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.

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.

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.

The Role of Macronutrients in the Pathogenesis, Prevention and Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) in the Paediatric Population-A Review.

Paediatric non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in childhood. Obesity is the main risk factor. Nutrition and lifestyle are the key elements in preventing and treating NAFLD in the absence of approved drug therapy. Whilst recommendations and studies on macronutrients (carbohydrates, fat and protein) in adult NAFLD exist, the discussion of this topic in paediatric NAFLD remains contradictory. The purpose of this review is to provide state-of-the-art knowledge on the role of macronutrients in paediatric NAFLD regarding quality and quantity. PubMed was searched and original studies and review articles were included in this review. Fructose, sucrose, saturated fatty acids, trans-fatty acids and ω-6-fatty-acids are strongly associated with paediatric NAFLD. High consumption of fibre, diets with a low glycaemic index, mono-unsaturated-fatty-acids and ω-3-fatty-acids reduce the risk of childhood-onset NAFLD. Data regarding the role of dietary protein in NAFLD are contradictory. No single diet is superior in treating paediatric NAFLD, although the composition of macronutrients in the Mediterranean Diet appears beneficial. Moreover, the optimal proportions of total macronutrients in the diet of paediatric NAFLD patients are unknown. Maintaining a eucaloric diet and avoiding saturated fatty acids, simple sugars (mainly fructose) and a high-caloric Western Diet are supported by literature.

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.

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.

The relationship between glucose and the liver-alpha cell axis - A systematic review.

Until recently, glucagon was considered a mere antagonist to insulin, protecting the body from hypoglycemia. This notion changed with the discovery of the liver-alpha cell axis (LACA) as a feedback loop. The LACA describes how glucagon secretion and pancreatic alpha cell proliferation are stimulated by circulating amino acids. Glucagon in turn leads to an upregulation of amino acid metabolism and ureagenesis in the liver. Several increasingly common diseases (e.g., non-alcoholic fatty liver disease, type 2 diabetes, obesity) disrupt this feedback loop. It is important for clinicians and researchers alike to understand the liver-alpha cell axis and the metabolic sequelae of these diseases. While most of previous studies have focused on fasting concentrations of glucagon and amino acids, there is limited knowledge of their dynamics after glucose administration. The authors of this systematic review applied PRISMA guidelines and conducted PubMed searches to provide results of 8078 articles (screened and if relevant, studied in full). This systematic review aims to provide better insight into the LACA and its mediators (amino acids and glucagon), focusing on the relationship between glucose and the LACA in adult and pediatric subjects.

The Role of Protein and Fat Intake on Insulin Therapy in Glycaemic Control of Paediatric Type 1 Diabetes: A Systematic Review and Research Gaps.

Carbohydrate counting (CHC) is the established form of calculating bolus insulin for meals in children with type 1 diabetes (T1DM). With the widespread use of continuous glucose monitoring (CGM) observation time has become gapless. Recently, the impact of fat, protein and not only carbohydrates on prolonged postprandial hyperglycaemia have become more evident to patients and health-care professionals alike. However, there is no unified recommendation on how to calculate and best administer additional bolus insulin for these two macronutrients. The aim of this review is to investigate: the scientific evidence of how dietary fat and protein influence postprandial glucose levels; current recommendations on the adjustment of bolus insulin; and algorithms for insulin application in children with T1DM. A PubMed search for all articles addressing the role of fat and protein in paediatric (sub-)populations (<18 years old) and a mixed age population (paediatric and adult) with T1DM published in the last 10 years was performed. Conclusion: Only a small number of studies with a very low number of participants and high degree of heterogeneity was identified. While all studies concluded that additional bolus insulin for (high) fat and (high) protein is necessary, no consensus on when dietary fat and/or protein should be taken into calculation and no unified algorithm for insulin therapy in this context exists. A prolonged postprandial observation time is necessary to improve individual metabolic control. Further studies focusing on a stratified paediatric population to create a safe and effective algorithm, taking fat and protein into account, are necessary.

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.

Age-Related Deterioration of Mitochondrial Function in the Intestine.

Aging is an important and inevitable biological process in human life, associated with the onset of chronic disease and death. The mechanisms behind aging remain unclear. However, changes in mitochondrial function and structure, including reduced activity of the mitochondrial respiratory chain and increased production of reactive oxygen species-thus oxidative damage-are believed to play a major role. Mitochondria are the main source of cellular energy, producing adenosine triphosphate (ATP) via oxidative phosphorylation. Accumulation of damaged cellular components reduces a body's capacity to preserve tissue homeostasis and affects biological aging and all age-related chronic conditions. This includes the onset and progression of classic degenerative diseases such as cardiovascular disease, kidney failure, neurodegenerative diseases, and cancer. Clinical manifestations of intestinal disorders, such as mucosal barrier dysfunction, intestinal dysmotility, and chronic obstipation, are highly prevalent in the elderly population and have been shown to be associated with an age-dependent decline of mitochondrial function. This review summarizes our current understanding of the role of mitochondrial dysfunction in intestinal aging.

Serum Ferritin Correlates With Liver Fat in Male Adolescents With Obesity.

Non-alcoholic fatty liver disease (NAFLD) contributes essentially to the burden of obesity and can start in childhood. NAFLD can progress to cirrhosis and hepatocellular carcinoma. The early phase of NAFLD is crucial because during this time the disease is fully reversible. Pediatric NAFLD shows unique features of histology and pathophysiology compared to adults. Changes in serum iron parameters are common in adult NAFLD and have been termed dysmetabolic iron overload syndrome characterized by increased serum ferritin levels and normal transferrin saturation; however, the associations of serum ferritin, inflammation, and liver fat content have been incompletely investigated in children. As magnetic resonance imaging (MRI) is an excellent measure for the degree of liver steatosis, we applied this method herein to clarify the interaction between ferritin and fatty liver in male adolescents. For this study, one hundred fifty male pediatric patients with obesity and who are overweight were included. We studied a subgroup of male patients with (n = 44) and without (n = 18) NAFLD in whom we determined liver fat content, visceral adipose tissue, and subcutaneous adipose tissue extent with a 1.5T MRI (Philips NL). All patients underwent a standardized oral glucose tolerance test. We measured uric acid, triglycerides, HDL-, LDL-, total cholesterol, liver transaminases, high sensitive CRP (hsCRP), interleukin-6, HbA1c, and insulin. In univariate analysis, ferritin was associated with MRI liver fat, visceral adipose tissue content, hsCRP, AST, ALT, and GGT, while transferrin and soluble transferrin receptor were not associated with ferritin. Multivariate analysis identified hsCRP and liver fat content as independent predictors of serum ferritin in the pediatric male patients. Our data indicate that serum ferritin in male adolescents with obesity is mainly determined by liver fat content and inflammation but not by body iron status.

Brown adipose tissue estimated with the magnetic resonance imaging fat fraction is associated with glucose metabolism in adolescents.

BACKGROUND: Despite therapeutic potential against obesity and diabetes, the associations of brown adipose tissue (BAT) with glucose metabolism in young humans are relatively unexplored. OBJECTIVES: To investigate possible associations between magnetic resonance imaging (MRI) estimates of BAT and glucose metabolism, whilst considering sex, age, and adiposity, in adolescents with normal and overweight/obese phenotypes. METHODS: In 143 subjects (10-20 years), MRI estimates of BAT were assessed as cervical-supraclavicular adipose tissue (sBAT) fat fraction (FF) and T2* from water-fat MRI. FF and T2* of neighbouring subcutaneous adipose tissue (SAT) were also assessed. Adiposity was estimated with a standardized body mass index, the waist-to-height ratio, and abdominal visceral and subcutaneous adipose tissue volumes. Glucose metabolism was represented by the 2h plasma glucose concentration, the Matsuda index, the homeostatic model assessment of insulin resistance, and the oral disposition index; obtained from oral glucose tolerance tests. RESULTS: sBAT FF and T2* correlated positively with adiposity before and after adjustment for sex and age. sBAT FF, but not T2* , correlated with 2h glucose and Matsuda index, also after adjustment for sex, age, and adiposity. The association with 2h glucose persisted after additional adjustment for SAT FF. CONCLUSIONS: The association between sBAT FF and 2h glucose, observed independently of sex, age, adiposity, and SAT FF, indicates a role for BAT in glucose metabolism, which potentially could influence the risk of developing diabetes. The lacking association with sBAT T2* might be due to FF being a superior biomarker for BAT and/or to methodological limitations in the T2* quantification.

Guava (Psidium guajava) Fruit Extract Prepared by Supercritical CO2 Extraction Inhibits Intestinal Glucose Resorption in a Double-Blind, Randomized Clinical Study.

Inhibition of intestinal glucose resorption can serve as an effective strategy for the prevention of an increase in blood glucose levels. We have recently shown that various extracts prepared from guava (Psidium guajava) inhibit sodium-dependent glucose cotransporter 1 (SGLT1)- and glucose transporter 2 (GLUT2)-mediated glucose transport in vitro (Caco-2 cells) and in vivo (C57BL/6N mice). However, the efficacy in humans remains to be confirmed. For this purpose, we conducted a parallelized, randomized clinical study with young healthy adults. Thirty-one volunteers performed an oral glucose tolerance test (OGTT) in which the control group received a glucose solution and the intervention group received a glucose solution containing a guava fruit extract prepared by supercritical CO2 extraction. The exact same extract was used for our previous in vitro and in vivo experiments. Blood samples were collected prior to and up to two hours after glucose consumption to quantitate blood glucose and insulin levels. Our results show that, in comparison to the control group, consumption of guava fruit extract resulted in a significantly reduced increase in postprandial glucose response over the basal fasting plasma glucose levels after 30 min (Δ control 2.60 ± 1.09 mmol/L versus Δ intervention 1.96 ± 0.96 mmol/L; p = 0.039) and 90 min (Δ control 0.44 ± 0.74 mmol/L versus Δ intervention -0.18 ± 0.88 mmol/L; p = 0.023). In addition, we observed a slightly reduced, but non-significant insulin secretion (Δ control 353.82 ± 183.31 pmol/L versus Δ intervention 288.43 ± 126.19 pmol/L, p = 0.302). Interestingly, storage time and repeated freeze-thawing operations appeared to negatively influence the efficacy of the applied extract. Several analytical methods (HPLC-MS, GC-MS, and NMR) were applied to identify putative bioactive compounds in the CO2 extract used. We could assign several substances at relevant concentrations including kojic acid (0.33 mg/mL) and 5-hydroxymethylfurfural (2.76 mg/mL). Taken together, this clinical trial and previous in vitro and in vivo experiments confirm the efficacy of our guava fruit extract in inhibiting intestinal glucose resorption, possibly in combination with reduced insulin secretion. Based on these findings, the development of food supplements or functional foods containing this extract appears promising for patients with diabetes and for the prevention of insulin resistance. Trial registration: 415-E/2319/15-2018 (Ethics Commissions of Salzburg).

Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity, and impaired glucose tolerance.

OBJECTIVE: To delineate potential mechanisms for fasting hyperglucagonemia in childhood obesity by studying the associations between fasting plasma glucagon concentrations and plasma lipid parameters and fat compartments. METHODS: Cross-sectional study of children and adolescents with obesity (n = 147) and lean controls (n = 43). Differences in free fatty acids (FFAs), triglycerides, insulin, and fat compartments (quantified by magnetic resonance imaging) across quartiles of fasting plasma glucagon concentration were analyzed. Differences in oral glucose tolerance test (OGTT) glucagon response was tested in high vs low FFAs, triglycerides, and insulin. Human islets of Langerhans were cultured at 5.5 mmol/L glucose and in the absence or presence of a FFA mixture with total FFA concentration of 0.5 mmol/L and glucagon secretion quantified. RESULTS: In children with obesity, the quartile with the highest fasting glucagon had higher insulin (201 ± 174 vs 83 ± 39 pmol/L, P < .01), FFAs (383 ± 52 vs 338 ± 109 µmol/L, P = .02), triglycerides (1.5 ± 0.9 vs 1.0 ± 0.7 mmol/L, P < .01), visceral adipose tissue volume (1.9 ± 0.8 vs 1.2 ± 0.3 dm3 , P < .001), and a higher prevalence of impaired glucose tolerance (IGT; 41% vs 8%, P = .01) than the lowest quartile. During OGTT, children with obesity and high insulin had a worse suppression of glucagon during the first 10 minutes after glucose intake. Glucagon secretion was 2.6-fold higher in islets treated with FFAs than in those not treated with FFAs. CONCLUSIONS: Hyperglucagonemia in childhood obesity is associated with hyperinsulinemia, high plasma FFAs, high plasma triglycerides, visceral adiposity, and IGT. The glucagonotropic effect of FFAs on isolated human islets provides a potential mechanism linking high fasting plasma FFAs and glucagon levels.

Fully convolutional networks for automated segmentation of abdominal adipose tissue depots in multicenter water-fat MRI.

PURPOSE: An approach for the automated segmentation of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in multicenter water-fat MRI scans of the abdomen was investigated, using 2 different neural network architectures. METHODS: The 2 fully convolutional network architectures U-Net and V-Net were trained, evaluated, and compared using the water-fat MRI data. Data of the study Tellus with 90 scans from a single center was used for a 10-fold cross-validation in which the most successful configuration for both networks was determined. These configurations were then tested on 20 scans of the multicenter study beta-cell function in JUvenile Diabetes and Obesity (BetaJudo), which involved a different study population and scanning device. RESULTS: The U-Net outperformed the used implementation of the V-Net in both cross-validation and testing. In cross-validation, the U-Net reached average dice scores of 0.988 (VAT) and 0.992 (SAT). The average of the absolute quantification errors amount to 0.67% (VAT) and 0.39% (SAT). On the multicenter test data, the U-Net performs only slightly worse, with average dice scores of 0.970 (VAT) and 0.987 (SAT) and quantification errors of 2.80% (VAT) and 1.65% (SAT). CONCLUSION: The segmentations generated by the U-Net allow for reliable quantification and could therefore be viable for high-quality automated measurements of VAT and SAT in large-scale studies with minimal need for human intervention. The high performance on the multicenter test data furthermore shows the robustness of this approach for data of different patient demographics and imaging centers, as long as a consistent imaging protocol is used.