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Childhood obesity is characterized by the loss of vascular insulin sensitivity along with altered oxidant-antioxidant state and chronic inflammation, which play a key role in the onset of endothelial dysfunction. We previously demonstrated a reduced insulin-stimulated Nitric Oxide (NO) bioavailability in Human Umbilical Vein Endothelial cells (HUVECs) cultured with plasma from obese pre-pubertal children (OB) compared to those cultured with plasma of normal-weight children (CTRL). However, mechanisms underlying endothelial dysfunction in childhood obesity remains poorly understood. Hence, the present study aimed to better investigate these mechanisms, also considering a potential involvement of mammalian Target Of Rapamycin Complex1 (mTORC1)-ribosomal protein S6 Kinase beta1 (S6K1) pathway. OB-children (N = 32, age: 9.2 ± 1.7; BMI z-score: 2.72 ± 0.31) had higher fasting insulin levels and increased HOMA-IR than CTRL-children (N = 32, age: 8.8 ± 1.2; BMI z-score: 0.33 ± 0.75). In vitro, HUVECs exposed to OB-plasma exhibited significant increase in Reactive Oxygen Species (ROS) levels, higher vascular and intercellular adhesion molecules exposure, together with increased monocytes-endothelial interaction. This was associated with unbalanced pro- and anti-atherogenic endothelial insulin stimulated signaling pathways, as measured by increased Mitogen Activated Protein Kinase (MAPK) and decreased Insulin Receptor Substrate-1 (IRS-1)/protein kinase B (Akt)/ endothelial NO Synthase (eNOS) phosphorylation levels, together with augmented S6K1 activation. Interestingly, inhibition of mTORC1-S6K1 pathway using rapamycin significantly restored the IRS-1/Akt/eNOS activation, suggesting a feedback regulation of IRS-1/Akt signal through S6K1. Overall, our in vitro data shed light on new mechanisms underlying the onset of endothelial dysfunction in childhood obesity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose of Review: It is well known that obesity represents the main modifiable risk factor for insulin resistance in children and adolescents; obesity-induced insulin resistance in children is the most important risk factor for developing cardiovascular diseases and type 2 diabetes in adulthood. The mechanisms through which obesity causes insulin resistance are complex and not completely known to date., Recent Findings: In children, global adiposity is the main factor determining insulin resistance. Excessive fatty acids play a determinant role in the pathogenesis of insulin resistance in obese children, inducing an increased production of acetyl-CoA in the liver and enhancing inflammation in adipose tissue. The aetiology of insulin resistance in polycystic ovary syndrome is multifactorial and still debated., Summary: The aim of this review is to present an updated frame and new insights of the numerous pathways involved in the development of insulin resistance in obese patients, focusing on the peculiarities of children and adolescents. Improving the knowledge of mechanisms through which obesity leads to insulin resistance is fundamental in order to recommend particular follow-up and possible treatment to specific categories of obese children and adolescents.

Background: Recent findings have supposed that the underlying association between the increased prevalence of both asthma and obesity may be insulin resistance (IR)., Methods: Insulin and glucose serum levels were analyzed to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) for IR in 98 pre-pubertal children. Lung function and allergy status evaluation were performed. The study population was divided into four groups: (1) obese asthmatic children (ObA); (2) normal-weight asthmatic children (NwA); (3) normal-weight non-asthmatic children (Nw) and (4) obese non-asthmatic children (Ob)., Results: Forced expiratory volume in 1 s (FEV1) was slightly lower in obese subjects compared with normal-weight subjects and forced vital capacity (FVC) appeared lower in asthmatics, whereas between non-asthmatics subjects, it was lower in the obese group than in the normal-weight one. The post hoc analysis revealed a statistically significant reduction in FEV1, peak expiratory flow (PEF), forced expiratory flows (FEF) between 50% and 25% of the FVC (FEF50 and FEF25) between ObA and Nw and in FEV1, FVC, PEF, FEF50 and FEF25 between NwA and Nw, but no statistically significant differences of lung function parameters were observed between ObA and NwA. We found an inverse relationship between HOMA-IR and all spirometric parameters, although without any statistical significance. We also observed a significantly lower FVC in insulin-resistant children (HOMA-IR>95th percentile) (p=0.03)., Conclusions: This study suggests that lung function could be early altered in obese children, already in pre-pubertal age. Although IR should not manifest its effects on lungs in pre-pubertal obese children, the prevention or treatment of obesity in the pre-pubertal period may prevent definitive negative effects on lungs.

Childhood obesity is commonly associated with early signs of endothelial dysfunction, characterized by impairment of insulin signaling and vascular Nitric Oxide (NO) availability. However, the underlying mechanisms remain to be established. Hence, we tested the hypothesis that endothelial insulin-stimulated NO production and availability was impaired and related to Endoplasmic Reticulum (ER) in human umbilical vein endothelial cells (HUVECs) cultured with plasma obtained from pre-pubertal obese (OB) children. OB children (N = 28, age: 8.8 ± 2.2; BMI z-score: 2.15 ± 0.39) showed impaired fasting glucose, insulin and HOMA-IR than normal weight children (CTRL; N = 28, age: 8.8 ± 1.7; BMI z-score: 0.17 ± 0.96). The in vitro experiments showed that OB-plasma significantly impaired endothelial insulin-stimulated NO production and bioavailability compared to CTRL-plasma. In parallel, in HUVECs OB-plasma increased GRP78 and activated PERK, eIF2α, IkBα and ATF6 (all ER stress markers). Moreover, OB-plasma increased NF-κB activation and its nuclear translocation. Notably, all these effects proved to be significantly restored by using PBA and TUDCA, known ER stress inhibitors. Our study demonstrate for the first time that plasma from obese children is able to induce in vitro endothelial insulin resistance, which is characterized by reduced insulin-stimulated NO production and bioavailability, endothelial ER stress and increased NF-κB activation., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Gastrointestinal hormones, such as glucagon-like peptide (GLP-1), have been hypothesized to play a role in the pathogenesis of obesity-related complications. However, few data are available in youth. The objective of this study was to investigate the GLP-1 response to oral glucose load in obese pre-pubertal children and its relationship with insulin secretion., Methods: Ten pre-pubertal obese children [five boys; 10.5±1.6 years; body mass index-standard deviation score (BMI-SDS): 2.2±0.5] and 10 controls (eight boys; 9.9±1.2 years; BMI-SDS: -0.7±0.5) underwent a modified oral glucose tolerance test (OGTT) to evaluate post-load glucose, insulin and GLP-1 responses. Insulin sensitivity [homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI)] and secretion [HOMA-beta, insulinogenic index (IGI)] indexes, area under the curve (AUC) for glucose, insulin and GLP-1 were calculated., Results: In obese children GLP-1 AUC values were higher and correlated with BMI-SDS (r=0.45; p=0.04), HOMA-IR (r=0.53; p=0.01) and fasting glucose (r=0.68; p=0.001)., Conclusions: Obese children showed an increased GLP-1 response to oral glucose. These changes might likely represent a compensatory mechanism to avoid post-prandial hyperglycemia and allow a normal glucose tolerance.

The purpose of this study was to assess the prevalence of abnormal blood pressure in a population of school children during a 3-year follow-up period and its relationship with obesity. Anthropometric and blood pressure data were collected from a population of Italian school children during three consecutive years. During each year blood pressure measurements were repeated three times, at intervals of 1 week. A total of 564 school-children [311 boys; mean (SD) age 8.8 ± 1.4 years] were recruited. During each year, systolic and diastolic blood pressure decreased from visit 1 to visit 3 (p < 0.001). This was associated with a decline in the percentage of prehypertension/hypertension from visit 1 to visit 3. An abnormal blood pressure value in at least one study visit was found in 8.8-17 % of children, whereas the prevalence of hypertension at all three study visits was between 5.2 and 7.8 %, and that of prehypertension at all three visits was between 2.8 and 3.8 %. High blood pressure was more frequent in obese children. In this population of school children the percentage of prehypertension/hypertension remarkably varied when based on one versus three annual assessments, thus emphasizing the importance of repeated measurement before making a diagnosis of abnormal blood pressure. Adiposity was confirmed to be a determinant of high blood pressure.

Background and Objective: Weight loss can determine significant improvement of migraine in obese patients. Herein, we evaluated a clinical sample of adolescent migraineurs with obesity who participated in an interdisciplinary programme for weight loss, in order to identify possible metabolic parameters associated with good migraine control., Subjects and Methods: Using a cross-sectional design, we evaluated 112 out of 135 adolescents who previously underwent our intervention programme. Based on persistence of headache, subjects for comparison were 40 migraine-free and 72 not migraine-free adolescents. Participants underwent anthropometric evaluations and biochemical tests., Results: Patients with persistence of migraine had significantly higher weight (P < 0.01), body mass index (P < 0.01), waist circumference (P < 0.01), homeostasis model assessment of insulin resistance (P < 0.001), triglyceride (P < 0.05), total cholesterol (P < 0.05) and low-density lipoprotein cholesterol (P < 0.05) values when compared with those who became migraine-free. Between potential predictors, only insulin resistance (odds ratio = 3.5, 95% confidence interval = 1.4-6.1; P <  0.001) was significantly associated with persistence of migraine after intervention programme., Conclusions: Among obese adolescents with migraine who underwent an intervention programme for weight loss, patients who did not become migraine-free showed higher adiposity values than those who became migraine-free. Patients with insulin resistance had 3.5 times the odds of having persistence of migraine compared with those without., (© 2014 The Authors. Pediatric Obesity © 2014 World Obesity.)

Objective: To investigate whether there is an association of the triglyceride-to-HDL cholesterol (TG:HDL-C) ratio with cardiovascular risk factors and early signs of vascular damage in obese prepubertal children., Design and Methods: In 50 obese (27 boys, 7.8±1.4 years) and 37 normal-weight (20 boys; 7.3±1.5 years) prepubertal children, anthropometric measurements, oxidative stress markers (urinary isoprostanes (PGF2α (prostaglandin F2α)), soluble receptor for advanced glycation end-products (sRAGE)) and insulin sensitivity (homeostasis model assessment of insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI)) were evaluated. Lipids profile was assessed and the TG:HDL-C ratio was calculated. In addition, high-resolution ultrasound was performed to assess carotid intima-media thickness (cIMT)., Results: Obese children showed significantly higher values of the TG:HDL-C ratio (1.9±1.1 vs 1.2±0.6, P=0.002) compared with controls. After dividing the population in tertiles of the TG:HDL-C ratio (<1.04, 1.04-1.67, >1.67), cIMT (P=0.0003), and HOMA-IR (P=0.0001) progressively increased from the lower to the upper tertile, whereas WBISI (P=0.0003) and sRAGE (P=0.05) progressively decreased. In a regression model, the TG:HDL ratio was significantly and positively associated with cIMT (r=0.493; P=0.0005). A cutoff point for TG:HDL-C ratio of 1.12 had 81% sensitivity and 49% specificity in the identification of children with cIMT values in the upper quartile (Area under the curve values from receiver operating characteristic curves=0.633±0.065, P=0.045)., Conclusion: This study confirms the reliability of the TG:HDL-C ratio as a useful marker of cardiovascular risk. Interestingly, our results underline that the TG:HDL-C ratio is directly related with early signs of vascular damage already present in prepubertal children.

In obese adults with non alcoholic fatty liver disease (NAFLD), treatment with Vitamin E has resulted in an improvement in liver histology, whereas variable and limited results are available in children. Our aim was to assess whether lifestyle combined with supplementation with Vitamin E might reduce oxidative stress and improve cardio-metabolic status in obese children with NAFLD. 24 obese prepubertal children (16M) followed a 6-month lifestyle intervention combined with Vitamin E supplementation (600 mg/day) and they were compared with 21 age and sex-matched obese peers who underwent lifestyle intervention only. At baseline and after 6-month urinary prostaglandin F2α (PGF-2α), endogenous secretory receptor for advanced glycation end products (esRAGE), high sensitivity C-reactive protein (hs-CRP), alanine aminotransferases (ALT), lipid profile, glucose, and insulin were assessed. The two groups were comparable for age (8.3 ± 1.6 vs 8.4 ± 1.3 yr), sex and BMI SDS (2.16 ± 0.29 vs 2.13 ± 0.28). At the beginning of the study, PGF2-α, esRAGE hsCRP, ALT, lipid profile and HOMA-IR levels were similar between the two groups (all p > 0.05). After 6-month treatment, levels of PGF2-α (p < 0.001) significantly decreased and esRAGE significantly increased (p < 0.001) in children treated with Vitamin E. A significant reduction was also found in ALT (p = 0.001), lipid profile and HOMA-IR (p < 0.001). In contrast, no significant change in any of these markers was detected in the lifestyle only group. In conclusion, Vitamin E supplementation was associated with a significant reduction in oxidative stress and improved cardio-metabolic alterations. These data suggest that Vitamin E supplementation could represent a valuable treatment in obese children affected by NAFLD.

Background: Insulin resistance (IR), a link of paramount importance between obesity and cardiovascular/metabolic complications, seems to be implicated in weight changes., Objective: To determine whether IR could influence weight status during a 1-year intervention program in obese prepubertal children., Methods: Forty-four children with IR (IR group) and 42 children without IR (NIR group) were enrolled. Body mass index standard deviation score (BMI-SDS), waist circumference (WC), and homeostasis model assessment (HOMA-IR) were evaluated., Results: NIR children showed a significant reduction of BMI-SDS and WC at final assessment (p = 0.009 and p = 0.001, respectively), whereas IR children presented unchanged values. HOMA-IR decreased after intervention in the NIR group (p = 0.0008), but was exacerbated in IR children (p = 0.004). A positive and significant association between HOMA-IR at baseline and BMI at follow-up was found (B ± SE = 0.87 ± 0.24, p = 0.001). HOMA-IR at baseline was also significantly associated with WC at follow-up (B ± SE = 2.12 ± 0.69, p = 0.003)., Conclusions: IR seems to influence adiposity changes in obese prepubertal children. Further longitudinal studies are needed to verify the relationship between IR and weight loss during childhood.

Early development of increased cardiovascular risk in obese children and the possible related cardiovascular diseases into adulthood have been shown; however, the underling pathogenetic mechanisms implicated are not yet completely defined. Receptors for advanced glycation end products (RAGE) pathway play a pivotal role in the genesis of abnormality of arterial wall. However, whether obese prepubertal children present impaired levels of endogenous and soluble secretory receptor for advanced glycation end products (esRAGE/sRAGE) and whether an association exists between RAGE levels and carotid intima media thickness (cIMT) are not yet evaluated in this age group. We note that esRAGE and sRAGE were significantly lower in obese children than controls and were independently related to cIMT. Our findings lead to the hypothesis that RAGE system seems to be related to the development of atherosclerosis even in obese prepubertal children.

Objective: To assess potential alterations in soluble and endogenous secretory receptors for advanced glycation end products (sRAGE and esRAGE) in normal-weight (NW) and obese (Ob) children born small (SGA) and large (LGA) compared with appropriate for gestational age (AGA) subjects and to explore if birth weight (BW), insulin resistance (IR), and obesity represent independent risk factors., Research Design and Methods: We categorized 130 prepubertal children into six groups according to BW and obesity and evaluated sRAGE, esRAGE, and homeostasis model assessment of IR., Results: sRAGE and esRAGE were lower in Ob SGA and LGA children than Ob AGA subjects (all P < 0.05), and in NW SGA and LGA children than NW AGA subjects (all P < 0.05). Interestingly, BW and IR were significantly and independently related to RAGE., Conclusions: sRAGE and esRAGE are decreased in SGA and LGA children, and BW and IR seem to play an important role in the reduction of RAGE.

Although a relationship between obesity and hyperthyrotropinemia has been hypothesized in obese children, the underlying pathogenesis is not completely known. In the current cross-sectional study, we evaluated the thyroid function in a group of 80 obese pre-pubertal children compared to 41 healthy normal weight peers, exploring the possible association between hyperthyrotropinemia and oxidative stress. In all children, thyrotropin (TSH), free T4 (fT4), free T3 (fT3) and anti-thyroid antibodies were evaluated. Homeostatic model assessment of insulin resistance (HOMA-IR) level was evaluated as index of insulin resistance. We measured the endogenous secretory receptor for advanced glycation end products (esRAGE) and soluble RAGE (sRAGE) and the urinary prostaglandin F2α (PGF-2α) as markers of oxidative stress. We found that TSH levels were significantly higher in obese children than controls. TSH significantly correlated with body mass index-standard deviation score (BMI-SDS), HOMA-IR, PGF-2α, esRAGE and sRAGE. The multiple linear regression showed that in obese children HOMA-IR, PGF-2α, esRAGE and sRAGE were significantly related to TSH, independently of BMI-SDS, age and gender. In obese children, hyperthyrotropinemia could be detected already in pre-pubertal age. The increased oxidative stress might represent one of the key regulators of TSH levels, early in life.

Background: There is a worsening high prevalence of global obesity. Special attention has been paid to the gut-endocrine system, represented by the regulators of appetite. In particular, it has been suggested that ghrelin ("hunger" peptide), and obestatin and glucagon-like peptide-1 (GLP-1) ("satiety" peptides) could play important roles in the pathogenesis of obesity., Objectives: The aims of this study were to compare fasting plasma ghrelin, obestatin, and GLP-1 levels between obese and nonobese prepubertal children, and to assess their relations with fatness indexes and insulin resistance (IR)., Subjects and Methods: Fifty-two prepubertal obese children and 22 controls were enrolled. Fasting levels of gastrointestinal hormones (ghrelin, obestatin, and GLP-1), glucose, and insulin were evaluated. IR was assessed using the homeostasis model assessment of IR (HOMA-IR) index. Analysis was performed by Mann-Whitney U-test, Kruskal-Wallis test, and Spearman's correlation., Results: Obese prepubertal children and normal-weight controls had similar age distribution. Obese children were more insulin resistant when compared to controls (HOMA-IR: p < 0.01 ). GLP-1 levels were significantly lower in obese children than in controls (p < 0.01). Obestatin was significantly higher in obese than normal-weight children (p < 0.01), while ghrelin was not different. There was a negative correlation between GLP-1 and standard deviation score-body mass index (r = -0.36, p = 0.009) and between GLP-1 and waist circumference (r = -0.45, p = 0.001), while no association was observed with HOMA-IR., Conclusions: GLP-1 levels have been shown to be correlated with adiposity indexes, but not with HOMA-IR, suggesting that this hormone could play an important role in the early development of obesity.

Concomitantly with the increasing prevalence of childhood obesity, the prevalence of metabolic syndrome (MS) is rising among children and adolescents, leading to fears for future epidemics of type 2 diabetes mellitus and cardiovascular disease in the young. This makes the accurate identification and the appropriate treatment of children and adolescents with MS an important priority for health care systems. This review will focus on the management of each component of MS, including the nonalcoholic fatty liver disease (NAFLD), which is currently considered as the hepatic component of the syndrome. The most relevant target of treatment of MS in children and adolescents is the abdominal obesity. To this end, we will discuss the efficacy of dietary approaches, possibly coupled with regular physical activity, on eliciting visceral fat reduction. We will also highlight several aspects of the treatment of the high triglyceride/low high-density lipoprotein cholesterol phenotype, including the use of non-pharmacological measures, and indications for instituting drug therapies. Part of this review will address treatment of glucose abnormalities, including the benefits of lifestyle modification alone, and the potential adjunctive role of hypoglycemic drugs. The treatment of hypertension in children with MS also requires a multifaceted approach and the available data of this topic will be examined. The remainder of this review will address treatment to reverse NAFLD and prevent progression to end-stage disease., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Increasing attention has been focused on the implications of obesity in adults on the development of kidney disease, but data on the obese pediatric population are lacking. The aim of this study was to investigate whether changes in various renal function indexes/markers, as expressed by the glomerular filtration rate [GFR, as estimated by the Schwartz formula (eGFR)], serum cystatin C (CysC) level, albumin excretion rate (AER), and modifications in nitric oxide (NO; an important modulator of renal function and morphology), urinary isoprostanes (markers of oxidative stress), and blood pressure (BP), can be detected in obese children and adolescents when compared to normal weight controls. Blood and urinary samples were collected to evaluate markers of renal function, serum and urinary NO, and urinary isoprostanes in 107 obese Caucasian subjects and 50 controls. Ambulatory BP monitoring (ABPM) was performed in all cases. Obesity was expressed by the body mass index standard deviation score (SDS-BMI), and insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR). CysC and eGFR did not significantly differ between the two groups; AER was increased in obese children. CysC and GFR were related to HOMA-IR, and AER was related to HOMA-IR and SDS-BMI. Obese subjects had reduced NO levels and increased urinary isoprostanes and BP measurements; all three parameters were related to SDS-BMI and insulin resistance. ABPM showed an increased incidence of hypertension and non-dipping in the obese group. Based on our comparison of obese and nonobese children, we conclude that renal involvement is not an early clinically evident manifestation of adiposity in childhood, since no overt changes in eGFR and only a mild albuminuria were detected. A longer exposure to obesity is probably needed before renal function impairment appears.

In the last years, a growing body of literature indicates an association between valproic acid therapy and weight gain. Weight gain during valproate treatment can be observed within the first 3 months of therapy and women seem to be more susceptible than men. The mechanism through which valproic acid may induce a weight gain is still controversial. The scope of this paper is to investigate the possible causal link between treatment and weight gain in epileptic patients. Systematic review of published epidemiological studies has been done in order to evaluate the real extent of this side effect of valproic acid and its clinical implications, such as an increased risk of insulin resistance and other secondary metabolic abnormalities. The knowledge of the potential of valproic acid to cause significant changes in body weight will help in appropriate selection and modification of antiepileptic therapy to minimize the risk for weight abnormalities. Measurements of body weight before initiation of valproic acid therapy should be done as part of the monitoring of patients with epilepsy to detect changes before there are serious adverse consequences; an increase of 2 kg of body weight after 1 month of treatment should imply considerations to change antiepileptic drug therapy., (© 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.)

The endogenous secretory receptor for advanced glycation end products (esRAGE) and soluble RAGE (sRAGE) have been shown in human plasma and have emerged as reliable biomarkers of several pathological conditions, including insulin resistance and liver injury. We examined esRAGE and sRAGE levels in obese prepubertal children with and without liver steatosis. esRAGE and sRAGE levels were significantly lower in obese prepubertal children affected by liver steatosis and were independently related to liver steatosis. These findings suggest that AGE-RAGE pathway plays an independent role in the development of liver injury already present in this age group.

The incidence of type 1 diabetes (T1D) is increasing worldwide and is associated with a significant burden, mainly related to the development of vascular complications. Over the last decades, concomitant with the epidemic of childhood obesity, there has been an increasing number of cases of type 2 diabetes (T2D) among children and adolescents. Microvascular complications of diabetes, which include nephropathy, retinopathy and neuropathy, are characterized by damage to the microvasculature of the kidney, retina and neurons. Although clinically evident microvascular complications are rarely seen among children and adolescents with diabetes, there is clear evidence that their pathogenesis and early signs develop during childhood and accelerate during puberty. Diabetic vascular complications are often asymptomatic during their early stages, and once symptoms develop, there is little to be done to cure them. Therefore, screening needs to be started early during adolescence and, in the case of T2D, already at diagnosis. Identification of risk factors and subclinical signs of complications is essential for the early implementation of preventive and therapeutic strategies, which could change the course of vascular complications and improve the prognosis of children, adolescents and young adults with diabetes.

Objective: Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points., Participants: The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants., Evidence: An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children., Consensus Process: The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement., Conclusions: Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases.

Although asthma and obesity are among the major chronic disorders their reciprocal or independent influences on lung function testing, airways hyperresponsiveness (AHR) and bronchial inflammation has not been completely elucidated. In 118 pre-pubertal Caucasian children anthropometric measurements functional respiratory parameters (flow/volume curves at baseline and after 6-minute walk test [6MWT]) together with bronchial inflammatory index (FeNO) were assessed. The study population was divided into four groups according to BMI and the presence or absence of asthma: Obese asthmatic (ObA) Normal-weight asthmatic (NwA), Obese non-asthmatic (Ob), non-asthmatic normal-weight children (Nw). Baseline PEF and MEF(75) (%-expected) were significantly different across the four groups with significantly lower values of MEF(75) in ObA and Ob children when compared to Nw children (P = 0.004 and P = .0001, respectively) and this independent role of obesity on upper respiratory flows was confirmed by multiple analysis of covariance. After 6 MWT respiratory parameters decreased only in ObA and NwA children and 12 children presented a positive fall in FEV(1), in contrast no changes of respiratory function testing were detected in Ob and Nw children, and only 2 Ob children presented a significant fall in FEV(1). FeNO analysis demonstrated significantly higher values in ObA and NwA children when compared to Ob (P = 0.008 and P = 0.0002, respectively) and Nw children (P = 0.0001 and P = 0.0003, respectively), although a significant difference was found between Ob and Nw children (P = 0.0004). Multiple analysis of covariance confirmed an independent role of asthma on this parameter. In conclusion while AHR and airway inflammation are clearly associated with an asthmatic status, obesity seems to induce reduction of upper airways flows associated with a certain degree of pro-inflammatory changes.

This study was undertaken in 2 parts to investigate the relationship between body size and insulin resistance during treatment with valproic acid in children. The cross-sectional part revealed differences in terms of body size and homeostasis model assessment of insulin resistance, which were higher in the group on medication. The longitudinal part showed a major increase in body size and insulin resistance during the first year of therapy. There was a subsequent decrease in insulin resistance in association with the rise of body size, however with a trend to level off. These results might be helpful to enhance the knowledge of valproic acid action on both insulin resistance and weight gain, allowing to plan appropriate approach for the prevention of the consequences of the treatment with valproic acid.

Insulin resistance is a key component of the metabolic syndrome (MS) and is strongly associated with liver steatosis. Our aim was to evaluate whether MS should be diagnosed already in obese prepubertal children and whether its prevalence is influenced by the inclusion of hepatic steatosis as a diagnostic criterion. Eighty-nine obese children (43 boys; age median [range], 8.5 [6-10] years) were enrolled. Metabolic syndrome was diagnosed according to a classic definition: presence of 3 or more of the following criteria-body mass index greater than 2 standard deviation score, triglycerides greater than the 95th percentile, high-density lipoprotein cholesterol less than the fifth percentile, blood pressure greater than the 95th percentile, and impaired glucose tolerance. Afterward, liver steatosis was included as an additional criterion to this definition. Metabolic syndrome was diagnosed in 12 children (13.5%) according to the first definition and in 18 children (20.2%) when liver steatosis was included. The prevalence of MS increased across homeostasis model assessment of insulin resistance tertiles (P for trend = .01). The prevalence of the single components of the MS was as follows: obesity, 100%; hypertriglyceridemia, 27%; low high-density lipoprotein cholesterol, 2.2%; hypertension, 34.8%; impaired glucose tolerance, 4.5%; and nonalcoholic fatty liver disease, 21.3%. In conclusion, MS is common already among prepubertal obese children, particularly when liver steatosis is included among the diagnostic criteria. Therefore, screening for the MS should be performed in this age group; and hepatic steatosis should be considered as an additional diagnostic criterion.

A significant increase in the prevalence of end-stage renal disease (ESRD) has been reported over the last three decades, paralleling the increasing prevalence of obesity and insulin resistance, also in the pediatric population. Overweight, obesity and the metabolic syndrome, which frequently coexist, contribute substantially to cardiovascular disease and ESRD. A higher body mass index, the presence of type 2 diabetes, hypertension and, of particular importance, reduced insulin sensitivity (IS), have recently emerged as strong independent risk factors for chronic kidney disease and ESRD. Of particular concern, the long-term cardiovascular impact of obesity, although deferred to adult life, has its origins in childhood. Clustering of cardiovascular risk factors is seen in children and adolescents with the highest degree of reduced IS, suggesting that adult consequences of obesity on target organs, including the kidney, are more likely to develop in these young people. This review will discuss the association between obesity and the risk of kidney disease, focusing on the way in which obesity and its metabolic complications may lead to renal involvement and injury, with particular regard to childhood. It is beyond the scope of this article to examine kidney disease as a component of syndromes that result in obesity in childhood., (Copyright 2010 S. Karger AG, Basel.)

Background: Ghrelin, a peptide mainly derived from the stomach, plays a pivotal role in the regulation of food intake, energy metabolism, and storage, as well as in insulin sensitivity. Ghrelin circulates in acylated (A-Ghr) and nonacylated (NA-Ghr) forms, and their potential differential associations with insulin resistance (IR) in childhood obesity remain undefined., Objective: We investigated the associations of ghrelin forms with IR in normal weight and obese children and the impact of metabolic syndrome (MS) on their plasma values., Design: A total of 210 children in four subgroups of normal weight/obese children with and without components of MS were studied. Fasting blood glucose, insulin, lipid profile, and acylated and total ghrelin were examined. IR was determined by a homeostasis model assessment (HOMA) of IR., Results: In the entire population, plasma insulin and HOMA-IR were associated negatively with T-Ghr and NA-Ghr, but positively with the ratio of A/NA-Ghr after adjustment for age, gender, and Tanner stage. Obese metabolically abnormal children had lower T-Ghr and NA-Ghr, but comparable A-Ghr and a higher A/NA-Ghr ratio than obese metabolically normal subjects. Compared with lean healthy children, lean metabolically abnormal subjects had higher A-Ghr and the A/NA-Ghr ratio, but comparable T-Ghr and NA-Ghr. A multiple regression analysis showed that A-Ghr and the A/NA-Ghr ratios were positively associated with HOMA-IR, independent of age, gender, Tanner stage, and body mass index (or waist circumference) and other components of MS., Conclusions: A-Ghr excess may negatively modulate insulin action in obese and nonobese children, and may contribute to the association of IR and MS.

Valproic acid (VPA) is effective for the treatment of many types of epilepsy, but its use can be associated with an increase in body weight. We report a case of nonalcoholic fatty liver disease (NAFLD) arising in a child who developed obesity during VPA treatment. Laboratory data revealed hyperinsulinemia with insulin resistance. After the withdrawal of VPA therapy, our patient showed a significant weight loss, a decrease of body mass index, and normalization of metabolic and endocrine parameters; moreover, ultrasound measurements showed a complete normalization. The present case suggests that obesity, hyperinsulinemia, insulin resistance, and long-term treatment with VPA may be all associated with the development of NAFLD; this side effect is reversible after VPA withdrawal.

Objective: To determine the prevalence of metabolic syndrome (MS) in a primary care pediatric setting and to collect clinical and biochemical data, allowing for a prediction of its presence in a supposedly healthy population., Methods: Belonging to a pediatric population followed by pediatricians of the Italian National Health Service, 415 subjects with obesity as a unique selection criterion were enrolled. The entire cohort was screened for MS, which was defined as the presence of at least 2 other findings out of obesity: fasting hyperglycemia, low levels of high-density lipoproteins cholesterol, hypertriglyceridemia, and hypertension., Results: The overall prevalence of MS was 30.8%. Major findings (out of obesity) were low high-density lipoproteins cholesterol levels (46.2%), hypertension (23.6%), hypertriglyceridemia (22.2%), and fasting hyperglycemia (16.6%). Waist-to-height ratio was the only clinical parameter directly related to MS, with the same predictive power of insulin resistance., Conclusions: Metabolic syndrome can be present in a significant percentage of "healthy" obese children, and a simple clinical parameter could identify at-risk subjects. This observation justifies the development and implementation of pediatric networks for obesity screening programs.

Objective: Our aim was to evaluate the effect of BW and obesity on oxidative stress and IR in prepubertal SGA and LGA children compared with appropriate-for-gestational-age (AGA) children., Methods: We performed a cross-sectional study comparing oxidative stress and IR in 103 children categorized into 6 groups according to BW (26 SGA, 15 AGA, and 16 LGA normal-weight children) and obesity (15 SGA, 15 AGA, and 16 LGA obese children). Indexes of IR (HOMA-IR, G/I) and the marker of oxidative stress (urinary isoprostanes) were evaluated., Results: Homeostasis Model Assessment was higher in both normal-weight SGA and LGA children than in normal-weight AGA children (all P

Design: In order to characterize whether different degrees of adipose tissue storage may be associated with markers of early atherosclerosis, we evaluated oxidant-antioxidant status and inflammatory markers and determined carotid intima-media thickness (cIMT) in healthy constitutional lean and obese pre-pubertal children., Methods: Eighty healthy pre-pubertal lean and obese children were recruited and compared with 40 age, gender, and pubertal stage-matched normal controls. Anthropometric measurements, oxidant (urinary isoprostanes (PGF-2alpha), lag phase, and malondialdehyde (MDA)) and antioxidant status (vitamin E), inflammatory markers (high sensitive C-reactive protein (hs-CRP)), and insulin sensitivity (fasting glucose-insulin ratio, homeostasis model assessment of insulin resistance (HOMA-IR)) were investigated. Furthermore, cIMT was measured by high-resolution ultrasound., Results: hs-CRP was not different between lean and control subjects (P=0.45), while higher values were found in obese compared with lean and control children (P<0.001 and P<0.001 respectively). PGF-2alpha and MDA were higher while lag phase shorter in lean and obese subjects compared with controls (lean P<0.001; P<0.001; P<0.001 and obese P<0.001; P<0.001; P<0.001 respectively), while no differences were documented between lean and obese subjects (P=0.78, P=0.019, and P=0.53 respectively). Compared with controls, cIMT was increased in lean and in obese subjects (P=0.001; P=0.004), while no differences were documented between obese and lean subjects (P=0.1). In a multiple stepwise linear regression analysis, cIMT was related with PGF-2alpha (beta=0.641, P<0.001) and HOMA-IR (beta=0.307; P<0.001)., Conclusions: Pre-pubertal lean and obese children present increased oxidative stress and impaired inflammation and insulin sensitivity, which in turn seem to result in similar impaired endothelial dysfunction and early signs of atherosclerosis, already in childhood.

Background: Valproic acid (VPA), a widely used antiepileptic drug, has broad-spectrum activity against both generalized and partial epilepsy. Among the side effects of VPA, weight gain is frequently reported, although the real incidence and magnitude of this problem is unknown. Its pathogenesis is most likely multifactorial, and is controversial., Methods: In order to evaluate the role of hyperinsulinemia and related hormonal abnormalities in VPA-induced obesity, data from the existing literature have been analyzed and discussed critically., Results: Patients suffering from weight gain show various metabolic and endocrinologic abnormalities. The most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance, and an increase in the availability of long-chain free fatty acids. Significant weight gain is associated with increased levels of insulin and leptin, suggesting a close relationship between obesity-induced hyperinsulinemia and hyperleptinemia. VPA can directly stimulate pancreatic beta-cells and indirectly enhance insulin resistance by suppressing insulin-mediated peripheral glucose uptake. Leptin activation seems to be similar in obese VPA-treated subjects to that seen in otherwise obese subjects., Conclusions: The mechanisms of hyperinsulinemia in VPA-induced weight gain remain unclear, although it is likely that obesity is the cause of hyperinsulinemia and all related metabolic changes. However, this heterogeneous metabolic disorder requires further research., (Copyright 2009 S. Karger AG, Basel.)

Childhood obesity is a significant health problem that has reached epidemic proportions around the world and is associated with several metabolic and cardiovascular complications. Insulin resistance is a common feature of childhood obesity and is considered to be an important link between adiposity and the associated risk of type 2 diabetes and cardiovascular disease. Insulin resistance is also a key component of the metabolic syndrome, and its prevalence in the paediatric population is increasing, particularly among obese children and adolescents. Several factors are implicated in the pathogenesis of obesity-related insulin resistance, such as increased free fatty acids and many hormones and cytokines released by adipose tissue. Valid and reliable methods are essential to assess the presence and the extent of insulin resistance, the associated risk factors and the effect of pharmacological and lifestyle interventions. The two most common tests to assess insulin resistance are the hyperinsulinemic euglycemic clamp and the frequently sampled i.v. glucose tolerance test utilizing the minimal model. However, both these tests are not easily accomplished, are time consuming, expensive and invasive. Simpler methods to assess insulin resistance based on surrogate markers derived from an oral glucose tolerance test or from fasting insulin and glucose levels have been validated in children and adolescents and widely used. Given the strong association between obesity, insulin resistance and the development of metabolic syndrome and cardiovascular disease, prevention and treatment of childhood obesity appear to be essential to prevent the development of insulin resistance and the associated complications.

Aim: To assess the telomere length in apparently healthy obese and normal-weight subjects., Methods: Seventy-six Caucasian subjects were chosen including 53 children (age 8.2+/-3.5 years) and 23 adults (age 40.5+/-8.4 years). Among these, 22 (12 children and 10 adults) were obese with a body mass index (BMI, kg/m2)>2 SD above the norm. Bioelectrical impedance analysis (BIA), measured with a multiple frequency analyzer, was used to estimate body composition. DNA extraction from white blood cells was used to estimate the telomere length by detection of terminal restriction fragments (TRF)., Results: No difference was found between the TRF lengths of obese and normal children. Obese adults had shorter TRF lengths than adults who were not obese (mean TRF length difference, -884.5; 95% confidence intervals -1727 to -41.8; t=2.183; df=17; p<0.041)., Conclusions: Obese adults have shorter telomeres than their normal-weight counterparts, while this phenomenon is not present in childhood.

Obesity in children appears to be associated with increased risk of cardiovascular and metabolic diseases later in life. Early development of insulin resistance and impaired oxidant-antioxidant status may lead to endothelial dysfunction and increased carotid intima media thickness (IMT) even in childhood. The aim of this study was to measure IMT and the relationship between IMT, insulin resistance and oxidant status in obese pre-pubertal children. In 53 obese pre-pubertal children (27M/26F, mean age 8+/-2 years), anthropometric measurements and inflammatory markers (hs-CRP and PGF-2 alpha), were evaluated compared with 41 healthy pre-pubertal subjects (21M/20F, mean age 7+/-2 years). OGTT was performed and insulin resistance (IR) indices (HOMA-IR, WBISI, G/I and QUICKI) were calculated in all patients. High-resolution ultrasound techniques were used to evaluate IMT. Obese children had higher levels of PGF-2 alpha and hs-CRP compared to healthy subjects (p=0.001 and p=0.005). Furthermore, fasting insulin levels and HOMA-IR were higher in obese children than in controls (p=0.001 and p=0.001) while WBISI was significantly lower (p=0.002). In addition, obeses had an increased IMT (p=0.001). In obese children there was a significant correlation between IMT and indices of IR (HOMA-IR: beta=-1.233, p=0.002; WBISI: beta=-0.921, p=0.008; G/I: beta=-0.811, p=0.003) and between IMT and PGF-2 alpha (beta=0.505, p=0.004). After categorizing subjects according to tertiles of body mass index (BMI) (or=26.23 kg/m(2)) and to waist circumference (WC) (or=79.04 cm), no influence of BMI or WC on IMT were found in the three groups. In conclusion, early changes in glucose metabolism and an alteration of oxidant-antioxidant status may be present in obese pre-pubertal children; this could lead to increase IMT and early cardiovascular disease.

Objective: To determine whether in obese prepubertal children insulin resistance (IR) is associated with the development of liver steatosis., Methods and Procedures: Cross-sectional study evaluating the prevalence of liver steatosis in 100 severely obese prepubertal children and comparing IR indexes between children with (group 1) and without steatosis (group 2). Furthermore, IR indexes were compared to values of 50 normal weight children. Fasting blood samples were collected for the evaluation of liver function tests, lipid profile, plasma glucose, and insulin levels. All children underwent an oral glucose tolerance test and anthropometric measurements. Hepatic ultrasound was performed according to international criteria and by one single operator. Analysis was performed by Mann-Whitney U-test, Pearson correlation, and logistic regression., Results: Liver steatosis was found in 52% obese children and was equally distributed between the two sexes. Obese children were more insulin resistant when compared to controls (homeostasis model assessment of IR (HOMA-IR): P = 0.0001; whole body insulin sensitivity index (WBISI): P = 0.0005; fasting glucose/fasting insulin ratio (G/I): P = 0.0001), and group 1 presented an even higher degree of IR when compared to group 2 (HOMA-IR P = 0.0001; WBISI P = 0.0004; G/I P = 0.0001). The area under the curve (AUC) for insulin was significantly higher in group 1 when compared to group 2, while no difference was found in the AUC for glucose. There was no association between IR and adiposity indexes (P >0.05). The role of IR as a predictor for the development of steatosis was analyzed by multiple logistic regression, which documented that IR indexes were significantly related to steatosis independently of BMI-SDS., Discussion: Liver steatosis is an emerging problem in prepubertal severely obese children, and it appears to be an association between liver steatosis and IR in these subjects.

Objectives: To investigate the relationship between ambulatory blood pressure (ABPM) parameters and insulin resistance in obese children., Methods: A population of 56 obese prepubertal children was recruited for the study. They underwent ABPM, an oral glucose tolerance test and complete physical examination, including adiposity indexes such as body mass index (BMI), skinfolds, waist-to-hip ratio (WHR) and fat mass., Results: The standard deviation score for BMI was significantly correlated with 24-h systolic blood pressure (SBP) (r = 0.30; P = 0.02) and diastolic blood pressure (DBP) (r = 0.29; P = 0.03), daytime SBP and DBP (r = 0.28; P = 0.04 and r = 0.32; P = 0.02), night-time SBP and DBP (r = 0.32; P = 0.01 and r = 0.27; P = 0.04). Fat mass was correlated with 24-h SBP (r = 0.46; P = 0.005), daytime SBP (r = 0.40; P = 0.01) and night-time SBP (r = 0.49; P = 0.03). No correlations were found between ABPM parameters and WHR. Furthermore, significant correlations were found between insulin resistance indexes, such as the homeostasis model assessment of insulin resistance and quantitative insulin-sensitivity check index, and 24-h DBP (r = 0.34; P = 0.01 and r = -0.29; P = 0.03), daytime DBP (r = 0.35; P = 0.009 and r = -0.34; P = 0.01) and daytime SBP (r = 0.32; P = 0.02 and r = -0.27; P = 0.04). Only 24-h and daytime DBP remained correlated with insulin resistance after adjustment for obesity. The analysis of the circadian rhythm of blood pressure revealed that 24 out the 56 children were non-dippers., Conclusions: The results of the present study indicate that adiposity and insulin resistance have an important role in influencing blood pressure in obese children, and also show a high prevalence of non-dipping phenomenon. This is of particular relevance because blood pressure tracks from childhood into adulthood and an already early-life high blood pressure is associated with an increased cardiovascular risk.

The authors studied 40 epileptic patients treated with valproate and 40 healthy controls for at least 2 years. At the end of follow-up, 15 epileptic patients (37.5%) had development of obesity. They showed circulating leptin and insulin levels significantly higher and ghrelin and adiponectin levels significantly lower than those of patients who did not gain weight.

Oxidant-antioxidant status was investigated in a group of severely obese prepubertal children in comparison with healthy subjects and in relation to a dietary restriction-weight loss program. All subjects underwent anthropometric measurements and determination of lipid profile, lag phase, malondialdehyde (MDA), and vitamin E. Compared with controls, obese children had a significantly higher body mass index (BMI) (28.97 +/- 2.42 vs. 16.03 +/- 1.88 kg/m2; P = 0.0002) and waist-to-hip ratio (WHR) (0.89 +/- 0.03 vs. 0.80 +/- 0.01; P = 0.0004); lag phase and vitamin E levels were significantly decreased [24.05 +/- 16.21 vs. 43.16 +/- 10 min (P = 0.004) and 21.12 +/- 14.96 vs. 35.54 +/- 13.62 micromol/liter (P = 0.02), respectively], whereas MDA was significantly increased (0.90 +/- 0.31 vs. 0.45 +/- 0.24 nmol/mg; P = 0.001). Both lag phase and MDA significantly correlated with BMI [respectively, r = -0.34 (P = 0.004) and r = 0.57 (P = 0.002)] and WHR [respectively, r = -0.63 (P = 0.0001) and r = 0.38 (P = 0.04)]. Oxidant status normalized after 6 months of dietary restriction [lag phase, 59.11 +/- 14.74 min (P = 0.002); MDA, 0.47 +/- 0.09 nmol/mg (P = 0.003)], which was associated with a reduction of BMI (27.34 +/- 1.87 kg/m2; P = 0.003), WHR (0.87 +/- 0.02; P = 0.001), and fat mass (34.49 +/- 2.68%; P = 0.008), but returned to baseline levels together with fatness indexes after another 6 months of free diet. Altered oxidant-antioxidant status is already present in prepubertal severely obese children and is reversible with a dietary restriction-weight loss program, which should be highly encouraged and maintained over time in this age group.

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.

Obesity is constantly increasing among children. Since treatment for obesity on outpatient bases often fails, we evaluated whether camps may help to improve eating habits. Forty-one children, 21 males and 20 females (BMI > 97 degrees percentile, weight excess > 30%, Tanner stage I) agreed to participate to a 8 day camp. After 1-year follow-up, measurements carried out by plicometry, bioelectrical impedance, metabolic and hormonal evaluations, showed a significant reduction of skinfolds, as well as glycemic and insulinemic response to the oral glucose tolerance test. These results suggest that camps may help to improve nutritional and physical education and psychological outcome of obese children.

To investigate whether epileptic patients who become obese after valproic acid (VPA) therapy can have a high risk of atherosclerosis related to the oxidation of low-density lipoprotein, we prospectively studied the plasma concentrations of lipid-soluble antioxidant vitamins in a group of 20 epileptic girls and 20 controls. After 1 year of VPA treatment, epileptic patients who gained weight had decreased plasma concentrations of alpha-tocopherol and alpha- and beta-carotene, the main lipid-soluble antioxidants. Moreover, 5 patients who gained weight were reevaluated 6 months after withdrawal from VPA therapy and showed normal body mass indices and normalized plasma levels of antioxidants. In conclusion, the data suggest that epileptic patients who gain weight after VPA therapy have reduced plasma concentrations of antioxidant vitamins and that these reductions are reversible after VPA withdrawal., (Copyright 2004 S. Karger AG, Basel)

To evaluate the changes of serum leptin levels after weight reduction in diabetic subjects with and without microalbuminuria, we studied 10 obese healthy subjects, 12 obese diabetics with persistent microalbuminuria and 10 obese diabetic subjects without microalbuminuria. Obese diabetic patients with microalbuminuria showed serum leptin levels significantly higher than normoalbuminuric diabetics, while no difference was found between obese diabetics without microalbuminuria and healthy controls. All obese subjects followed a 12-month intensive weight reduction program during which the mean change in body mass index was similar between obese diabetic and obese healthy subjects (obese diabetics without microalbuminuria: 35.2+/-4.3 vs 29.9+/-4.1, p<0.05; obese diabetics with microalbuminuria: 35.7+/-3.9 vs 30.3+/-4.0, p<0.05; obese healthy subjects: 35.5+/-4.0 vs 30.1+/-3.9, p<0.05). The mean changes in serum leptin levels tended to be similar in two groups of subjects studied (obese diabetics without microalbuminuria: 37.6+/-4.1 vs 19.7+/-4.9, p<0.001; obese healthy subjects: 37.1+/-4.3 vs 20.1+/-5.1, p<0.001); obese microalbuminuric subjects showed higher leptin levels (42.4+/-4.0 vs 30.3+/-4.2, p<0.001) than normoalbuminuric diabetic and obese healthy subjects. In conclusion, during weight loss, independently from the quality of metabolic control, serum leptin concentrations declined in both groups of obese diabetics. The changes of leptin in diabetics seem to be similar to those observed in healthy obese subjects.

Leptin, the product of the ob gene, is an adipocyte-derived hormone that positively correlates with body fat percantage and body mass index (BMI). There are many data which demonstrate a significant relationship between leptin and insulin, but the mechanism underlying the changes of leptin induced by insulin and vice versa remains to be studied in more detail. In this review, we analysed the data on the behaviour of serum leptin levels in non-obese and obese children with type 1 diabetes mellitus. It has been shown that the diminished serum leptin concentrations in patients with newly discovered insulin-dependent diabetes mellitus (IDDM) could be caused by insulin deficiency and/or increased lipolysis. Moreover, while in some studies in diabetic children with good metabolic control the serum leptin levels are similar to those of healthy children, in other studies children with IDDM have leptin levels higher than non diabetic children; it is possible that in some diabetic children intensified insulin therapy could cause chronic hyperinsulinemia with high leptin levels. The mean serum leptin concentrations in the obese diabetic subjects were significantly higher when compared with non-obese diabetics. Obese diabetic patients showed no significant differences in leptin concentrations in comparison to the non diabetic obese group matched by age, sex and BMI. In obese diabetics, during weight loss, independent of the quality of metabolic control, serum leptin concentration declines. The changes of leptin in diabetes seem to be similar to those observed in healthy obese subjects.

Objective: To evaluate serum leptin levels in children and young adults with type 1 (insulin-dependent) diabetes mellitus and to investigate whether they are different in prepuberty, puberty and young adulthood., Design: Three groups of diabetics (prepubertal, pubertal and young adults) subdivided into obese and non-obese were studied. Three groups of healthy subjects matched for sex, age and body mass index served as controls., Results: Diabetic patients had serum leptin concentrations similar to those of controls in all three groups. A small non-significant increase in leptin from the prepubertal to the young adult age group for both diabetics and controls was found. A significant association of serum leptin level with body mass index (P < 0.001), female sex (P < 0.001) and age (P < 0.01) in both the diabetic and control group was present. Insulin-dependent diabetes was not associated with higher leptin concentration., Conclusions: Serum leptin concentrations are similar in diabetic patients and healthy controls. The association between obesity and leptin concentration was similar in the diabetic and non-diabetic subjects. Type 1 diabetes mellitus does not modify serum leptin concentration.

Objective: To determine the relationship between insulin and the metabolic profile and eventual weight loss in obese children., Design: We first attempted to define the metabolic profile for 18 obese children; we then studied weight loss in this group longitudinally., Setting: Department of Pediatrics in a university hospital., Participants: Eighteen randomly selected, young, obese male subjects from 5 to 16 years of age., Interventions: (1) Metabolic screening at the outset, including insulinemia and glycemia after the oral glucose tolerance test and plasma levels of total cholesterol, high-density lipoprotein cholesterol, and triglycerides, and (2) weight loss treatment., Results: We divided the sample into "normoinsulinemic" and "hyperinsulinemic" groups, similar for all the variables tested except for weight loss and plasma triglyceride levels. A direct relationship between weight loss results and duration of treatment was found for the entire group. The "hyperinsulinemic" group had a lower percentage reduction in excess weight, and the results in this group were not dependent on the duration of treatment., Conclusions: The effort to keep "normoinsulinemic" obese children in treatment may be useful; it is advisable to study "hyperinsulinemic" children more in depth.

Notwithstanding the high prevalence and morbidity, current knowledge of obesity is rather rudimentary. Nevertheless recent findings have enabled us to surmount anachronistic nosographic generalizations whereby excess weight was attributed only to inappropriate and excessive food intake and the lack of physical exercise. Various studies indicate that there are complex interactions in determining weight excess: genetic, psychosocial, cultural but also biochemical factors are incriminated and it is now recognised that the aetiology of obesity is multifactorial and that, consequently, there are different types of obesity. However, in most studies concerning the therapeutic approach, it is noted that the same type of treatment is applied to groups of subjects that are probably highly heterogeneous for type of obesity. No easy or final solution to the problem is proposed as for the moment no ideal treatment exists. What is suggested is the need to attempt to identify possible factors linked to weight excess before commencing the therapeutic approach. For each single case, this could permit the use of the most appropriate treatment and make therapeutic results less frustrating.