Studies in children with obesity in two European treatment centres show a high prevalence of impaired glucose metabolism in the Swedish cohort.

AIM: To investigate the prevalence and possible risk factors for the development of impaired glucose metabolism in children and adolescents with obesity. METHODS: This was a cross-sectional retrospective cohort study, including 634 patients with obesity and 98 normal weight controls aged 4-18 years from the Beta-cell function in Juvenile Diabetes and Obesity (Beta-JUDO) cohort, a dual-centre study at Uppsala University Hospital (Sweden) and Paracelsus Medical University Hospital (Salzburg, Austria) conducted between 2012 and 2021. A longitudinal subgroup analysis, including 188 of these subjects was performed. Impaired glucose metabolism was diagnosed by oral glucose tolerance tests according to American Diabetes Association criteria. RESULTS: The prevalence of impaired glucose metabolism was 72% in Uppsala patients, 24% in Salzburg patients, 30% in Uppsala controls and 13% in Salzburg controls. The prevalence was lower at the follow-up visits compared with baseline both in Uppsala and Salzburg patients. A family history of type 2 diabetes showed the strongest association with impaired glucose metabolism at the follow-up visits besides belonging to the Uppsala cohort. CONCLUSION: The prevalence of impaired glucose metabolism was extraordinarily high in Swedish children and adolescents with obesity, but decreased during the follow-up period.

Adolescents with obesity treated with exenatide maintain endogenous GLP-1, reduce DPP-4, and improve glycemic control.

Background: GLP-1 receptor agonists (GLP-1RA) are increasingly used to treat adolescent obesity. However, the effect on endogenous GLP-1 secretory patterns following treatment in adolescents is unknown. The GLP-1RA exenatide was shown to significantly lower BMI and 2-hour glucose in adolescents with obesity, in the placebo-controlled, randomized controlled trial Combat-JUDO. The aim of this study was to evaluate effects of weekly injections of 2 mg exenatide extended release on secretory patterns of endogenous hormones during OGTT. Subjects and Measurements: This study was a pre-planned sub-study of the Combat-JUDO trial, set at the Pediatric clinic at Uppsala University Hospital, Sweden and Paracelsus Medical University, Austria. 44 adolescents with obesity were included and randomized 1:1 to treatment:placebo. 19 patients in the treatment group and 18 in the placebo group completed the trial. Before and after treatment, GLP-1, glucose, insulin, glucagon and glicentin levels were measured during OGTT; DPP-4 and proinsulin were measured at fasting. A per-protocol approach was used in the analyses. Results: Exenatide treatment did not affect GLP-1 levels during OGTT. Treatment significantly lowered DPP-4, proinsulin and the proinsulin-to-insulin ratio at fasting, increased glicentin levels but did not affect insulin, C-peptide or glucagon levels during OGTT. Conclusion: Weekly s.c. injections with 2 mg of exenatide maintains endogenous total GLP-1 levels and lowers circulating DPP-4 levels. This adds an argument in favor of using exenatide in the treatment of pediatric obesity. Clinical trial registration: clinicaltrials.gov, identifier NCT02794402.

Screening for Inflammatory Markers Identifies IL-18Rα as a Potential Link between Exenatide and Its Anti-Inflammatory Effect: New Results from the Combat-JUDO Randomized Controlled Trial.

INTRODUCTION: Obesity is associated with chronic inflammation. Chronic inflammation has also been linked to insulin resistance and type 2 diabetes, metabolic associated fatty liver disease, and cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor analogs (GLP-1RA) are clinically used to treat obesity, with known anti-inflammatory properties. How the GLP-1RA exenatide effects inflammation in adolescents with obesity is not fully investigated. METHODS: Forty-four patients were randomized to receive weekly subcutaneous injections with either 2 mg exenatide or placebo for 6 months. Plasma samples were collected at baseline and at the end of the study, and 92 inflammatory proteins were measured. RESULTS: Following treatment with exenatide, 15 out of the 92 proteins were decreased, and one was increased. However, after adjustment for multiple testing, only IL-18Rα was significantly lowered following treatment. CONCLUSIONS: Weekly injections with 2 mg of exenatide lowers circulating IL-18Rα in adolescents with obesity, which may be a potential link between exenatide and its anti-inflammatory effect in vivo. This contributes to exenatide's pharmaceutical potential as a treatment for obesity beyond weight control and glucose tolerance, and should be further studied mechanistically.

Short-term effects of canagliflozin on glucose and insulin responses in insulin dysregulated horses: A randomized, placebo-controlled, double-blind, study.

BACKGROUND: Decreasing hyperinsulinemia is crucial in preventing laminitis in insulin dysregulated (ID) horses. Complementary pharmacological treatments that efficiently decrease postprandial hyperinsulinemia in ID horses are needed. OBJECTIVES: Compare short-term effects of canagliflozin vs placebo on glucose and insulin responses to an oral sugar test (OST) as well as the effects on body weight and triglyceride concentrations in horses with ID. ANIMALS: Sixteen privately-owned ID horses. METHODS: A single-center, randomized, double-blind, placebo-controlled, parallel design study. The horses were randomized (ratio 1:1) to either once daily PO treatment with 0.6 mg/kg canagliflozin or placebo. The study consisted of an initial 3-day period for obtaining baseline data, a 3-week double-blind treatment period at home, and a 3-day follow-up period similar to the initial baseline period but with continued double-blind treatment. Horses were subjected to an 8-sample OST in the morning of the third day on both visits. RESULTS: Maximal geometric least square (LS) mean insulin concentration (95% confidence interval [CI]) during the OST decreased after 3 weeks of canagliflozin treatment compared with placebo (83.2; 55.4-125.0 vs 215.2; 143.2-323.2 µIU/mL). The geometric LS mean insulin response (insulin AUC0-180 ) for canagliflozin-treated horses was >66% lower compared with placebo. Least square mean body weight decreased by 11.1 (4-18.1) kg and LS mean triglyceride concentrations increased by 0.99 (0.47-1.5) mmol/L with canagliflozin treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Canagliflozin is a promising drug for treatment of ID horses that requires future studies.

Metformin restores prohormone processing enzymes and normalizes aberrations in secretion of proinsulin and insulin in palmitate-exposed human islets.

AIM: To elucidate how proinsulin synthesis and insulin was affected by metformin under conditions of nutrient overstimulation. MATERIALS AND METHODS: Isolated human pancreatic islets from seven donors were cultured at 5.5 mmol/L glucose and 0.5 mmol/L palmitate for 12, 24 or 72 h. Metformin (25 µmol/L) was introduced after initial 12 h with palmitate. Proinsulin and insulin were measured. Expression of prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE), was determined by western blot. Adolescents with obesity, treated with metformin and with normal glucose tolerance (n = 5), prediabetes (n = 14), or type 2 diabetes (T2DM; n = 7) were included. Fasting proinsulin, insulin, glucose, 2-h glucose and glycated haemoglobin were measured. Proinsulin/insulin ratio (PI/I) was calculated. RESULTS: In human islets, palmitate treatment for 12 and 24 h increased proinsulin and insulin proportionally. After 72 h, proinsulin but not insulin continued to increase which was coupled with reduced expression of PC1/3 and CPE. Metformin normalized expression of PC1/3 and CPE, and proinsulin and insulin secretion. In adolescents with obesity, before treatment, fasting proinsulin and insulin concentrations were higher in subjects with T2DM than with normal glucose tolerance. PI/I was reduced after metformin treatment in subjects with T2DM as well as in subjects with prediabetes, coupled with reduced 2-h glucose and glycated haemoglobin. CONCLUSIONS: Metformin normalized proinsulin and insulin secretion after prolonged nutrient-overstimulation, coupled with normalization of the converting enzymes, in isolated islets. In adolescents with obesity, metformin treatment was associated with improved PI/I, which was coupled with improved glycaemic control.

Metformin Can Attenuate Beta-Cell Hypersecretion-Implications for Treatment of Children with Obesity.

In children with obesity, insulin hypersecretion is proposed to precede insulin resistance. We investigated if metformin could be used to attenuate insulin secretion from palmitate-treated isolated islets and its implication for children with obesity. Human islets were exposed to palmitate for 0.5 or 1 day, when metformin was introduced. After culture, glucose-stimulated insulin secretion (GSIS) was measured. Children with obesity, who had received metformin for over six months (n = 21, age 13.9 ± 1.8), were retrospectively evaluated. Children were classified as either "reducing" or "increasing" based on the difference between AUC0-120 of insulin during OGTT before and after metformin treatment. In human islets, GSIS increased after culture in palmitate for up to 1 day but declined with continued palmitate exposure. Whereas adding metformin after 1 day of palmitate exposure increased GSIS, adding metformin after 0.5 days reduced GSIS. In children with "reducing" insulin AUC0-120 (n = 9), 2 h glucose and triglycerides decreased after metformin treatment, which was not observed in patients with "increasing" insulin AUC0-120 (n = 12). In isolated islets, metformin attenuated insulin hypersecretion if introduced when islet secretory capacity was maintained. In children with obesity, improved glycemic and lipid levels were accompanied by reduced insulin levels during OGTT after metformin treatment.

Effects of a novel weight-loss combination product containing orlistat and acarbose on obesity: A randomized, placebo-controlled trial.

OBJECTIVE: The aim of this study was to evaluate the effect of a novel, oral, modified-release formulation of the lipase inhibitor orlistat and the glucosidase/amylase inhibitor acarbose (denoted EMP16) on relative body weight after 26 weeks compared with placebo. METHODS: The randomized, double-blind, placebo-controlled trial had a 26-week treatment period, with dose escalation up to 6 weeks. Participants, adults between ages 18 and 75 years, with BMI ≥30 kg/m2 or ≥28 kg/m2 with risk factors, were randomly assigned to EMP16 120-mg orlistat/40-mg acarbose (EMP16-120/40), EMP16-150/50, or placebo. The primary end point was relative weight loss from baseline to week 26 assessed in participants with at least one post-baseline weight measurement. RESULTS: Of 156 randomized participants, 149 constituted the intention-to-treat population. The mean (95% CI) estimated treatment difference to placebo in relative weight loss after 26 weeks in the intention-to-treat population was -4.70% (-6.16% to -3.24%; p < 0.0001) with EMP16-120/40 and -5.42% (-6.60% to -4.24%; p < 0.0001) with EMP16-150/50. CONCLUSIONS: This trial indicates that orlistat and acarbose can be successfully combined in a modified-release formulation to provide efficacious weight loss with no unexpected safety issues. EMP16 may be a promising candidate among other medications for improved weight management.

Determinants of hyperglucagonemia in pediatric non-alcoholic fatty liver disease.

Objective: Over the years, non-alcoholic fatty liver (NAFLD) disease has progressed to become the most frequent chronic liver disease in children and adolescents. The full pathology is not yet known, but disease progression leads to cirrhosis and hepatocellular carcinoma. Risk factors included hypercaloric diet, obesity, insulin resistance and genetics. Hyperglucagonemia appears to be a pathophysiological consequence of hepatic steatosis, thus, the hypothesis of the study is that hepatic fat accumulation leads to increased insulin resistance and impaired glucagon metabolism leading to hyperglucagonemia in pediatric NAFLD. Methods: 132 children and adolescents between 10 and 18 years, with varying degrees of obesity, were included in the study. Using Magnetic Resonance Imaging (MRI) average liver fat was determined, and patients were stratified as NAFLD (>5% liver fat content) and non-NAFLD (<5%). All patients underwent a standardized oral glucose tolerance test (OGTT). Additionally, anthropometric parameters (height, weight, BMI, waist circumference, hip circumference) such as lab data including lipid profile (triglycerides, HDL, LDL), liver function parameters (ALT, AST), uric acid, glucose metabolism (fasting insulin and glucagon, HbA1c, glucose 120 min) and indices evaluating insulin resistance (HIRI, SPISE, HOMA-IR, WBISI) were measured. Results: Children and adolescents with NAFLD had significantly higher fasting glucagon values compared to the non-NAFLD cohort (p=0.0079). In the NAFLD cohort univariate analysis of fasting glucagon was associated with BMI-SDS (p<0.01), visceral adipose tissue volume (VAT) (p<0.001), average liver fat content (p<0.001), fasting insulin concentration (p<0.001), triglycerides (p<0.001) and HDL (p=0.034). This correlation equally applied to all insulin indices HOMA-IR, WBISI, HIRI (all p<0.001) and SPISE (p<0.002). Multivariate analysis (R² adjusted 0.509) for the same subgroup identified HIRI (p=0.003) and VAT volume (p=0.017) as the best predictors for hyperglucagonemia. Average liver fat content is predictive in pediatric overweight and obesity but not NAFLD. Conclusions: Children and adolescents with NAFLD have significantly higher fasting plasma glucagon values, which were best predicted by hepatic insulin resistance and visceral adipose tissue, but not average liver fat content.

Obesity in adolescents associated with vascular aging - a study using ultra-high-resolution ultrasound.

Background: Obesity in adolescents is increasing worldwide and associated with an elevated cardiovascular risk later in life. In a group-comparative study, we investigated the association between adiposity in adolescents and signs of vascular aging and inflammation. Methods: Thirty-nine adolescents (10-18 years old), 19 with obesity and 20 with normal weight, were enrolled. The intima thickness and intima/media thickness ratio (I/M) were assessed using high-resolution ultrasound in the common carotid artery (center frequency 22 MHz) and the distal radial artery (RA; 50 MHz). Increased intima and high I/M are signs of vascular aging. Body characteristics, high-sensitivity C-reactive protein (hs-CRP), plasma lipids, and glycemic parameters were measured. Results: Adolescents with obesity, compared to normal-weight peers, had elevated plasma lipid, insulin c-peptide, and hs-CRP levels, the latter increasing exponentially with increasing adiposity. Obese adolescents had a thicker RA intima layer [0.005 mm; 95% confidence intervals (0.000, 0.009); P = 0.043] and a higher RA I/M [0.10; (0.040, 0.147); P < 0.0007]. Group differences for the RA I/M remained significant after adjustment for age, sex, fasting plasma insulin, and body mass index, both separately and together (P = 0.032). The RA I/M was correlated with hs-CRP, and both were correlated with the analyzed cardiovascular risk factors. Receiver operating curve c-values for RA I/M (0.86) and hs-CRP (0.90) strongly indicated correct placement in the obese or non-obese group. Conclusions: Adolescents with obesity had significantly more extensive vascular aging in the muscular RA, than normal-weight peers. The findings support an inflammatory link between obesity and vascular aging in adolescents.

Association between alanine aminotransferase as surrogate of fatty liver disease and physical activity and sedentary time in adolescents with obesity.

To compare patterns of sedentary (SED) time (more sedentary, SED + vs less sedentary, SED-), moderate to vigorous physical activity (MVPA) time (more active, MVPA + vs less active, MVPA-), and combinations of behaviors (SED-/MVPA + , SED-/MVPA-, SED + /MVPA + , SED + /MVPA-) regarding nonalcoholic fatty liver diseases (NAFLD) markers. This cross-sectional study included 134 subjects (13.4 ± 2.2 years, body mass index (BMI) 98.9 ± 0.7 percentile, 48.5% females) who underwent 24-h/7-day accelerometry, anthropometric, and biochemical markers (alanine aminotransferase (ALT) as first criterion, and aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), AST/ALT ratio as secondary criteria). A subgroup of 39 patients underwent magnetic resonance imaging-liver fat content (MRI-LFC). Hepatic health was better in SED- (lower ALT, GGT, and MRI-LFC (p < 0.05), higher AST/ALT (p < 0.01)) vs SED + and in MVPA + (lower ALT (p < 0.05), higher AST/ALT (p < 0.01)) vs MVPA- groups after adjustment for age, gender, and Tanner stages. SED-/MVPA + group had the best hepatic health. SED-/MVPA- group had lower ALT and GGT and higher AST/ALT (p < 0.05) in comparison with SED + /MVPA + group independently of BMI. SED time was positively associated with biochemical (high ALT, low AST/ALT ratio) and imaging (high MRI-LFC) markers independently of MVPA. MVPA time was associated with biochemical markers (low ALT, high AST/ALT) but these associations were no longer significant after adjustment for SED time. CONCLUSION: Lower SED time is associated with better hepatic health independently of MVPA. Reducing SED time might be a first step in the management of pediatric obesity NAFLD when increasing MVPA is not possible. WHAT IS KNOWN: • MVPA and SED times are associated with cardiometabolic risks in youths with obesity. • The relationships between NAFLD markers and concomitant MVPA and SED times have not been studied in this population. WHAT IS NEW: • Low SED time is associated with healthier liver enzyme profiles and LFC independent of MVPA. • While low SED/high MVPA is the more desirable pattern, low SED/low MVPA pattern would have healthier liver enzyme profile compared with high MVPA/high SED, independent of BMI, suggesting that reducing SED time irrespective of MVPA is needed to optimize liver health.

Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients.

PURPOSE: the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival. METHODS: All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March-September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure. RESULTS: A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5-34.4) and 4.2 (1.1-15.7), respectively. CONCLUSION: In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality.

There Is a Clinical Need to Consider the Physical Activity: Sedentary Pattern in Children with Obesity - Position Paper of the European Childhood Obesity Group.

INTRODUCTION: While international prevention guidelines recently advocated, in addition to moderate and vigorous physical activity (MVPA) guidelines, for a minimization of sedentary (SED) time, recommendations remain to be developed for youths with obesity. METHODS: A literature search was conducted in PubMed, the Cochrane Library, plus the reference lists of selected articles for relevant publications in English, including original papers, systematic reviews, and meta-analyses, with search terms "sedentary behaviors" or "sedentary time" or "screen time" AND "children" or "adolescents" AND "obesity" or "adiposity" or "cardiometabolic risk" or "cardiometabolic disease." The results were summarized as a narrative review and presented to the scientific board of the European Childhood Obesity Group (ECOG), who then discussed their implication in clinical practice and proposed the position outlined in this paper. RESULTS: SED and screen times are associated with adiposity and cardiometabolic risks, independently of youths' physical activity (PA) level. Besides considering MVPA and SED times as separate variables, comprehensive studies have questioned the impact of different patterns of MVPA and SED levels. Although lower body adiposity and better cardiometabolic health are achieved among those with desirable movement behavior patterns (i.e., more MVPA/less SED or active/not SED), youths with intermediate patterns (i.e., high MVPA/high SED and low MVPA/low SED, or active/SED and inactive/not SED) have been found to be associated with intermediate risks. CONCLUSION: There is a need to decrease SED behaviors irrespective of MVPA and to consider PA-SED patterns in youth with obesity. The ECOG encourages anti-obesity strategies targeting both PA and SED behaviors to support the shift from long periods of SED time, especially screen time, to daily routines incorporating bouts of PA. Stepwise or sequential approaches to movement behavior counseling might start with targeting SED at first to decrease cardiometabolic risks when implementing MVPA is not yet possible.

Single Point Insulin Sensitivity Estimator in Pediatric Non-Alcoholic Fatty Liver Disease.

Background: Attenuated insulin-sensitivity (IS) is a central feature of pediatric non-alcoholic fatty liver disease (NAFLD). We recently developed a new index, single point insulin sensitivity estimator (SPISE), based on triglycerides, high-density-lipoprotein and body-mass-index (BMI), and validated by euglycemic-hyperinsulinemic clamp-test (EHCT) in adolescents. This study aims to assess the performance of SPISE as an estimation of hepatic insulin (in-)sensitivity. Our results introduce SPISE as a novel and inexpensive index of hepatic insulin resistance, superior to established indices in children and adolescents with obesity. Materials and Methods: Ninety-nine pubertal subjects with obesity (13.5 ± 2.0 years, 59.6% males, overall mean BMI-SDS + 2.8 ± 0.6) were stratified by MRI (magnetic resonance imaging) into a NAFLD (>5% liver-fat-content; male n=41, female n=16) and non-NAFLD (≤5%; male n=18, female n=24) group. Obesity was defined according to WHO criteria (> 2 BMI-SDS). EHCT were used to determine IS in a subgroup (n=17). Receiver-operating-characteristic (ROC)-curve was performed for diagnostic ability of SPISE, HOMA-IR (homeostatic model assessment for insulin resistance), and HIRI (hepatic insulin resistance index), assuming null hypothesis of no difference in area-under-the-curve (AUC) at 0.5. Results: SPISE was lower in NAFLD (male: 4.8 ± 1.2, female: 4.5 ± 1.1) than in non-NAFLD group (male 6.0 ± 1.6, female 5.6 ± 1.5; P< 0.05 {95% confidence interval [CI]: male NAFLD 4.5, 5.2; male non-NAFLD 5.2, 6.8; female NAFLD 4.0, 5.1, female non-NAFLD 5.0, 6.2}). In males, ROC-AUC was 0.71 for SPISE (P=0.006, 95% CI: 0.54, 0.87), 0.68 for HOMA-IR (P=0.038, 95% CI: 0.48, 0.88), and 0.50 for HIRI (P=0.543, 95% CI: 0.27, 0.74). In females, ROC-AUC was 0.74 for SPISE (P=0.006), 0.59 for HOMA-IR (P=0.214), and 0.68 for HIRI (P=0.072). The optimal cutoff-level for SPISE between NAFLD and non-NAFLD patients was 5.18 overall (Youden-index: 0.35; sensitivity 0.68%, specificity 0.67%). Conclusion: SPISE is significantly lower in juvenile patients with obesity-associated NAFLD. Our results suggest that SPISE indicates hepatic IR in pediatric NAFLD patients with sensitivity and specificity superior to established indices of hepatic IR.

High levels of FSH before puberty are associated with increased risk of metabolic syndrome during pubertal transition.

BACKGROUND: During perimenopause, the rise in serum follicle-stimulating hormone (FSH) is associated with increased adiposity, insulin resistance (IR), and metabolic syndrome (MetS). However, data for the pubertal period, which is characterized by increasing FSH levels and changing body composition, are limited. OBJECTIVES: To investigate the relationships between FSH and anthropometric changes, IR markers, and development of MetS in the peripubertal period. METHODS: Uppsala Longitudinal Study of Childhood Obesity (ULSCO) is an ongoing study that aims to understand the factors contributing to childhood obesity and the development of obesity-related diseases. We analysed the subset of participants who were prepubertal at the first visit (n = 95, 77 with obesity). Mean follow-up time was 3.0 ± 1.4 years. RESULTS: Higher serum FSH levels at the first visit were associated with an increased likelihood of elevation in body mass index (BMI SDS) (p = 0.025, OR = 16.10) and having MetS (p = 0.044, OR = 4.67) at the follow-up. We observed nonlinear relationships between varying serum FSH levels and markers of adiposity and IR, especially in girls. At the first visit, when girls were prepubertal, FSH was negatively associated with BMI (ß = -0.491, p = 0.005) and positively associated with sex hormone-binding globulin (SHBG) (ß = 0.625, p = 0.002). With the progression of puberty, negative associations between BMI and SHBG disappeared while FSH became positively associated with HOMA-IR (ß = 0.678, p = 0.025) and fasting insulin (ß = 0.668, p = 0.027). CONCLUSIONS: Higher serum FSH levels in prepubertal children were associated with an increased risk of MetS development during pubertal transition. Along with nonlinear associations between varying serum FSH levels and IR markers, our results might imply a relationship between FSH and IR of puberty.

Sedentary time has a stronger impact on metabolic health than moderate to vigorous physical activity in adolescents with obesity: a cross-sectional analysis of the Beta-JUDO study.

BACKGROUND: Relationships between movement-related behaviours and metabolic health remain underexplored in adolescents with obesity. OBJECTIVES: To compare profiles of sedentary time (more sedentary, SED+ vs. less sedentary, SED-), moderate to vigorous physical activity (MVPA) time (more active, MVPA+ vs. less active, MVPA-) and combinations of behaviours (SED-/MVPA+, SED-/MVPA-, SED+/MVPA+, SED+/MVPA-) in regard to metabolic health. METHODS: One hundred and thirty-four subjects (mean age 13.4 ± 2.2 yrs, mean body mass index [BMI] 98.9 ± 0.7 percentile, 48.5% females) underwent 24 h/7 day accelerometry, anthropometric, body composition, blood pressure (BP), lipid profile and insulin resistance (IR) assessments. RESULTS: Metabolic health was better in SED- [lower fat mass (FM) percentage (p < 0.05), blood pressure (BP) (p < 0.05), homeostasis model assessment of insulin resistance (HOMA-IR) (p < 0.001) and metabolic syndrome risk score (MetScore) (p < 0.001), higher high-density lipoprotein-cholesterol (HDL-c) (p = 0.001)] vs. SED+ group and in MVPA+ [lower triglyceridemia (TG), (p < 0.05), HOMA-IR (p < 0.01) and MetScore (p < 0.001), higher HDL-c (p < 0.01)] vs. MVPA- group after adjustment with age, gender, maturation and BMI. SED-/MVPA+ group had the best metabolic health. While sedentary (p < 0.001) but also MVPA times (p < 0.001) were lower in SED-/MVPA- vs. SED+/MVPA+, SED-/MVPA- had lower FM percentage (p < 0.05), HOMA-IR (p < 0.01) and MetScore (p < 0.05) and higher HDL-c (p < 0.05), independently of BMI. Sedentary time was positively correlated with HOMA-IR and Metscore and negatively correlated with HDL-c after adjustment with MVPA (p < 0.05). MVPA was negatively correlated with HOMA-IR, BP and MetScore and positively correlated with HDL-c after adjustment with sedentary time (p < 0.05). CONCLUSION: Lower sedentary time is associated with a better metabolic health independently of MVPA and might be a first step in the management of pediatric obesity when increasing MVPA is not possible.

Deviating glucose results in an international dual-center study. A root cause investigation.

During a dual-center study on obese and normal weight children and adolescents, focusing on glucose metabolism, we observed a marked difference in glucose results (N = 16,840) between the two sites, Salzburg, Austria and Uppsala, Sweden (P < 0.001). After excluding differences in patient characteristics between the two populations as cause of this finding, we investigated other preanalytic influences. Finally, only the tubes used for blood collection at the two sites were left to evaluate. While the Vacuette FC-Mix tube (Greiner Bio-One, Kremsmünster, Austria) was used in Uppsala, in Salzburg blood collections were performed with a lithium heparin tube (LH-Monovette, Sarstedt, Germany). To prove our hypothesis, we collected two blood samples in either of these tubes from 51 children (Salzburg N = 27, Uppsala N = 24) and compared the measured glucose results. Indeed, we found the suspected bias and calculated a correction formula, which significantly diminished the differences of glucose results between the two sites (P = 0.023). Our finding is in line with those of other studies and although this issue should be widely known, we feel that it is widely neglected, especially when comparing glucose concentrations across Europe, using large databases without any information on preanalytic sample handling.

Metabolic Abnormalities in a Cohort of Overweight and Obese Children in an Urban Setting of Sri Lanka.

Childhood obesity-related metabolic derangements are increasing among South Asian populations. Most of these changes persist to adulthood. This study aims to describe the distribution of metabolic abnormalities among 7- to 17-year-old overweight and obese children in the Gampaha District of Sri Lanka. Overweight children (age- and gender-adapted BMI>+1SD, WHO standards) were selected from a community survey carried out in the Negombo Education Zone of Gampaha District. After a 12-hour overnight fast, blood was drawn, and blood glucose (FBG), lipid profile, insulin, and liver transaminases were measured. Two hours after a glucose load, blood was drawn for random blood glucose (RBG) and insulin. Metabolic syndrome (MetS) was diagnosed using modified IDF criteria for children. Anthropometry, fat mass (FM), and blood pressure were measured. Hepatic fat pattern was assessed ultrasonically. The data of 403 children (210 boys) were analysed. Of the study population, 16.4% were overweight (BMI for age +1 to +2SD), 72% were obese (BMI for age >+2 to +3SD), and 11.6% were severely obese (BMI for age >+3SD). Insulin resistance was seen in 46.8%, and prevalence increased with age. Mean postprandial insulin ranged from 368 to 625 pmol/L and was elevated in 35%. Dysglycaemia was seen among 20.8%. MetS was present in 19.8%, and 84% had at least one metabolic abnormality. Different degrees of hepatic steatosis were observed in 32.5%, and elevated ALT/AST ratio was seen in 58% of the population. Overweight and obesity during childhood were associated with multiple metabolic abnormalities including MetS, and they occur from a young age. It is important to screen children for overweight/obesity early in life and intervene to prevent them from developing metabolic complications.

Safety of a Novel Weight Loss Combination Product Containing Orlistat and Acarbose.

The safety of a novel modified-release oral capsule with orlistat and acarbose (MR-OA) was investigated in 67 obese middle-aged White men with a body mass index of 32 to 40 kg/m2 or 30 to 32 kg/m2 plus waist circumference >102 cm. The purpose of this investigation was to compare MR-OA with the existing conventional orlistat regarding systemic safety defined as plasma orlistat concentration at the end of the treatment period of 14 days. Participants took the MR-OA fixed-dose combination formulation 3 times a day together with a major meal. Three different doses of MR-OA were evaluated-60/20, 90/30, and 120/40 (mg orlistat/mg acarbose)-as well as 1 reference group who received the conventional orlistat, Xenical, with 120 mg of orlistat. Blood plasma was sampled on days 1 and 14. The orlistat plasma concentrations of the MR-OA dose showed a delayed absorption and were lower compared with conventional orlistat at the end of the study. All doses were safe and well tolerated without any unexpected adverse events and no serious adverse events. The delay in the rise of orlistat plasma concentration indicates that the modified-release properties of the MR-OA formulation are effective. The systemic exposure of orlistat resulting from MR-OA was similar, albeit a bit lower than the conventional orlistat with 120 mg of orlistat. We can therefore assume that the safety profile regarding the orlistat moiety of MR-OA is comparable to the conventional orlistat and a promising approach for weight control in obese patients. Further clinical evaluation is underway.

Evaluation of fasting plasma insulin and proxy measurements to assess insulin sensitivity in horses.

BACKGROUND: Proxies are mathematical calculations based on fasting glucose and/or insulin concentrations developed to allow prediction of insulin sensitivity (IS) and ß-cell response. These proxies have not been evaluated in horses with insulin dysregulation. The first objective of this study was to evaluate how fasting insulin (FI) and proxies for IS (1/Insulin, reciprocal of the square root of insulin (RISQI) and the quantitative insulin sensitivity check index (QUICKI)) and ß-cell response (the modified insulin-to-glucose ratio (MIRG) and the homeostatic model assessment of ß-cell function (HOMA-ß)) were correlated to measures of IS (M index) using the euglycemic hyperinsulinemic clamp (EHC) in horses with insulin resistance (IR) and normal IS. A second objective was to evaluate the repeatability of FI and proxies in horses based on sampling on consecutive days. The last objective was to investigate the most appropriate cut-off value for the proxies and FI. RESULTS: Thirty-four horses were categorized as IR and 26 as IS based on the M index. The proxies and FI had coefficients of variation (CVs) ≤ 25.3 % and very good reliability (intraclass correlation coefficients ≥ 0.89). All proxies and FI were good predictors of the M index (r = 0.76-0.85; P < 0.001). The proxies for IS had a positive linear relationship with the M index whereas proxies for ß-cell response and FI had an inverse relationship with the M index. Cut-off values to distinguish horses with IR from horses with normal IS based on the M index were established for all proxies and FI using receiver operating characteristic curves, with sensitivity between 79 % and 91 % and specificity between 85 % and 96 %. The cut-off values to predict IR were < 0.32 (RISQI), < 0.33 (QUICKI) and > 9.5 µIU/mL for FI. CONCLUSIONS: All proxies and FI provided repeatable estimates of horses' IS. However, there is no advantage of using proxies instead of FI to estimate IR in the horse. Due to the heteroscedasticity of the data, proxies and FI in general are more suitable for epidemiological studies and larger clinical studies than as a diagnostic tool for measurement of IR in individual horses.

Association between Metabolic Syndrome Diagnosis and the Physical Activity-Sedentary Profile of Adolescents with Obesity: A Complementary Analysis of the Beta-JUDO Study.

Metabolic syndrome (MetS) is highly prevalent in children and adolescents with obesity and places them at an increased risk of cardiovascular-related diseases. However, the associations between objectively measured movement-related behaviors and MetS diagnosis remain unexplored in youths with obesity. The aim was to compare profiles of sedentary (SED) time (more sedentary, SED+ vs. less sedentary, SED-), moderate to vigorous physical activity (MVPA) time (more active, MVPA+ vs. less active, MVPA-) and combinations of behaviors (SED-/MVPA+, SED-/MVPA-, SED+/MVPA+, SED+/MVPA-) regarding the MetS diagnosis. One hundred and thirty-four adolescents with obesity (13.4 ± 2.2 years) underwent 24 h/7 day accelerometry, waist circumference (WC), blood pressure (BP), high-density lipoprotein-cholesterol (HDL-c), triglycerides (TG) and insulin-resistance (IR) assessments. Cumulative cardiometabolic risk was assessed by using (i) MetS status (usual dichotomic definition) and (ii) cardiometabolic risk z-score (MetScore, mean of standardized WC, BP, IR, TG and inverted HDL-c). SED- vs. SED+ and MVPA+ vs. MVPA- had lower MetS (p < 0.01 and p < 0.001) and MetScore (p < 0.001). SED-/MVPA+ had the lowest risk. While SED and MVPA times were lower in SED-/MVPA- vs. SED+/MVPA+ (p < 0.001), MetScore was lower in SED-/MVPA- independently of body mass index (BMI) (p < 0.05). MVPA, but not SED, time was independently associated with MetS diagnosis (p < 0.05). Both MVPA (p < 0.01) and SED times (p < 0.05) were associated with MetScore independently of each other. A higher MVPA and lower SED time are associated with lower cumulative cardiometabolic risk.