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Insulin resistance is a condition of gluco-metabolic sufferance that may hesitate in the further development of type 2 diabetes and cardiovascular disease. The development of insulin resistance is mostly associated with the accumulation of excessive fat in the body. The epidemic impact of obesity in the youngest promoted an increase of the prevalence of insulin resistance also in children and adolescents. Increased fat accumulation in the peri-visceral area of the abdomen, occurring preferably at and after puberty, and in the liver, as non-alcoholic fatty liver disease, plays a role in the process. After puberty, males are at higher risk than females to develop insulin resistance. Also ethnicity contributes to sensitivity of children to develop insulin resistance, where Hispanics, South-Asians, and Indians are at higher risk than Whites and Blacks.In spite of the research progress in the field, several questions on the relationship between body composition and insulin resistance are still unanswered. Multiomics approach, combined with nutrition as well as imaging techniques might contribute to unravel the role of body composition on insulin resistance.

Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in children, paralleling the increasing prevalence of obesity worldwide. The pathogenesis of paediatric NAFLD is not fully understood, but it is known that obesity, nutrition, lifestyle variables, genetic and epigenetic factors may be causally involved in the development of this common metabolic liver disease. In particular, obesity and nutrition are among the strongest risk factors for paediatric NAFLD, which may exert their adverse hepatic effects already before birth. Excess energy intake induces hypertrophy and hyperplasia of adipose tissue with subsequent development of systemic insulin resistance, which is another important risk factor for NAFLD. Diet composition and in particular simple carbohydrate intake (especially high fructose intake) may promote the development of NAFLD, whereas non-digestible carbohydrates (dietary fiber), by affecting gut microbiota, may favour the integrity of gut wall and reduce inflammation, opposing this process. Saturated fat intake may also promote NAFLD development, whereas unsaturated fat intake has some beneficial effects. Protein intake does not seem to affect the development of NAFLD, but further investigation is needed. In conclusion, lifestyle modifications to induce weight loss, through diet and physical activity, remain the mainstay of treatment for paediatric NAFLD. The use of dietary supplements, such as omega-3 fatty acids and probiotics, needs further study before recommendation.

The dramatic increase in overweight and obesity among children and adolescents has become a major public health problem. Obesity in children and young adults is associated with an increased prevalence of cardiometabolic risk factors. Obesity during adolescence represents a strong predictor of obesity and higher mortality in adulthood. Due to the serious implications of obesity in adolescents, effective treatments are urgently needed. Lifestyle interventions represent the recommended therapy. Nevertheless, real world data show that the majority of adolescents do not achieve weight loss in the long term, and are reluctant to participate in lifestyle interventions. Pharmacological treatment is recommended if a formal lifestyle modification program fails to limit weight gain or to improve comorbidities. However, until 2020 the European Medicines Agency (EMA) had not approved any pharmacotherapeutic agents for obesity in pediatric patients. On April 2021, EMA has authorized the use of Liraglutide, a glucagon-like peptide (GLP)-1 analog, for the treatment of obesity in adolescents (12–17 years). The efficacy and safety of Liraglutide were demonstrated in a randomized, double-blind trial, enrolling 251 adolescents. After 56 weeks, a reduction in BMI of at least 5% was observed in 43.3% of participants in the liraglutide group vs. 18.7% in the placebo group, and a reduction in BMI of at least 10% was observed in 26.1 and 8.1%, respectively. Gastrointestinal events were the events most frequently reported with liraglutide. Bariatric surgery represents another effective treatment for adolescents with severe obesity, with sustained benefits on weight loss and cardiometabolic risk factors. However, long-term safety and effectiveness data in adolescents are still scarce. Risks of bariatric surgery include the need for additional abdominal surgical procedures and specific micronutrient deficiencies. Hopefully, new pharmacological treatments in addition to lifestyle interventions will offer more chances of success.

Nonspecific low back pain (LBP) is one of the most common causes of disability, affecting all individuals at least once in their lifetime. Such a condition is also becoming increasingly frequent in the pediatric population, especially in children and adolescents with overweight/obesity. Furthermore, new-onset LBP during adolescence has been demonstrated to be a strong predictor of developing LBP later in life, contributing to poorer outcomes and increasing social and medical costs. Several causes and different mechanisms have been considered for the development of LBP in pediatric individuals affected by obesity. For this reason, planning adequate prevention and treatment strategies, mainly through conservative lifestyle changes, would be crucial to anticipate the negative consequences of persisting LBP in adulthood. The aim of this narrative review was to characterize the relationship between LBP and overweight/obesity in the pediatric population, highlighting epidemiological and pathophysiological aspects. In addition, prevention and treatment approaches will be reviewed considering the need to reduce the burden of LBP on this population. According to our search, LBP was more frequent in children and adolescents with overweight and obesity and has been associated with several anthropometric and lifestyle factors, including lumbar hyperlordosis, sedentary habits, physical inactivity, carrying a heavy schoolbag, low vitamin D levels, psychosocial ill-being, and premature intervertebral disc degeneration. Most of these conditions may be addressed with conservative strategies mainly consisting of dietary adjustments, physical exercise, education programs, and physical therapy.

Mice deficient in the lipid sensor GPR120 develop obesity, glucose intolerance and fatty liver when fed a high-fat diet, and a loss-of-function variant in the GPR120 gene strongly contributes to increased obesity in human. A signal for obesity The G-protein-coupled receptor GPR120 is a receptor for free fatty acids, and is involved in homeostasis mechanisms such as fat-cell generation and the regulation of appetite. Here it is shown that without GPR120, mice on a high-fat diet develop obesity, glucose intolerance and fatty liver. In humans, GPR120 expression in adipose tissue is shown to be significantly elevated in obesity. The authors also identify a mutation that inhibits GPR120 signalling activity and is associated with an increased risk for obesity in Europeans. Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes 1 , 2 , 3 , 4 . Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference 5 , 6 , 14 , 15 , 16 . Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Maternal and placental conditions that are unfavourable for the embryo/foetus have long-lasting effects on different tissues and functions of the body, which may persist for life and, potentially, also be transmitted to the offspring. This review resumes current evidence on principle maternal and gestational conditions associated with unfavourable metabolic programming of the offspring, along with their mechanisms of action, either supposed or already proved.

Background the growing prevalence of paediatric obesity represents a problem of considerable urgency, with potential repercussions on the health of the individual in both the short and long term. The aim of this study was to identify risk factors associated with the development of obesity and overweight in children at age six years. Methods this longitudinal observational study included 8,621 out of 15,903 children born in Trentino region between 1st January 2010 and 31st December 2012 and still alive and resident in the same region at the age of 6, with a coverage of 54.2%. Data from the Italian Birth Attendance Certificate database and the Health Surveillance Forms filled out by paediatricians during the 12-month and 6-year check-ups were collected. Two multivariable models on the estimation of Prevalence Ratios (PRs) were conducted to identify independent predictors of the probability of presenting obesity or overweight at 6 years of life, separately. Results Using the threshold values of the International Obesity Task Force as a reference, the prevalence of overweight and obesity at 6 years of age was 15.7% and 6.7%, respectively. Among prenatal factors, pre-pregnancy maternal body mass index (BMI) and the presence of gestational diabetes were found to positively influence the risk of obesity at 6 years. Regarding postnatal factors, birth weight, being the firstborn, male gender, as well as a BMI exceeding 2 standard deviations at 12th month of life were identified as risk factors for obesity. South American ethnicity, low maternal education, smoking during pregnancy and a smoking habit by at least one parent were also identified as risk factors for obesity. Similar results were obtained for the risk of overweight. Conclusions the record linkage of routine paediatric healthcare data has made it possible to identify the updated prevalence of obesity and overweight in 6-year-old children and to anticipate the timing of interception of these children (pre-school age).

ObjectiveTo test the hypothesis that lipid intake is associated with triglycerides to HDL-cholesterol ratio (TG/HDL-cholesterol), a predictor of the development of cardiovascular disease, in obese children and adolescents, independently from the level of overweight, insulin resistance, blood pressure, and non-alcoholic fatty liver disease (NAFLD).Study designOne hundred and eighty non-diabetic obese children/adolescents (age range 6–16 years) were enrolled. Diet (3-day weighed dietary record), physical and biochemical parameters and liver ultrasonography were measured. The impact of lipid intake on TG/HDL-cholesterol ratio >2.2 was measured by regression models, adjusting for covariates (age, gender, height, weight, systolic and diastolic blood pressure, NAFLD positivity, HOMA-IR, and total energy intake).ResultsIndependently from covariates, children consuming a diet with a fat content higher than 35% of total energy had a significantly higher chance [OR = 3.333 (95% CI: 1.113–9.979), P = 0.031] to have a TG/HDL-cholesterol >2.2 than children consuming less than 35% of fat. Moreover, if saturated fatty acids (SFA) intake was higher than 13% of total energy, children had a significantly higher chance [OR = 4.804 (95% CI: 1.312–17.593), P = 0.018] to have a TG/HDL-cholesterol >2.2 than children consuming less than 13% of SFA in their diet.ConclusionsHigh fat intake, especially SFA intake, is associated with TG/HDL-cholesterol levels of obese children and adolescents, independently from other cardiovascular risk co-factors. Further intervention studies will contribute to clarify the potential role of changes in the composition and amount of fat in the diet of obese children and adolescents, on their cardiovascular risk factors.

Abstract Context Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR) and predicts type 2 diabetes. Currently, it is uncertain whether NAFLD may directly cause IR or vice versa. Objective To test the hypothesis that NAFLD is causally related to IR. Design and Methods We performed a Mendelian randomization (MR) in 904 obese children/adolescents using an NAFLD-related genetic risk score (GRS) as an instrumental variable. We assessed NAFLD by ultrasonography and IR by homeostasis model assessment (HOMA-IR). We also interrogated the MAGIC Consortium dataset of 46 186 adults to assess the association between PNPLA3 rs738409 (ie, the most robust NAFLD-related polymorphism) and HOMA-IR, and we performed a 2-sample MR with 2 large datasets to test reverse causation (HOMA-IR increasing the risk of NAFLD). Results Nonalcoholic fatty liver disease prevalence increased by 20% for every increase in the GRS (β-coefficient = 0.20, P < 0.001), and NAFLD was associated with ln-HOMA-IR (β-coefficient = 0.28, P < 0.001). Thus, the expected increase in ln-HOMA-IR for every increase in the GRS (expected β-coefficient) was 0.056 (0.28*0.20) in the case of complete NAFLD-HOMA-IR causal association, and 0.042 in the case of 75% causality. In our cohort, the GRS did not predict ln-HOMA-IR (β-coefficient = 0.007, P = 0.75). In the MAGIC cohort, the PNPLA3 rs738409 did not associate with ln-HOMA-IR. The 2-sample MR failed to show a causal association between ln-HOMA-IR and NAFLD. Conclusions Our study shows that genetically-influenced NAFLD does not increase HOMA-IR, and genetically-influenced HOMA-IR does not increase the risk of NAFLD. Shared pathogenic pathways or NAFLD subtypes not “captured” by our MR design might underpin the association between NAFLD and HOMA-IR.

Aims/hypothesisWe aimed to analyse the association between plasma circulating microRNAs (miRNAs) and the immunometabolic profile in children with type 1 diabetes and to identify a composite signature of miRNAs/immunometabolic factors able to predict type 1 diabetes progression.MethodsPlasma samples were obtained from children at diagnosis of type 1 diabetes (n = 88) and at 12 (n = 32) and 24 (n = 30) months after disease onset and from healthy control children with similar sex and age distribution (n = 47). We quantified 60 robustly expressed plasma circulating miRNAs by quantitative RT-PCR and nine plasma immunometabolic factors with a recognised role at the interface of metabolic and immune alterations in type 1 diabetes. Based on fasting C-peptide loss over time, children with type 1 diabetes were stratified into the following groups: those who had lost >90% of C-peptide compared with diagnosis level; those who had lost <10% of C-peptide; those showing an intermediate C-peptide loss. To evaluate the modulation of plasma circulating miRNAs during the course of type 1 diabetes, logistic regression models were implemented and the correlation between miRNAs and immunometabolic factors was also assessed. Results were then validated in an independent cohort of children with recent-onset type 1 diabetes (n = 18). The prognostic value of the identified plasma signature was tested by a neural network-based model.ResultsPlasma circulating miR-23~27~24 clusters (miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27a-3p and miR-27b-3p) were upmodulated upon type 1 diabetes progression, showed positive correlation with osteoprotegerin (OPG) and were negatively correlated with soluble CD40 ligand, resistin, myeloperoxidase and soluble TNF receptor in children with type 1 diabetes but not in healthy children. The combination of plasma circulating miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27b-3p and OPG, quantified at disease onset, showed a significant capability to predict the decline in insulin secretion 12 months after disease diagnosis in two independent cohorts of children with type 1 diabetes.Conclusions/interpretationsWe have pinpointed a novel miR-23a-3p/miR-23b-3p/miR-24-3p/miR-27b-3p/OPG plasma signature that may be developed into a novel blood-based method to better stratify patients with type 1 diabetes and predict C-peptide loss.