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To investigate whether GE is affected in children/adolescents with obesity and abnormalities of the metabolic syndrome (MetS). Cross-sectional study of oral GE (oGE), insulin sensitivity and secretion (calculated on 5 time-points oral glucose tolerance test) and metabolic abnormalities in 1012 patients with overweight/obesity (aged 6.0–17.9 years old). A MetS risk score was calculated on the basis of distribution of fasting glucose, triglycerides, HDL-cholesterol, total cholesterol, systolic and diastolic blood pressure. Non-alcoholic fatty liver disease (NAFLD) was suspected based on thresholds of alanine aminotransferases. Four-hundred and eighty patients (47.73%) had low-MetS risk score, 488 medium (48.22% with 1–2 risk factors) and 41 (4.05% with ≥ 3 factors) high risk. oGE was significantly lower in subjects with obesity [3.81 (1.46) mg/dl/min− 1] than in those with overweight [4.98 (1.66) mg/dl/min− 1; p value

Objective Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design Retrospective analysis of the Italian data set of patients with TNDM. Methods Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. Results Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; −2.27 SD) than those with KATP mutations (4.0 weeks; −1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Background/Aims: The prevalence of impaired glucose tolerance (IGT) is rising among obese adolescents in parallel with epidemic obesity. In some cases, IGT reverts to normal glucose tolerance (NGT) by the end of puberty. The aims of the present study were to investigate metabolic factors determining changes over time of glucose at 120 min (Glu120) following an oral glucose tolerance test (OGTT), and to verify whether preserved β-cell glucose sensitivity (βCGS) protects against persistent IGT. Methods: We performed a cohort study of 153 severely obese children and adolescents evaluated with a 5-point OGTT at baseline and at follow-up with measurements of glucose, insulin, and C-peptide to estimate several empirical parameters of insulin sensitivity (includ ing oral glucose insulin sensitivity [OGIS] and OGTT-derived glucose effectiveness) and secretion. Results: At follow-up (range 0.9–4.8 year), 113 (73.9%) patients remained with NGT, 9 (5.9%) had IGT, and 28 (18.3%) had reverted to NGT; 3 NGT patients had developed IGT. In multivariable models, change in loge(βCGS) was inversely associated with time-related change in loge(Glu120), with (model 2) and without (model 1) correction for the change in loge(OGIS). Model 2 was more strongly associated with change in loge(Glu120). Conclusions: Changes in βCGS and insulin sensitivity were inversely associated with changes in Glu120 at follow-up, contributing a likely explanation for the reversal of IGT to NGT.

Background and aims Prader–Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. Methods and results We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1–50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children 18 yrs), Body Mass Index (BMI = kg/m2), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. Conclusion This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program.

Summary We tested the hypothesis that patients with Prader–Willi syndrome (PWS) may be at lower risk of developing non-alcoholic fatty liver disease (NAFLD) because of a higher insulin sensitivity. Twenty-one PWS patients and 42 control subjects closely similar for age, gender, pubertal stage and body mass index (CNT), were studied. Metabolic profile and body composition were assessed. NAFLD was established by a validated method of US grading (range from G0 to G3). PWS patients showed a significantly better metabolic profile (lower waist circumference, fasting glucose levels, HOMA-IR, cholesterol, transaminase levels and trunk fat mass/fat mass ratio). Furthermore, NAFLD G1stage was significantly more frequent in PWS subjects (P

Background: Body Mass Index Italian reference data are available for clinical and/or epidemiological use, but no study compared the ability of this system to classify overweight and obesity and detect subjects with clustered cardiometabolic risk factors with international standards. Therefore our aim was to assess 1) the agreement among the Italian Society for Pediatric Endocrinology and Diabetology (ISPED), the World Health Organisation (WHO) and the International Obesity Task Force (IOTF) Body Mass Index cut-offs in estimating overweight or obesity in children and adolescents; 2) the ability of each above-mentioned set of cut-points to detect subjects with cardiometabolic risk factors. Methods: Data of 6070 Italian subjects aged 5-17 years were collected. Prevalence of normal-weight, overweight and obesity was determined using three classification systems: ISPED, WHO and IOTF. High blood pressure, hypertriglyceridemia, low high density lipoprotein-cholesterol and impaired fasting glucose were considered as cardiometabolic risk factors. Results: ISPED and IOTF classified more subjects as normal-weight or overweight and less subjects as obese as compared to WHO (p 0.900), while it differed for obesity definition, ranging from the highest agreement between ISPED and IOTF (k 0.875) to the lowest between ISPED and WHO (k 0.664). WHO had the highest sensitivity, while ISPED and IOTF systems had the highest specificity, in identifying obese subjects with clustered cardiometabolic risk factors. Analogous results were found in subjects stratified by gender or age. Conclusions: ISPED and IOTF systems performed similarly in assessing overweight and obesity, and were more specific in identifying obese children/adolescents with clustered cardiometabolic risk factors; on the contrary, the WHO system was more sensitive. Given the seriousness of the obesity epidemic, we wonder whether the WHO system should be preferable to the national standards for clinical practice and/or obesity screening.

Circa il 10% dei neonati alla nascita presenta dimensioni ridotte per l’eta gestazionale (small for gestational age, SGA). I soggetti nati SGA sono a maggior rischio di sviluppare nella vita adulta insulino-resistenza, obesita, cardiopatia ischemica, diabete di tipo 2. Le alterazioni metaboliche sono presenti fin dall’infanzia. I bambini e gli adolescenti nati SGA presentano, rispetto ai soggetti nati di normale peso per eta gestazionale, ridotta insulino-secrezione, aumentata insulino-resistenza, aumento del grasso addominale, aumentata prevalenza di sindrome metabolica.

SummaryObjective Hepatic steatosis is strongly associated with insulin resistance, but causative mechanisms that link these conditions are still largely unknown. Nowadays, it is difficult to establish whether fatty liver is the cause of insulin resistance or instead the complex metabolic derangements of insulin resistance determine hepatic steatosis and its progression to fibrosis. In patients with familial hypobetalipoproteinemia (FHBL), hepatic steatosis is because of the genetically determined defective form of apolipoprotein B, independently of metabolic derangements. Therefore patients with FHBL represent a good in vivo model to evaluate the relationships between fatty liver and insulin sensitivity. Methods We evaluated insulin resistance through HOMA-IR in 60 children with echografic and histological features of steatosis; 30 of whom had nonalcoholic fatty liver disease (NAFLD) and 30 had FHBL. Results All patients had histological features of hepatic steatosis. Patients with FHBL were hypolipidemic, as expected. No significant differences between two groups were observed in liver function tests. IRI and HOMA-IR were statistically higher in NAFLD subjects compared to the FHBL group. Conclusion In our study, we demonstrated that in children with FHBL, hepatic steatosis is dissociated from insulin resistance. This finding suggests that fat accumulation per se may be not a sufficient causal factor leading to insulin resistance, and that other mediators may be involved in the development of alteration in glucose metabolism and metabolic syndrome in patients with NAFLD.

Aim: Our aim was to investigate the relationships between the degree of IGF2 methylation and the metabolic status in obese children and adolescents. Subjects and Methods: Eighty-five obese subjects aged 11.6 ± 2.1 years were studied. Anthropometry, metabolic parameters, blood pressure and body composition were assessed. DNA methylation analysis was performed by restriction enzyme digestion assay. The study population was subdivided into two groups according to the percentage of IGF2 cytidine-guanosine (CpG) island methylation. Results: Twenty-two subjects showed intermediate methylation (a percentage of CpG site methylation comprised between 10 and 60%), 56 were hypomethylated (percentage of methylation lower than 10%), and only 1 showed a high rate of hypermethylation (percentage of methylation above 60%). Children with intermediate methylation showed significantly higher levels of triglycerides (107.6 ± 41.99 vs. 76.6 ± 30.18 mg/dl, p < 0.005) and a higher triglyceride/high-density lipoprotein-cholesterol ratio (2.23 ± 0.98 vs. 1.79 ± 0.98, p < 0.02) compared with hypomethylated children. Conclusions: These preliminary findings show for the first time a relationship between IGF2 methylation pattern and lipid profile in obese children. Although the correlation does not imply causation, if our findings are confirmed in further studies, IGF2 methylation might represent an epigenetic marker of metabolic risk.

Objective: Childhood obesity has become epidemic and has been accompanied by an increase in prevalence of type 2 diabetes (T2DM) in youth. Addressing obesity and insulin resistance by drug treatment represents a rational strategy for the prevention of T2DM. A systematic review was performed to evaluate the effectiveness of metformin in reducing weight and ameliorating insulin resistance in obese nondiabetic children. Methods: A PubMed database search was conducted, using ‘metformin', ‘obesity', ‘insulin resistance', ‘children', ‘adolescents' as search terms. Results: Eleven trials were included in the present review. Metformin was administered for 6-12 months at a dosage of 1,000-2,000 mg/daily, decreasing BMI by 1.1-2.7 compared with placebo or lifestyle intervention alone. Concomitantly, fasting insulin resistance improved after metformin therapy. Posttreatment follow-up was performed in one study, showing that after 1 year of discontinuation of therapy the decrease in BMI disappears. Conclusions: Short-term metformin treatment appears to moderately affect weight reduction in severely obese children and adolescents, with a concomitant improvement in fasting insulin sensitivity. Further studies with longer treatment period are needed to establish how much metformin can reduce weight and its real utility in preventing T2DM development in pediatric patients.

Summary Objectives The aim of our study was to evaluate the physical and sedentary activities and energy expenditure (EE) in a group of children affected by non-alcoholic fatty liver disease (NAFLD), compared with normal and obese subjects, using a physical activity questionnaire (PAQ) and a SenseWear armband (SWA). Methods Forty NAFLD (10 females), 41 lean (NRM; 11 females) and 30 obese (OB; 10 females), age- and pubertal stage-matched, children were included. Results Sedentary activity (PAQ) was similar in NAFLD and NRM but less in OB, while SWA showed that NAFLD spent less time in physical activity and more in sedentary activities compared with NRM, but not with OB. Insulin sensitivity index result is related to active EE (cal kg–1 d–1) in NAFLD, while homeostatic model assessment index result was negatively related to total EE in OB. Conclusions Regular physical activity must be encouraged in all obese children affected by NAFLD or not, and SWA might be a possible valid tool for evaluating actual EE.

Background: Benefit of fitness on children with type 1 diabetes mellitus (T1DM) is still debated. Aim: To evaluate the influence of physical activity on metabolic balance and exercise tolerance in prepubertal children affected by T1DM. Methods: We analyzed 35 pre-/peripubertal T1DM children and 31 matched controls using an activity monitor (SenseWear Armbad) and physical activity questionnaire (PAQ) to assess energy expenditure (EE), total and active, sedentary and physical activities (h/day and Mets = metabolic equivalents). The maximal cardiopulmonary exercise test (CPET) was also performed. Results: Total physical activities and total and active EE (>3 Mets) resulted higher in controls than in T1DM patients and self-reported perception of physical and sedentary activities was altered in T1DM children as well in controls and were different from the measured data. No differences were found in CPET parameters with the exception of a higher maximal blood pressure in T1DM children. In multivariate analysis HbA1c negatively correlated with VO2. Conclusion: Prepubertal T1DM children seem to have a lower level of physical activity and EE and a probable altered feeling of physical and sedentary activities. On the other hand, T1DM children do not show any alteration of cardiovascular performance, although glycemic control (HbA1c) may play a role in cardiovascular performance.

ObjectivesThe aim of this study was to investigate the usefulness of ambulatory blood pressure monitoring versus head-up tilt test in the evaluation of children with a history of syncope.Study designWe considered 146 consecutive children with more than one episode of syncope. All patients had a normal electrocardiogram at rest and were otherwise considered to be healthy. Forty-six patients,19 male, with a mean age of 13.6 plus or minus 5.6 years, were studied with a head-up tilt test and 100 patients, 41 male with a mean age of 9.4 plus or minus 5.6 years, were studied with ambulatory blood pressure monitoring. Twelve patients underwent both procedures. Hypotension during ambulatory blood pressure monitoring was defined when mean blood pressure values were lower than the 50th centile and the head-up tilt test was positive when syncope occurred. All patients were followed for 10 plus or minus 2 months.ResultsAmbulatory blood pressure monitoring showed postural hypotension in 91% children, while head-up tilt test was positive for 54%. In the group of children having both tests, two of them were negative for both, 10 of 12 children had a positive ambulatory blood pressure monitoring while only five of 10 children had a positive response to head-up tilt test.ConclusionsWhen a child with a normal resting electrocardiogram is referred with a typical history of syncope, the use of ambulatory blood pressure monitoring as a non-invasive first step for diagnosis of postural hypotension may be more sensitive than the head-up tilt test. Behavioural adjustments resolved the continued syncope in most cases. If episodes persist then the head-up tilt test is indicated.

Objective: To investigate whether body mass index (BMI) and body composition can affect peak bone mass in a population of obese (OB) (BMI SDS>2.0) and normal-weight (NORM) (BMI-SD score

A long pre-diabetic phase of abnormal glucose tolerance is described in subjects with cystic fibrosis (CF) since childhood.ObjectiveThe aims of the study were to compare oral glucose tolerance test (OGTT) and continuous glucose monitoring system (CGMS) in the diagnosis of altered glucose metabolism, and to longitudinally evaluate the role of CGMS in predicting glucose metabolism deterioration in children with CF.MethodsSeventeen children with CF and 14 controls were enrolled (mean age 13.3±3.0 years). All subjects underwent OGTT and CGMS registration. On the basis of OGTT, children were classified as normal glucose tolerance, impaired glucose tolerance (IGT), IGT plus at least one glucose value above 200 mg/dl at intermediate OGTT points (IGT+200) and CF-related diabetes (CFRD). HbA1c, glucose area under the curve, insulin sensitivity, and insulinogenic and disposition indexes were also considered. Subjects with CF underwent another OGTT after 2.5 years.ResultsBaseline OGTT revealed 3/17 (7.6%) children with CF with at least one glucose value above 200 mg/dl (1 CFRD and 2 IGT+200), while CGMS revealed 6/17 (35.3%) children with glucose excursions above 200 mg/dl (P=0.010). None of the controls showed glucose over 200 mg/dl either at OGTT or at CGMS. At the 2.5-year follow-up OGTT, all the six subjects who had diabetic glucose excursion (i.e. >200 mg/dl) at baseline CGMS presented IGT+200 or CFRD. In logistic regression analysis, CGMS diabetic excursion was the strongest predictor of IGT+200 and CFRD (PConclusionsCGMS could be a useful tool to predict glucose metabolism derangements in children affected by CF.

Brufani C, Ciampalini P, Grossi A, Fiori R, Fintini D, Tozzi A, Cappa M, Barbetti F. Glucose tolerance status in 510 children and adolescents attending an obesity clinic in Central Italy. Childhood obesity is epidemic in developed countries and is accompanied by an increase in the prevalence of type 2 diabetes (T2DM). Aims: Establish prevalence of glucose metabolism alterations in a large sample of overweight/obese children and adolescents from Central Italy. Methods: The study group included 510 overweight/obese subjects (3–18 yr). Oral glucose tolerance test (OGTT) was performed with glucose and insulin determination. Homeostatic model assessment of insulin resistance (HOMA-IR) and insulin sensitivity index (ISI) were derived from fasting and OGTT measurements. Beta-cell function was estimated by insulinogenic index. Fat mass was measured by dual-energy x-ray absorptiometry. Results: Glucose metabolism alterations were detected in 12.4% of patients. Impaired glucose tolerance (IGT) was the most frequent alteration (11.2%), with a higher prevalence in adolescents than in children (14.8 vs. 4.1%, p < 0.001); silent T2DM was identified in two adolescents (0.4%). HOMA-IR and glucose-stimulated insulin levels were higher in patients with IGT than individuals with normal glucose tolerance (HOMA-IR = 4.4 ± 2.5 vs. 3.4 ± 2.3, p = 0.001). Fat mass percentage and insulinogenic index were not different between the two groups. In multivariate analysis, age, fasting glucose, and insulin resistance influenced independently plasma glucose at 120 min of OGTT. Individuals with combined impaired fasting glucose/IGT (IFG/IGT) and T2DM were older and had reduced plasma insulin values at OGTT when compared to patients with simple IGT. Conclusions: Glucose metabolism alterations are frequently found among children and adolescents with overweight/obesity from Central Italy. Age, fasting glucose, and insulin resistance are main predictors of IGT. We suggest the use of OGTT as a screening tool in obese European adolescents.

Danilo Fintini, Claudia Brufani, Marco CappaEndocrinology Unit, “Bambino Gesù” Children’s Hospital-IRCCS, Rome, ItalyAbstract: Growth hormone insensitivity syndrome (GHI) or insulin-like growth factor-1 (IGF-1) deficiency (IGFD) is characterized by deficit of IGF-1 production due to alteration of response of growth hormone (GH) receptor to GH. This syndrome is due to mutation of GH receptor or IGF-1 gene and patients affected showed no response to GH therapy. The only treatment is recombinant IGF-1 (mecasermin), which has been available since 1986, but approved in the United States by the US Food and Drug Administration only in 2005 and in Europe by the European Medicines Agency in 2007. To date, few studies are available on long-term treatment with mecasermin in IGFD patients and some of them have a very small number of subjects. In this review we discuss briefly clinical features of severe primary IGFD, laboratory findings, and indications for treatment. Results of long-term therapy with rhIGF1 (mecasermin) in patients affected by severe primary IGFD and possible side effects are explained.Keywords: mecasermin, therapy, Laron syndrome, IGF-1

Estrogen deficiency in females and androgen deficiency in males may harm periosteal and endosteal apposition, reduce bone size and both cortical and trabecular thickness, modifying in this way the bone structure later in life. To date, few systematic studies on bone mineral density (BMD) and hypogonadism in adolescents are available. Therefore we aimed to determine if sexual hormone deficiency during pubertal age might have an impact on peak bone mass and body composition. We compared areal BMD (L-aBMD), volumetric lumbar spine BMD (L-vBMD), lumbar spine Z-score (L-Z-score), lumbar spine bone mineral content (L-BMC), whole body (wbBMD), normalized whole body (n-wbBMD) BMD, and whole body BMC (wb-BMC) of 25 male children with hypogonadism (HYPO) with 37 sex-, age-, and body mass index-matched healthy subjects (CNT) using dual-energy X-ray absorptiometry. Furthermore we analyzed whether a difference in lean (lean%) and fat (fat%) mass as percentage of body weight and as a lean/fat ratio is present in the two groups of children. HYPO demonstrated a statistically lower L-aBMD, LvBMD, L-BMC, Z score, wbBMD, n-wbBMD, and wb-BMC compared to CNT. CNT showed a higher lean% and lower fat% and a higher lean/fat ratio when compared with HYPO group. Lean mass correlated positively with L-aBMD, L-BMC, and wb-BMC. Our study seems to confirm previous observations that sex hormone deficiency during puberty reduces bone mass accrual. Body composition alterations may play a role in bone parameters during development in healthy as such as in hypogonadal children during developmental age.

BackgroundPuberty is a period of rapid growth associated with metabolic, hormonal, and body composition changes that can influence risk factors for chronic diseases such as type 2 diabetes.ObjectiveTo evaluate body composition and insulin sensitivity (IS) modifications throughout puberty in a large group of obese Caucasian subjects.MethodsFive hundred and nineteen obese subjects (4–19 years), grouped according to gender and Tanner stage (T), underwent oral glucose tolerance test. Quantitative insulin check index (QUICKI) and ISI were calculated as indexes of IS. In 309 subjects, body composition by dual-energy X-ray absorptiometry, IGF1, adiponectin, and leptin were also evaluated.ResultsBody composition modifications were sexually dimorphic, with girls not modifying fat and lean percentage and fat distribution (P>0.15), and boys decreasing fat percentage and increasing lean percentage and central fat depot (PPPPConclusionsIn obese Caucasian subjects, further decrease of IS observed during puberty is a transient phenomenon. Factors that independently from T or age influence IS are central fat depot in girls, lean amount in boys, and total fat mass in both sexes.

L’iperplasia congenita surrenalica da deficit dell’enzima 21-idrossilasi e una malattia del surrene caratterizzata da deficit di cortisolo, eccesso di ormoni andro-geni, e in alcuni casi anche da deficit di aldosterone. La forma classica e presente in 1:15.000 nati vivi; la forma non classica, molto piu frequente, e una causa comune di iperandrogenismo. Lo studio del gene della 21-idrossilasi consente oggi di effettuare diagnosi e terapia prenatale della malattia. I maggiori problemi a cui vanno incontro i soggetti con la forma classica sono: crisi surrenalica neonatale, fatale se non riconosciuta e prontamente trattata; riduzione della statura finale, specialmente in soggetti di sesso maschile con la forma virilizzante semplice; esiti a breve e lungo termine dei genitali ambigui nelle femmine. Iperandrogenismo, ipercortisolismo iatrogeno, infertilita e sindrome metabolica sono frequenti negli adulti sia nella forma classica sia nella forma non classica.

A high incidence of glucose metabolism alterations (impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes) has been observed in Prader-Willi syndrome (PWS) (7–40%), particularly after pubertal age and in obese subjects (1). Glucagon-like peptide 1 (GLP-1) receptor agonist (exenatide) and analog (liraglutide) are the new drugs recently introduced for type 2 diabetes that simultaneously reduce appetite and body weight, and their beneficial effects have been reported only in few cases with PWS (2–5). We report, for the first time, the effects of long-term liraglutide or exenatide treatment in six genetically confirmed (3 deletion and 3 uniparental disomy of chromosome 15) (UPD) adult PWS patients (3 males, aged 20.7–37.7 years; all but one obese, BMI 28–57.2 kg/m2) never treated with growth hormone, affected by type 2 diabetes. All patients were treated at least …

AIMS—To investigate whether diabetic retinopathy (DR), already associated with microvascular alterations, ischaemia, and endothelial dysfunction, was also characterised by abnormal modulation of coagulation pathways. METHODS—Plasma samples, collected from 67 type 1 diabetics comparable for age, duration of disease (DD), and metabolic control (MC), were processed for prothrombin degradation products (F1+2) and factor VII coagulant activity (FVII:c). 50 normal subjects served as a control group. The ETDRS-Airlie House Classification of DR was used. RESULTS—A significant correlation between FVII:c and F1+2 plasma concentrations was observed (p 0.05). CONCLUSIONS—These findings pointed out the presence of a hypercoagulable state associated with endothelial dysfunction in patients with insulin dependent diabetes mellitus (IDDM), demonstrated both by increased FVII:c and F1+2 plasma levels. Moreover, the observation of different DR related degrees of procoagulant activity, despite comparable DD and MC, strengthens the hypothesis of multiple risk factors in the pathogenesis of DR.

Our aim was to investigate the relationships between the degree of IGF2 methylation and the metabolic status in obese children and adolescents.Eighty-five obese subjects aged 11.6 ± 2.1 years were studied. Anthropometry, metabolic parameters, blood pressure and body composition were assessed. DNA methylation analysis was performed by restriction enzyme digestion assay. The study population was subdivided into two groups according to the percentage of IGF2 cytidine-guanosine (CpG) island methylation.Twenty-two subjects showed intermediate methylation (a percentage of CpG site methylation comprised between 10 and 60%), 56 were hypomethylated (percentage of methylation lower than 10%), and only 1 showed a high rate of hypermethylation (percentage of methylation above 60%). Children with intermediate methylation showed significantly higher levels of triglycerides (107.6 ± 41.99 vs. 76.6 ± 30.18 mg/dl, p0.005) and a higher triglyceride/high-density lipoprotein-cholesterol ratio (2.23 ± 0.98 vs. 1.79 ± 0.98, p0.02) compared with hypomethylated children.These preliminary findings show for the first time a relationship between IGF2 methylation pattern and lipid profile in obese children. Although the correlation does not imply causation, if our findings are confirmed in further studies, IGF2 methylation might represent an epigenetic marker of metabolic risk.

Background/Aims: Elevated thyroid-stimulating hormone (TSH) concentrations in association with normal/slightly elevated free triiodothyronine (fT3) and/or free thyroxine (fT4) have been consistently found in obese children. To examine relationships between adiposity, insulin sensitivity, and TSH, fT3 and fT4. Methods: 240 overweight/obese prepubertal children were studied. Fasting TSH, fT3, fT4, glucose, insulin, C-peptide, lipids, leptin and adiponectin were evaluated. Insulin sensitivity and resistance were estimated [quantitative insulin check index (QUICKI), insulin sensitivity index (ISI), and hepatic insulin resistance index]. Body fat was measured by dual-energy X-ray absorptiometry. The central obesity index was calculated as the ratio of fat tissue in the trunk region to fat tissue in the leg region. Results: The multiple regression analysis with age, gender and measures of fatness as covariates showed that QUICKI was the only significant negative predictor of TSH and central obesity index the strongest positive predictor of fT3, in association with either age or hepatic insulin resistance index, and that the only positive determinant of fT4 was hepatic insulin resistance index. Conclusions: Reduced insulin sensitivity is associated with augmented TSH and fT4, while progressive central fat accumulation is strictly related to a parallel increase in fT3 levels, independently from total body fat. Further studies are needed to understand mechanisms linking thyroid function to insulin sensitivity and body composition in obese children.

Adults with normal glucose tolerance (NGT) but exaggerated plasma glucose excursion at 1 h (1HPG) following the oral glucose tolerance test (OGTT) have significantly higher risk of developing impaired glucose tolerance (IGT) or diabetes. Aim of the study will be to characterize the metabolic phenotype of NGT obese youth according to values of 1HPG. To accomplish this aim, obese patients (N = 1,454; 761 men; 79 IGT; BMI z-score 2.56 ± 0.16 SDS; age 11 ± 0.7 years) from two data sets were analyzed. In all patients, empirical parameters of insulin metabolism were calculated in fasting condition and following an OGTT (1.75 mg of glucose per kilogram/ body weight). Receiver-operating characteristic (ROC) analysis was performed in the first group (training set, N = 920) to establish the cutoff value of 1HPG best identifying IGT. The second set (validation set, N = 534) served to verify the goodness of the model and the identified cutoff values. 1HPG ≥ 132.5 mg/dl identified IGT with 80.8% sensitivity and 74.3% specificity in the training set (AUC 0.855, 95% CI 0.808-0.902, P

Brufani C, Fintini D, Nobili V, Patera PI, Cappa M, Brufani M. Use of metformin in pediatric age.

Objective: Epidemiological studies have shown an association between birth weight and future risk of type 2 diabetes, with individuals born either small or large for gestational age at increased risk. We sought to investigate the influence of birth weight on the relation between insulin sensitivity and β-cell function in obese children. Subjects and Methods: A total of 257 obese/overweight children (mean body mass index-sd score, 2.2 ± 0.3), aged 11.6 ± 2.3 yr were divided into three groups according to birth weight percentile: 44 were small for gestational age (SGA), 161 were appropriate for gestational age (AGA), and 52 were large for gestational age (LGA). Participants underwent a 3-h oral glucose tolerance test with glucose, insulin, and C-peptide measurements. Homeostasis model of assessment for insulin resistance, insulinogenic index, and disposition index were calculated to evaluate insulin sensitivity and β-cell function. Glucose and insulin area under the curve (AUC) were also considered. One-way ANOVA was used to compare the three groups. Results: SGA and LGA subjects had higher homeostasis model of assessment for insulin resistance than AGA subjects, but they diverged when oral glucose tolerance test response was considered. Indeed, SGA subjects showed higher glucose AUC and lower insulinogenic and disposition indexes. Insulin AUC was not different between groups, but when singular time points were considered, SGA subjects had lower insulin levels at 30 min and higher insulin levels at 180 min. Conclusions: SGA obese children fail to adequately compensate for their reduced insulin sensitivity, manifesting deficit in early insulin response and reduced disposition index that results in higher glucose AUC. Thus, SGA obese children show adverse metabolic outcomes compared to AGAs and LGAs. Small for gestational age obese children manifest a deficit in the early insulin response that results in a higher glucose area under the curve.

Aim: To evaluate if insulin resistance (IR) and metabolic syndrome (MS) were associated with poor cardiovascular fitness in very obese prepubertal Italian subjects. Methods: Children referred to the Endocrinology and Diabetes Unit of Bambino Gesù Children’s Hospital underwent an OGTT with glucose and insulin assays. QUICKI, ISI and HOMA-IR were calculated. Total and HDL cholesterol, triglycerides and percentage of body fat (DEXA) were determined. Cardiovascular fitness (maximal treadmill time) was evaluated using a treadmill protocol. The MS was defined as having 3 or more of following risk factors: obesity, impaired glucose tolerance, high blood pressure, low HDL-cholesterol, high triglycerides. Results: Fifty-five very obese prepubertal Italian children were enrolled in the study. Unadjusted correlation revealed maximal treadmill time negatively related to fasting insulin (r = –0.53, p < 0.0001) and HOMA-IR (r = –0.57, p < 0.0001) and positively to QUICKI (r = 0.51, p < 0.0001) and ISI (r = 0.46, p = 0.0035). These relationships remained significant when in multivariate analysis age, gender, BMI SD and body composition were accounted for (all p < 0.01). The presence of the MS was independently associated with maximal treadmill time. Conclusion:Poorcardiovascular fitness, IR and MS were independently related, suggesting that the relationship between fitness and insulin action develops early in life.

To compare clinical and ultrasound (US) changes induced in cold thyroid nodules by US-guided percutaneous laser ablation (PLA) versus follow-up or levothyroxine (LT4) suppressive therapy.62 patients randomly assigned to a single PLA (Group 1), LT4 (Group 2), or follow-up (Group 3). Entry criteria: euthyroid patients with a solid thyroid nodule5 mL and benign cytological findings.Group 1: PLA was performed with a 1.064 mum neodymium yttrium-aluminum-garnet laser with output power of 3 W for 10 minutes; Group 2: the LT4 dose was adjusted to induce thyrotropin suppression; Group 3: no treatment.In Group 1 a significant nodule reduction was found 6 and 12 months after PLA (delta volume: -42.7 +/- 13.6%; p = 0.001). A reduction50% was found in 33.3% of cases. In Group 2 a nonsignificant nodule shrinkage was observed. A nonsignificant volume increase was observed in Group 3. Improvement of local symptoms was registered in 81.2% of patients in Group 1 vs. 13.3% in Group 2 and 0.0% in Group 3 ( p = 0.001). No complications were noted.A single PLA induced significant volume reduction and improvement of local symptoms. PLA was more effective than LT4. Follow-up was associated with nodule growth and progression of local symptoms. PLA should be considered a potential mini-invasive alternative to surgery in symptomatic patients with benign cold thyroid nodules.

Acute exercise is a well-known stimulus for GH secretion but the effect of chronic training on GH secretion still remains equivocal. The aim of our study was to analyse spontaneous pulsatile GH secretion (during a period of 2 hours in the morning) in a group of young elite athletes (EA) compared with non-elite athletes (NEA), and sedentary subjects (SS). Mean and peak GH levels proved significantly higher in EA than in NEA and SS (p=0.0004 and p