten whose clinical presentation ranges from the asymptomatic form to clinical patterns characterized by ...multiple systemic involvement. Although CD is a disease more frequently diagnosed in patients with symptoms of malabsorption such as diarrhea, steatorrhea, weight loss, or failure to thrive, the raised rate of overweight and obesity among general pediatric and adult populations has increased the possibility to diagnose celiac disease in obese patients as well. Consequently, it is not difficult to also find obesity-related disorders in patients with CD, including "metabolic associated fatty liver disease" (MAFLD). The exact mechanisms linking these two conditions are not yet known. The going assumption is that a gluten-free diet (GFD) plays a pivotal role in determining an altered metabolic profile because of the elevated content of sugars, proteins, saturated fats, and complex carbohydrates, and the higher glycemic index of gluten-free products than gluten-contained foods, predisposing individuals to the development of insulin resistance. However, recent evidence supports the hypothesis that alterations in one of the components of the so-called "gut-liver axis" might contribute to the increased afflux of toxic substances to the liver triggering the liver fat accumulation and to the subsequent hepatocellular damage. The aim of this paper was to describe the actual knowledge about the factors implicated in the pathogenesis of hepatic steatosis in pediatric patients with CD. The presented review allows us to conclude that the serological evaluations for CD with anti-transglutaminase antibodies, should be a part of the general workup in the asymptomatic patients with "non-alcoholic fatty liver disease" (NAFLD) when metabolic risk factors are not evident, and in the patients with steatohepatitis when other causes of liver disease are excluded.
Bone age represents a common index utilized in pediatric radiology and endocrinology departments worldwide for the definition of skeletal maturity for medical and non-medical purpose. It is defined ...by the age expressed in years that corresponds to the level of maturation of bones. Although several bones have been studied to better define bone age, the hand and wrist X-rays are the most used images. In fact, the images obtained by hand and wrist X-ray reflect the maturity of different types of bones of the skeletal segment evaluated. This information, associated to the characterization of the shape and changes of bone components configuration, represent an important factor of the biological maturation process of a subject. Bone age may be affected by several factors, including gender, nutrition, as well as metabolic, genetic, and social factors and either acute and chronic pathologies especially hormone alteration. As well several differences can be characterized according to the numerous standardized methods developed over the past decades. Therefore, the complete characterization of the main methods and procedure available and particularly of all their advantages and disadvantages need to be known in order to properly utilized this information for all its medical and non-medical main fields of application.
Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the ...last decades. These reports imply an increased risk of fat accumulation in hepatic cells leading to a series of histological hepatic damages gathered under the acronym NAFLD (Non-Alcoholic Fatty Liver Disease). Due to the complex dynamics underlying this condition, it has been recently renamed as 'Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)', supporting the hypothesis that hepatic steatosis is a key component of the large group of clinical and laboratory abnormalities of Metabolic Syndrome (MetS). This review aims to share the latest scientific knowledge on MAFLD in children in an attempt to offer novel insights into the complex dynamics underlying this condition, focusing on the novel molecular aspects. Although there is still no treatment with a proven efficacy for this condition, starting from the molecular basis of the disease, MAFLD's therapeutic landscape is rapidly expanding, and different medications seem to act as modifiers of liver steatosis, inflammation, and fibrosis.
Linear growth during childhood is the result of the synergic contribution of different factors. The best growth determinant system during each period of life is represented by the growth ...hormone-insulin-like growth factor axis (GH-IGF), even if several other factors are involved in normal growth. Within the broad spectrum of growth disorders, an increased importance has been placed on growth hormone insensitivity (GHI). GHI was reported for the first time by Laron as a syndrome characterized by short stature due to GH receptor (GHR) mutation. To date, it is recognized that GHI represents a wide diagnostic category, including a broad spectrum of defects. The peculiar characteristic of GHI is the low IGF-1 levels associated with normal or elevated GH levels and the lack of IGF-1 response after GH administration. Recombinant IGF-1 preparations may be used in the treatment of these patients.
Currently, Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent form of chronic liver disease in children and adolescents worldwide. Simultaneously to the epidemic spreading of childhood ...obesity, the rate of affected young has dramatically increased in the last decades with an estimated prevalence of NAFLD of 3%-10% in pediatric subjects in the world. The continuous improvement in NAFLD knowledge has significantly defined several risk factors associated to the natural history of this complex liver alteration. Among them, Insulin Resistance (IR) is certainly one of the main features. As well, not surprisingly, abnormal glucose tolerance (prediabetes and diabetes) is highly prevalent among children/adolescents with biopsy-proven NAFLD. In addition, other factors such as genetic, ethnicity, gender, age, puberty and lifestyle might affect the development and progression of hepatic alterations. However, available data are still lacking to confirm whether IR is a risk factor or a consequence of hepatic steatosis. There is also evidence that NAFLD is the hepatic manifestation of Metabolic Syndrome (MetS). In fact, NAFLD often coexist with central obesity, impaired glucose tolerance, dyslipidemia, and hypertension, which represent the main features of MetS. In this Review, main aspects of the natural history and risk factors of the disease are summarized in children and adolescents. In addition, the most relevant scientific evidence about the association between NAFLD and metabolic dysregulation, focusing on clinical, pathogenetic, and histological implication will be provided with some focuses on the main treatment options.
The growing interest in metabolomics has spread to the search for suitable predictive biomarkers for complications related to the emerging issue of pediatric obesity and its related cardiovascular ...risk and metabolic alteration. Indeed, several studies have investigated the association between metabolic disorders and amino acids, in particular branched-chain amino acids (BCAAs). We have performed a revision of the literature to assess the role of BCAAs in children and adolescents' metabolism, focusing on the molecular pathways involved. We searched on Pubmed/Medline, including articles published until February 2022. The results have shown that plasmatic levels of BCAAs are impaired already in obese children and adolescents. The relationship between BCAAs, obesity and the related metabolic disorders is explained on one side by the activation of the mTORC1 complex-that may promote insulin resistance-and on the other, by the accumulation of toxic metabolites, which may lead to mitochondrial dysfunction, stress kinase activation and damage of pancreatic cells. These compounds may help in the precocious identification of many complications of pediatric obesity. However, further studies are still needed to better assess if BCAAs may be used to screen these conditions and if any other metabolomic compound may be useful to achieve this goal.
The innate immune cell sensor leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome controls the activation of caspase-1, and the release of proinflammatory cytokines ...interleukin (IL)-1β and IL-18. The NLRP3 inflammasome is implicated in adipose tissue inflammation and the pathogenesis of insulin resistance. Herein, we tested the hypothesis that adipose tissue inflammation and NLRP3 inflammasome are linked to the downregulation of subcutaneous adipose tissue (SAT) adipogenesis/lipogenesis in obese adolescents with altered abdominal fat partitioning. We performed abdominal SAT biopsies on 58 obese adolescents and grouped them by MRI-derived visceral fat to visceral adipose tissue (VAT) plus SAT (VAT/VAT+SAT) ratio (cutoff 0.11). Adolescents with a high VAT/VAT+SAT ratio showed higher SAT macrophage infiltration and higher expression of the NLRP3 inflammasome-related genes (i.e., TLR4, NLRP3, IL1B, and CASP1). The increase in inflammation markers was paralleled by a decrease in genes related to insulin sensitivity (ADIPOQ, GLUT4, PPARG2, and SIRT1) and lipogenesis (SREBP1c, ACC, LPL, and FASN). Furthermore, SAT ceramide concentrations correlated with the expression of CASP1 and IL1B. Infiltration of macrophages and upregulation of the NLRP3 inflammasome together with the associated high ceramide content in the plasma and SAT of obese adolescents with a high VAT/VAT+SAT may contribute to the limited expansion of the subcutaneous abdominal adipose depot and the development of insulin resistance.
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