The treatment of obesity in children and adolescents: consensus position statement of the Italian society of pediatric endocrinology and diabetology, Italian Society of Pediatrics and Italian Society of Pediatric Surgery.

This Position Statement updates the different components of the therapy of obesity (lifestyle intervention, drugs, and surgery) in children and adolescents, previously reported in the consensus position statement on pediatric obesity of the Italian Society of Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics. Lifestyle intervention is the first step of treatment. In children older than 12 years, pharmacotherapy is the second step, and bariatric surgery is the third one, in selected cases. Novelties are available in the field of the medical treatment of obesity. In particular, new drugs demonstrated their efficacy and safety and have been approved in adolescents. Moreover, several randomized control trials with other drugs are in process and it is likely that some of them will become available in the future. The increase of the portfolio of treatment options for obesity in children and adolescents is promising for a more effective treatment of this disorder.

Oral Microbiota in Children and Adolescents with Type 1 Diabetes Mellitus: Novel Insights into the Pathogenesis of Dental and Periodontal Disease.

The oral microbiota can be influenced by multiple factors, but only a few studies have focused on the role of glycemic control in determining early alterations of oral microbiota and their association with pathogenesis of both periodontitis and caries. The aim of this study is to evaluate the interplay between bacteria composition, oral hygiene, and glycemic control in a cohort of children with T1D. A total of 89 T1D children were enrolled (62% males, mean age: 12.6 ± 2.2 years). Physical and clinical characteristics, glucometabolic parameters, insulin treatment, and oral hygiene habits data were collected. Microbiological analysis was performed from saliva samples. A high prevalence of cariogenic and periodontopathogens bacteria in our cohort was detected. In particular, in all subjects Actinomyces spp., Aggregatibacter actinomycetemcomitans, Prevotella intermedia, and Lactobacillus spp. were isolated. S. mutans was found in about half of the analyzed sample (49.4%), in particular in patients with imbalance values of glycemic control. Moreover, a higher presence of both S. mutans and Veillonella spp. was detected in subjects with poorer glycemic control, in terms of HbA1c, %TIR and %TAR, even adjusting for age, sex, and hygiene habits as covariates. Virtuous oral hygiene habits, such as frequency of toothbrush changes and professional oral hygiene, negatively correlated with the simultaneous presence of Tannerella forsythia, Treponema denticola, and Porphyromonas gingivalis, red complex bacteria. Our study shows it is crucial to pay attention to glycemic control and regular oral hygiene to prevent the establishment of an oral microbiota predisposing to dental and periodontal pathology in subjects with T1D since childhood.

Cardiovascular Risk Factors in Children and Adolescents with Type 1 Diabetes Mellitus: The Role of Insulin Resistance and Associated Genetic Variants.

INTRODUCTION: Type 1 diabetes (T1D) is associated with an increased risk of cardiovascular disease. Insulin resistance is an important cardiovascular risk factor (CVRF), also in subjects with T1D, but the influence of the genetic predisposition of insulin resistance on cardiovascular risk is still unknown in T1D. We aimed to determine whether a genetic score composed of six variants, previously associated with insulin resistance and type 2 diabetes (T2D) risk, associates with insulin sensitivity and known CVRFs in children and adolescents with T1D. MATERIALS AND METHODS: 330 children and adolescents (174 males; mean age 15.7 ± 3.5 years) with T1D were genotyped for the following genetic variants: rs1801278 (IRS1), rs1044498 (ENPP1), rs2295490 (TRIB3), rs1801282 (PPARG), rs780094 (GCKR), and rs35767 (IGF1). An additive genetic risk score (GRS) and cardiovascular risk score (CVRS) were calculated. Anthropometric, glycemic control, insulin sensitivity, blood pressure, and biochemical parameters were assessed. Multivariate regression between evaluated phenotypes and GRS was performed. RESULTS: We found a significant association between the GRS and estimated insulin sensitivity (ß = -0.027 [-0.040 to -0.013], R2 = 0.86, p≤ 0.001), diastolic blood pressure (ß = 0.68 [0.08-1.27], R2 = 0.20, p = 0.026), triglycerides (ß = 4.26 [1.74-6.77], R2 = 0.13, p = 0.001), waist to height ratio (ß = 0.003 [0.001-0.006], R2 = 0.75, p = 0.010), non-HDL-cholesterol (ß = 3.63 [1.39-5.87], R2 = 0.12, p = 0.002), and CVRS (ß = 0.063 [0.008-0.118], R2 = 0.19, p = 0.025), independent of age, sex, BMI, pubertal stage, diabetes duration, glycated hemoglobin, type of treatment, and total insulin requirement. The addition of the GRS to established clinical risk factors significantly improved the discriminatory capability of the regression model for predicting subjects with more CVRFs (C-statistic 0.89 [95% CI: 0.84-0.95] versus 0.83 (0.73-0.93); p = 0.037). CONCLUSIONS: Insulin resistance and T2D risk-associated genetic variants influence insulin sensitivity and known CVRFs in children and adolescents with T1D.

A novel transposable element-mediated mechanism causes antiviral resistance in Drosophila through truncating the Veneno protein.

Hosts are continually selected to evolve new defenses against an ever-changing array of pathogens. To understand this process, we examined the genetic basis of resistance to the Drosophila A virus in Drosophila melanogaster. In a natural population, we identified a polymorphic transposable element (TE) insertion that was associated with an ∼19,000-fold reduction in viral titers, allowing flies to largely escape the harmful effects of infection by this virulent pathogen. The insertion occurs in the protein-coding sequence of the gene Veneno, which encodes a Tudor domain protein. By mutating Veneno with CRISPR-Cas9 in flies and expressing it in cultured cells, we show that the ancestral allele of the gene has no effect on viral replication. Instead, the TE insertion is a gain-of-function mutation that creates a gene encoding a novel resistance factor. Viral titers remained reduced when we deleted the TE sequence from the transcript, indicating that resistance results from the TE truncating the Veneno protein. This is a novel mechanism of virus resistance and a new way by which TEs can contribute to adaptation.

Serum zonulin as an index of glucose dysregulation in children and adolescents with overweight and obesity.

Increased intestinal permeability has an important role in metabolic dysregulation. In this cross-sectional study, we examined whether serum intestinal permeability marker zonulin and related pro-inflammatory molecules were associated with the oral disposition index, a predictor for the development of type 2 diabetes, in a cohort of children and adolescents with overweight and obesity. Ninety-two children and adolescents were recruited [Male: 43; 12.7 (2.35) years; BMI SDS: 2.7 (0.96)]. Anthropometric and clinical parameters, lipid profile, glucose metabolism and plasma levels of zonulin, lipopolysaccharide-binding protein and Interleukin-6 were measured. We found an association between oral disposition index and zonulin (ß = -0.243; p = 0.019) and age (ß = -0.307; p = 0.004), independent of sex and BMI SDS [R2  = 0.16; p = 0.005]. Our results show an association between serum zonulin concentration and oral disposition index supporting the hypothesis of increased intestinal permeability as a possible risk factor for glucose metabolism dysregulation in children and adolescents with obesity.

Sex differences in cardiovascular risk factors of children and adolescents with type 1 diabetes mellitus: A role for diet?

BACKGROUND AND AIMS: Cardiovascular disease is the leading cause of morbidity and mortality in individuals with type 1 diabetes mellitus (T1DM). Cardiovascular risk is higher in women with diabetes than in men. With this study, we wanted to determine whether female children and adolescents with T1DM are more prone to cardiovascular risk factors (CVRFs) and an atherogenic diet than boys. METHODS AND RESULTS: For this cross-sectional study, anthropometric, clinical, biochemical, and dietary intake data of 314 children with diabetes (3-18 years; 178 boys) were analysed according to age and sex. Linear and binary logistic regression was performed to test independent associations between sex, dietary intake, and CVRFs. Low-density lipoprotein -cholesterol (LDL-c), triglyceride (TG), fibre, monounsaturated fatty acid levels (all p < 0.01), and lipid (p = 0.022) intake were higher in the girls than in the boys. Multiple regression analysis showed that LDL was associated with sex, glycated haemoglobin (HbA1c), and lipid intake percentage (R (Kannel, 1979) [2] = 0.130; p = 0.0004) independent of age, pubertal stage, body mass index (BMI), duration of diabetes, energy, and fibre intake. Logistic regression analysis showed that high LDL-c levels were present more often in girls [odds ratio, OR; confidence interval, CI = 2.569 (1.178-5.604); p = 0.018] who had a higher dietary lipid intake percentage [OR (CI) = 1.089 (1.011-1.173); p = 0.025]. CONCLUSIONS: Girls with diabetes have higher LDL-c levels associated with higher dietary lipid intake. Our findings suggest that young people with diabetes, especially girls, may benefit from early dietary interventions to reduce their cardiovascular risk.

Short-Term Effects of COVID-19 Lockdown in Italian Children and Adolescents with Type 1 Diabetes Mellitus: The Role of Separation Anxiety.

In March 2020, the Italian Government imposed mandatory home confinement to limit the spread of COVID-19. Few studies assessed the psychophysical impact of COVID-19 on chronically ill children. This study examined these effects on children with Type 1 Diabetes Mellitus (T1D) and their caregivers. Seventy-one patients (7-13 years) with T1D and their caregivers were administered a survey created ad hoc and some standardized questionnaires, assessing psychological well-being and anxiety. Medical data (physical and biochemical characteristics) were recorded before (T0, January-February) and after (T1, May-June) the lockdown. Paired Student t-test, Spearman two-tailed correlations, and a linear regression model were used for statistical analysis. Children at T1 showed higher BMI (body mass index), daily total and basal insulin dose, and time spent in therapeutic range, and they showed lower HbA1c (glycated hemoglobin), time spent above the therapeutic range, and standard deviations of the mean glucose values than at T0. A total of 32.9% scored in the clinical range for separation anxiety. The increase in separation anxiety was predicted by younger age, female gender, more recent T1D diagnosis, less time spent in therapeutic range at T1, and higher perceived fear of COVID-19 infection. In a pandemic context, separation anxiety may be stronger in younger females, with more recent T1D diagnosis and poor metabolic control, thus affecting the parent's ability to manage diabetes and to support children's autonomy.

In vivo confocal microscopy study of corneal nerve alterations in children and youths with Type 1 diabetes.

OBJECTIVE: To determine whether children and youths with Type 1 diabetes (T1D) have early alterations of the corneal subbasal nerve plexus detectable with in vivo confocal microscopy (IVCM) and to investigate the role of longitudinally measured major risk factors for diabetes complications associated with these alterations. METHODS: One hundred and fifty children and youths with T1D and 51 age-matched controls were enrolled and underwent IVCM. Corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal fiber total branch density (CTBD), and corneal fiber fractal dimension (CNFrD) were measured. Risk factors for diabetes complications (blood pressure, BMI, HbA1c, lipoproteins, urinary albumin-creatinine ratio) were recorded at IVCM and longitudinally since T1D onset. Unpaired t-test was used to compare variables between the groups. Multiple regression models were calculated using IVCM parameters as dependent variables and risk factors as independent variables. RESULTS: All IVCM parameters, except CTBD, were significantly lower in the T1D patients. Glycometabolic control (HbA1c, visit-to-visit HbA1c variability, and mean HbA1c), and blood pressure were inversely correlated with IVCM parameters. Multiple regression showed that part of the variability in CNFL, CNFD, CTBD, and CNFraD was explained by HbA1c, blood pressure percentiles and age at IVCM examination, independent of diabetes duration, BMI percentile and LDL cholesterol. Comparable results were obtained using the mean value of risk factors measured longitudinally since T1D onset. CONCLUSIONS: Early signs of corneal nerve degeneration were found in children and youths with T1D. Glycometabolic control and blood pressure were the major risk factors for these alterations.

The risk of metabolic derangements is higher in children and adolescents with overweight or obesity born small for gestational age.

BACKGROUND AND AIMS: Birth weight (BW) has been associated with the risk of obesity and metabolic derangements in children and adults. The aims of this study were: i. to evaluate the distribution of BW in a sample of overweight and obese children and adolescents compared with the general reference population; ii. to explore the relationship between the BW and insulin resistance and other cardiometabolic derangements in a population of children and adolescents with overweight and obesity. METHODS AND RESULTS: 710 overweight and obese children and adolescents were recruited and categorized into small (SGA), appropriate (AGA), and large (LGA) for gestational age, according to the BW percentile. Arterial blood pressure, lipid profile, glucose metabolism and hepatic steatosis were evaluated to assess cardiometabolic obesity-related derangements. The distribution of BW categories in our population was significantly different compared with the general population (SGA 6.9% vs. 8.6%, AGA 74.6% vs. 81.4%, LGA 18.5% vs. 10%; p < 0.0001). We found a higher frequency of prediabetes conditions (21.7% vs 8.9%, OR 2.97, 95% CI 1.38-6.38, p = 0.005) and borderline/high low-density lipoprotein cholesterol (31.8% vs 18.6%, OR 2.13, 95% CI 1.09-4.18, p = 0.033) in overweight and obese children born SGA compared to those born non-SGA, independently of age, sex, and BMI. CONCLUSIONS: BW is a risk factor of cardiometabolic derangements in a population of children and adolescents with overweight and obesity. Therefore, adequate obesity prevention strategies should be planned for children born SGA to minimize their risk to become obese and to reduce their short- and long-term cardiometabolic risks.

Lipid and saturated fatty acids intake and cardiovascular risk factors of obese children and adolescents.

OBJECTIVE: To 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 DESIGN: One 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). RESULTS: Independently 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. CONCLUSIONS: High 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.

13C/12C breath test ratio after the ingestion of a meal naturally enriched with (13C)carbohydrates is a surrogate marker of insulin resistance and insulin sensitivity in children and adolescents with Type 1 Diabetes.

AIMS: To test the hypotheses that exogenous carbohydrate oxidation affects postprandial glycaemic profiles and 13C/12C breath test could be used for estimating insulin resistance (IR) and insulin sensitivity (IS) in youths with Type 1 Diabetes (T1D). METHODS: Non-randomized, cross-sectional study for repeated measures; fifteen youths (11-15 years) with T1D were enrolled. Respiratory exchanges were measured by indirect calorimetry after the ingestion of a mixed meal [13% protein, 29% fat, 58% carbohydrate (CHO; naturally enriched with [13C]carbohydrates)]. Total and exogenous CHOs oxidation was calculated by indirect calorimetry and 13C/12C breath test. IR and IS were calculated using estimated Glucose Disposal Rate (eGDR) and Insulin Sensitivity Score (ISS). RESULTS: The blood glucose Area Under the Curve (BG-AUC) was significantly associated with the amount of exogenous CHOs oxidized (r = -0.67, p < 0.02) when adjusting for CHOs intake and %fat mass. A direct correlation between eGDR and ISS with exogenous CHOs oxidized (r = 0.70, p < 0.02; r = 0.61, p < 0.05 respectively) and with the differential of 13C/12C enrichment in the expired at breath test (r = 0.59, p < 0.05; r = 0.62, p < 0.05), was found. CONCLUSIONS: Assessing the capacity to oxidize exogenous CHOs (estimated by the differential of 13C/12C enrichment in the expired air at the breath test) could be used as a non-invasive surrogate marker of IR and IS in youths with T1D.

Reduced minimum rim width of optic nerve head: a potential early marker of retinal neurodegeneration in children and adolescents with type 1 diabetes.

AIMS: To determine whether early retinal neurodegenerative changes in pediatric patients with type 1 diabetes (T1D) can be detected by spectral domain-optical coherence tomography (SD-OCT) and whether such changes are associated with risk factors for T1D complications. METHODS: A total of 147 T1D children/adolescents and 51 healthy controls underwent SD-OCT. Spherical refractive error (SRE), macular total retinal thickness (TRT), ganglion cell layer (GCL), retinal nerve fiber layer (RNFL), minimum rim width (MRW), and Bruch's membrane opening area (BMOA) were measured. Clinical and biochemical parameters were recorded at the time of SD-OCT and starting at T1D onset. Multiple regression models were calculated using SD-OCT parameters as dependent and risk factors as independent variables. RESULTS: MRW was significantly thinner in the T1D patients (global MRW:361.58vs386.33 µm; p = 0.009), while RNFL and macular parameters were similar for both groups. MRW was inversely correlated with mean HbA1c (r ≥ -0.180, p < 0.05). Multiple regression showed that part of the variability in MRW was explained by HbA1c and BMOA (R2 = 0.21; p < 0.001), independent of other cardiometabolic risk factors. CONCLUSIONS: MRW reduction could be a potential early marker of retinal neurodegeneration detectable in pediatric patients with T1D. The association between MRW and mean HbA1c suggests that glucometabolic control may affect early retinal neurodegeneration starting in childhood.

Nutrition habits of children and adolescents with type 1 diabetes changed in a 10 years span.

BACKGROUND: Diet plays a key role in the treatment of type 1 diabetes (T1D). Dietary habits changed rapidly in the last decades and few data are available on recent dietary changes in children and adolescents with T1D. OBJECTIVE: To test the hypothesis that diet composition changed in a 10-year period in children and adolescents with T1D. METHODS: Two hundred and twenty-nine T1D subjects (M/F:121/108) aged 6 to 16 years were recruited: 114 (group A) enrolled in 2009, not using CGM and/or CSII, and 115 (group B) enrolled in 2019. Anthropometric biochemical (HbA1c, lipid profile), diet, and insulin therapy parameters were compared between the two groups. Multivariate logistic regression analysis was performed with HbA1c as dependent variable (HbA1c > 58 mmol/mol = 1) and nutritional variables and technology use as independent ones. RESULTS: Energy intake of group A was not statistically different from that of group B. Group B had a significantly (P < 0.001) higher protein and lipids intake and lower total carbohydrate and fiber intake than group A. HbA1c was significantly (P < 0.01) lower in group B than in group A. Logistic regression analysis showed that MUFA (OR 0.83, 95%CI:0.693-0.998), fiber intake (OR 0.82, 95%CI:0.699-0.0969), and technology use (OR 0.15, 95%CI:0.031-0.685), adjusted for age, gender, BMI, energy intake and diabetes duration, were associated with a HbA1c higher than 58 mmol/mol) (R2 = 0.27, P < 0.05). CONCLUSIONS: In a 10-year period, diet composition of children and adolescents with T1D changed and glucometabolic control improved. Fiber and MUFA intake showed a positive effect on HbA1c, independent from technology use, supporting the importance of educating children with T1D and families to maintain healthy eating habits.

Vitamin D affects insulin sensitivity and ß-cell function in obese non-diabetic youths.

OBJECTIVE: Vitamin D may potentially play a central role in glucose homeostasis and ß-cell function (BCF), although studies are not consistent. Aim of our study was to test the hypotheses of a direct relationship between vitamin D, insulin sensitivity (IS) and BCF in overweight and obese non-diabetic children. DESIGN AND METHODS: Cross-sectional study carried out at the Childhood Obesity Outpatient Clinic, University Hospital of Verona. One hundred twenty-two Caucasian overweight and obese children (age: 12.8 ± 0.2 years) were enrolled. Exclusion criteria: genetic or endocrine causes of obesity, chronic diseases or therapies. Patients underwent oral glucose tolerance test. HOMA-IR, Matsuda index and insulinogenic index were calculated. BCF was reconstructed by mathematical modeling and described by Derivative and Proportional Control. Total 25-hydroxyvitamin D and vitamin D-binding protein (VDBP) were measured. Two SNPs (rs4588 and rs7041) in the VDBP gene were studied, and bioavailable vitamin D (BVD) was calculated. RESULTS: Hypovitaminosis D was documented in 90% of patients. Forty-seven subjects were homozygous for both SNPs. Total vitamin D was positively correlated with Matsuda index (P = 0.002), VDBP (P = 0.045), and negatively with BMI SDS (P = 0.043), HOMA-IR (P = 0.008), HOMA-B (P = 0.001), IGI (P = 0.007), derivative control (P = 0.036) and proportional control (P = 0.018). Total vitamin D, adjusted for age, gender, BMI SDS, puberty and seasonality of vitamin D measurement, was a predictor of Matsuda index, HOMA-IR, HOMA-B, IGI, proportional control (all P < 0.05). BVD was positively correlated with total vitamin D (P < 0.001) and negatively with BMI SDS (P = 0.041). CONCLUSIONS: Hypovitaminosis D negatively influences BCF and IS, suggesting that vitamin D levels might be implicated in glucose metabolism impairment in overweight and obese individuals.

Contribution of a genetic risk score to clinical prediction of hepatic steatosis in obese children and adolescents.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in children and adolescents in Western countries. Complex traits arise from the interplay between environmental and genetic factors in the pathogenesis of NAFLD. AIMS: We examined the association between NAFLD and eleven single nucleotide polymorphisms (SNPs) at genetic loci potentially associated with liver damage (GCKR, MBOAT7, GPR120), oxidative stress (SOD2), lipid metabolism (PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP) and fibrogenesis (KLF6) in a paediatric population. A genetic risk score (GRS) was performed taking into account both these SNPs and clinical risk factors. METHODS: We recruited a cohort of 514 obese children and adolescents (mean age [±SD]: 11.2 ±â€¯2.8 years, z-BMI 3.3 ±â€¯0.8). NAFLD was identified by ultrasonography. Genotyping was performed by TaqMan-based RT-PCR system. RESULTS: The overall prevalence of NAFLD was 67.5% (347 patients). Among the eleven genotyped SNPs, the genetic variants in TM6SF2 rs58542926 (OR = 4.13, p = 0.002), GCKR rs1260326 (OR = 1.53, p = 0.003), PNPLA3 rs738409 (OR = 1.58, p = 0.004) and ELOVL2 rs2236212 (OR = 1.34, p = 0.047) were significantly associated with a higher risk of NAFLD. Addition of a 11-polymorphism GRS to established clinical risk factors significantly (albeit modestly) improved the discriminatory capability of the regression model for predicting the risk of NAFLD (with SNPs C-statistic 0.81 [95%CI 0.75-0.88] vs. 0.77 [0.70-0.84] without SNPs; p = 0.047). CONCLUSIONS: NAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326, and more slightly with ELOVL2 rs2236212, in obese children and adolescents. Addition of a 11-polymorphism GRS to clinical risk factors improved the predictability of NAFLD.

"IGT-like" status in normoglucose tolerant obese children and adolescents: the additive role of glucose profile morphology and 2-hours glucose concentration during the oral glucose tolerance test.

OBJECTIVE: To assess whether combining glucose shape and 2-h glucose concentration during an oral glucose tolerance test (OGTT) may help identifying normal glucose tolerant obese children/adolescents with an impaired glucose tolerant (IGT)-like metabolic profile in term of insulin sensitivity (Matsuda index) and ß-cell function (disposition index: DI). SUBJECTS, METHODS, AND MAIN OUTCOME MEASURE: In total, 654 non-diabetic obese children/adolescents underwent a 2 h OGTT. The whole population was classified according to 2-hour plasma glucose ( < 100, 100-119, 120-139, 140-200 mg/dL) and glucose shape (monophasic or biphasic). Monophasic morphology was characterized by an increase in OGTT glucose concentration followed by a decline of at least 4.5 mg/dL, a biphasic response was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 4.5 mg/dL. A subset of 69 participants had also a prolonged OGTT to estimate ß-cell function in "biphasic" versus "monophasic" patients. RESULTS: Matsuda index and DI decreased across 2-h glucose categories (both p < 0.001) and were lower in monophasic compared with biphasic children, independently of 2-h glucose category (both p < 0.001, both p for glucose category×shape interaction > 0.05). Normal glucose tolerant children with 2-h glucose of 120-139 mg/dl and monophasic glucose shape did not differ from IGT children, as regards Matsuda index and DI (both p > 0.05). Among children undergoing a prolonged OGTT, those with a monophasic glucose shape had worse ß-cell function, modeled as proportional control, than those with a biphasic shape (p = 0.031). CONCLUSIONS: A monophasic OGTT glucose shape is associated with unfavorable glucose metabolism independently of 2-h glucose concentration. Children combining monophasic shape and normal-high 2-h glucose have an IGT-like glucose metabolism.

Successful Management of Kaposiform Hemangioendothelioma with Long-Term Sirolimus Treatment: a Case Report and Review of the Literature.

BACKGROUND: Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumour of the infancy and the first decade of life. It is locally aggressive and potentially life threatening when associated with consumptive coagulopathy, known as Kasabach-Merritt syndrome (KMS). No consensus or guideline for the therapy has been reached because of the lack of prospective trials, and the different standard care suggestions are based on retrospective case series. CASE REPORT: We report the case of a 9-month-old male with KHE and KMS in which the initial response, obtained with prednisone and vincristine, was subsequently consolidated and strengthened by long-term treatment with sirolimus, a mTOR inhibitor. A summary of the published data is presented as well. CONCLUSIONS: The inhibition of mTOR pathway represents the most important therapeutic innovation introduced in the last few years for KHE. Our case shows the effectiveness and good tolerance of long-term therapy with sirolimus.

Minor diplotypes of FMO3 might protect children and adolescents from obesity and insulin resistance.

In order to assess whether flavin-containing monooxygenase-3 (FMO3) might be involved in early cardiovascular risk, we assessed adiposity and traditional metabolic variables in children/adolescents grouped according to their genotypes in two FMO3 exonic polymorphisms, rs2266782 (E158K) and rs2266780 (E308G), which are in linkage disequilibrium and have been associated with decreased FMO3 activity. Among 776 children/adolescents (10.8 ± 2.2 years) recruited from the general population (452) and from our obesity outpatient clinic (324), the 68 carrying either the 158K-308G/158K-308E or the 158K-308G/158K-308G diplotype had lower mean z-BMI and prevalence of obesity compared to their 708 peers carrying any of the other diplotypes (0.39 vs 0.80, p = 0.01; OR = 0.39[0.17-0.87], p = 0.018, respectively), and to the sub-sample of 303 children carrying the major diplotype (158E-308E/158E-308E) (0.39 vs 0.87, p = 0.008; OR = 0.35[0.16-0.81], p = 0.014, respectively). They also had lower z-BMI-adjusted lnHOMA-IR compared to all the other children (0.75 vs 0.97, p = 0.001) and those carrying the major diplotype, (0.75 vs 0.98, p = 0.03), as well as lower z-BMI-adjusted iln-triglycerides compared to all the other children (3.98 vs 4.17, p = 0.037). These associations provide the first evidence that FMO3 may be involved in early body weight, insulin sensitivity, and lipid regulation in humans.

Erratum to: Growth Hormone Deficiency and Lysinuric Protein Intolerance: Case Report and Review of the Literature.

The first and last names of the authors were inadvertently reversed in the original version.