Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder in pediatrics, yet the contribution of peripheral CD3⁺ T cell subsets to its pathogenesis remains poorly defined. We profiled peripheral CD3⁺ T cells from healthy controls, simple obesity, and MASLD children using single-cell RNA sequencing (scRNA-seq). MASLD was marked by expansions of CD4⁺ T effector-memory and CD8⁺ effector populations, intriguingly, by a proportional increase in mucosal associated invariant T (MAIT) cells. Corroborated by flow cytometry, untargeted metabolomics, and cytokine assays, we found MAIT cells were activated via both MR1 restricted and independent IL12/IL18 pathway. scRNA-seq analysis revealed that activated peripheral MAIT cells highly expressed CXCR6, whereas endothelial cells expressed its ligand CXCL16; these findings were validated by flow cytometry and immunofluorescence. In juvenile MASLD mice, CXCR6 blockade markedly impaired hepatic MAIT cell homing. The protective role of MAIT cells was confirmed by MAIT activation, MR1 knockout (MAIT deficiency), and adoptive transfer of pediatric peripheral MAIT cells. Consistently, lipid accumulation was reduced by the supplementing activated pediatric peripheral MAIT cells into human liver organoids. Our findings elucidate the peripheral CD3 + T cells profile and MAIT cells dynamics in pediatric MASLD and highlight their potential as early biomarkers and therapeutic targets.

INTRODUCTION:Lonapegsomatropin, a prodrug of somatropin, is approved for once-weekly treatment of paediatric growth hormone deficiency (GHD) in the USA and Europe. Here, we report the first trial to assess the efficacy and safety of weekly lonapegsomatropin compared to daily somatropin in treatment-naive Chinese children with GHD. METHODS:The briGHt trial was a randomized, open-label, active-controlled, 52-week, phase 3 trial (NCT04326374; CTR20200399) conducted at 17 sites across China. Treatment-naive, prepubertal children with GHD were enrolled and randomized 2:1 to either lonapegsomatropin 0.24 mg hGH/kg/week or equivalent weekly dose of daily somatropin 0.034 mg/kg/day. The primary endpoint was annualized height velocity (AHV) at week 52. Secondary endpoints included change in height standard deviation score (ΔHT SDS) from baseline, insulin-like growth factor 1, and safety. RESULTS:A total of 153 participants received treatment. Least squares (LS) mean ± standard error (±SE) of AHV at week 52 was 10.66 ± 0.22 cm/year for weekly lonapegsomatropin and 9.75 ± 0.26 cm/year for daily somatropin; weekly lonapegsomatropin demonstrated non-inferiority and superiority over daily somatropin, with a difference of 0.91 ± 0.28 cm/year (95% confidence interval: 0.37-1.45; p = 0.0010). LS mean (±SE) of ΔHT SDS was 1.01 ± 0.04 for weekly lonapegsomatropin and 0.83 ± 0.05 for daily somatropin at week 52, favouring lonapegsomatropin from week 13 (p < 0.05) onward. The safety profile was similar between treatment groups. CONCLUSIONS:Weekly lonapegsomatropin demonstrated non-inferiority and superiority in efficacy compared to daily somatropin among treatment-naive Chinese children with GHD. The treatment groups showed comparable safety and tolerability profiles.

BACKGROUND:Ectopic fat deposition in the liver and pancreas is closely linked to metabolic dysfunction, a key driver of the global burden of chronic disease. However, studies on intra-organ distribution of ectopic fat in the pediatric obese population remain limited. PURPOSE:To assess MRI-based spatial distribution patterns of hepatic and pancreatic fat using a fully automated nnU-Net model and evaluate their association with biochemical risk markers. STUDY TYPE:Prospective. SUBJECT:Eighty-one pediatric patients (age: 12 [11, 13] years, 57 males) with overweight or obesity based on body mass index z-score. FIELD STRENGTH/SEQUENCE:1.5 T, gradient-echo modified-DIXON T1W. ASSESSMENT:The spatial distribution of fat in liver and pancreas, the correlations between hepatic and pancreatic fat fraction (FF), and the association between the fat measures and biochemical risk markers were evaluated. STATISTICAL TESTS:Paired Wilcoxon test or t-test, repeated measure ANOVA or Friedman's test, Kruskal-Wallis test, Spearman correlation analysis. Significance was set at p < 0.05. RESULTS:Hepatic FF was significantly higher in the right lobe (median, 16.22%) than in the left lobe (median, 10.43%), and increased with distance from the portal vein. The degree of hepatic fat heterogeneity increased with the amount of fat deposition (whole variance: Level 0: 4.10; Level 1: 11.53; Level 2: 28.94; Level 3: 31.21). Then, the FF and its variance in the pancreatic body and tail were significantly higher than those in the head. A weak but statistically significant correlation (r range, 0.29-0.38) was observed between hepatic and pancreatic FF. Hepatic FF correlated with triglyceride and apolipoprotein B, but pancreatic fat showed no association (p range, 0.096-0.994) with lipid profiles, HOMA-IR, or HOMA-β. DATA CONCLUSION:Intra-hepatic and intra-pancreatic fat were heterogeneously distributed in pediatric obese population. Although fat accumulation in the liver and pancreas was weakly correlated, hepatic and pancreatic fat may arise from distinct metabolic disorders. EVIDENCE LEVEL:2. TECHNICAL EFFICACY:Stage 1.

OBJECTIVE:To evaluate the glycaemic outcomes of a novel calibration-free hybrid closed-loop (HCL) system in adolescents and adults with type 1 diabetes (T1D). METHODS:This multicentre pivotal trial enrolled 123 participants (21 adolescents aged 14-17 years and 102 adults aged ≥ 18 years) with T1D. All participants used the MicroTech Medical Equil S HCL system, which integrates a patch insulin pump with the AIDEX G7 calibration-free continuous glucose monitor. After a 2-week run-in period with the pump in manual mode, automated insulin delivery (auto mode) was enabled for a 12-week study phase. The primary outcome was the change in CGM-derived time in range (TIR; 70-180 mg/dL) from the run-in to the study phase. RESULTS:The median time spent in automated mode was 88.4% (IQR 76.6%-92.0%) in adolescents (mean age 15.5 ± 1.0 years) and 91.6% (IQR 87.8%-94.1%) in adults (mean age 39.4 ± 13.2 years). TIR increased significantly from 63.7% to 68.3% in adolescents (mean difference 4.6% [95% CI: 0.7-8.6]; p = 0.024) and from 69.6% to 78.0% in adults (mean difference 8.0% [95% CI: 6.3-9.8]; p < 0.001). Time below range (< 70 mg/dL) decreased from 4.1% to 3.0% in adolescents (p = 0.032) and from 3.8% to 2.7% in adults (p < 0.001). HbA1c decreased from 7.0% to 6.9% in adolescents (p = 0.011) and from 6.6% to 6.3% in adults (p < 0.001). No episodes of severe hypoglycaemia or diabetic ketoacidosis occurred. Patient-reported outcomes showed significantly higher treatment satisfaction and convenience scores at study end compared with baseline. CONCLUSIONS:In this first pivotal trial of a novel integrated HCL system, 3-month use was safe and significantly improved glycaemic control-increasing TIR while reducing HbA1c and hypoglycaemia-accompanied by enhanced treatment satisfaction in both adolescents and adults with T1D. TRIAL REGISTRATION:Chinese Clinical Trial Register Identifier: ChiCTR2300074200.

The incidence of type 2 diabetes (T2D) in children is rising rapidly, yet many cases remain undetected. Conventional diagnostic tools, including fasting glucose, HbA1c, and the gold-standard oral glucose tolerance test (OGTT), have limitations and often show low compliance in pediatric populations. This study aimed to evaluate a simplified OGTT (s-OGTT) with adjusted capillary glucose cut-off values as a novel approach for screening and diagnosing T2D in children and adolescents. A total of 468 children from four clinical centers in China underwent s-OGTT with capillary glucose testing. Capillary glucose values were compared with venous glucose levels using Bland-Altman analysis. Sensitivity and specificity for diagnosing diabetes and prediabetes were assessed using receiver operating characteristic (ROC) curves. Capillary glucose levels showed a strong correlation with venous measurements. Based on gold-standard criteria, 37 children were diagnosed with diabetes, 41 with impaired fasting glucose (IFG), and 74 with impaired glucose tolerance (IGT). Using optimized capillary cut-offs tailored for point-of-care testing, the s-OGTT demonstrated excellent diagnostic performance and improved specificity compared with applying conventional venous-based thresholds directly: for diabetes based on fasting glucose (sensitivity 97.56

Pediatric obesity presents with diverse metabolic phenotypes, yet the gut microbiota and metabolite signatures associated with obesity-related metabolic complications remain poorly defined. Here, we applied 16S rRNA gene sequencing and untargeted fecal metabolomics to investigate microbial and metabolic alterations in children with obesity, stratified according to metabolic complication burden. Stratification revealed graded differences in microbial composition and metabolite profiles across levels of metabolic complication burden. Children with more complications exhibited elevated levels of primary bile acids, accompanied by enrichment of taxa previously associated with bile acid metabolism. Conversely, the abundance of short-chain fatty acid (SCFA)-producing taxa was lower in groups with greater complication burden, suggesting potentially reduced fermentative capacity. These patterns differed from those previously reported in adult obesity and may reflect the distinct developmental context of the pediatric gut ecosystem. Our findings highlight the value of complication-based stratification in characterizing obesity-related metabolic heterogeneity and identify microbiota-metabolite associations that warrant further validation in longitudinal and mechanistic studies. Children with obesity were stratified according to metabolic complication burden. Primary bile acid levels were higher in groups with greater complication burden, accompanied by enrichment of taxa previously associated with bile acid metabolism. The abundance of putative SCFA-producing taxa was lower in groups with greater complication burden. Graded microbiota-metabolite differences were observed across levels of metabolic complication burden. Microbiota-metabolite signatures may help characterize the metabolic heterogeneity of pediatric obesity and warrant further validation.

This systematic review and meta-analysis synthesized evidence on the prevalence and types of diabetes technology-related skin complications in children and adolescents with type 1 diabetes. Thirteen primary studies were included in the systematic review. Five studies involving 796 children and adolescents contributed data to the primary meta-analysis of any skin complication. Using a random-effects model, the pooled prevalence was 63.8% (95% CI 47.8%-77.2%), with substantial heterogeneity (I2 = 92.1%). Among specific complications, the pooled prevalence was 36.7% for scarring/insertion marks, 24.1% for lipohypertrophy, 16.6% for eczema/dermatitis-like reactions, 8.6% for infection/folliculitis, and 5.1% for lipoatrophy. The findings indicate that skin complications are common among young users of insulin pumps and related diabetes technologies, but interpretation is limited by inconsistent definitions, outcome ascertainment, and heterogeneous outcome reporting. Future prospective studies using standardized outcome definitions and consistent skin-assessment methods are needed to clarify risk factors and guide regular skin assessment, site-rotation, and skin-care strategies in pediatric type 1 diabetes care.

Childhood obesity remains a pressing global health challenge, yet the impact of dynamic adiposity changes during active developmental window retains poorly understood. Leveraging longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (N=8519 at baseline; N=1873 at 4-year follow-up), our study reveals distinct neurodevelopmental implications of central fat dynamics during adolescence. At baseline, central fat indices (body roundness index, BRI / waist-to-height ratio, WHtR) outperformed BMI in predicting cognitive deficits, showing robust associations with impaired inhibitory control and episodic memory. The prediction effect was partially mediated by cortical changes in prefrontal and temporal regions. Longitudinally, the rate of fat accumulation (Δ) emerged as a critical predictor: faster adiposity accrual predicted attenuated cortical thinning (i.e., slower development) in parietal lobes and poorer executive function at follow-up, while baseline adiposity showed no significant effects on the follow-up brain morphology or cognitive development. Notably, subgroup analyses uncovered that obese adolescents with central fat reduction exhibited accelerated cortical thinning in posterior cingulate (change difference p=0.006-0.029) alongside rapid improvement in inhibitory control (Flanker slope difference p<0.05), whereas those with persistent adiposity showed delayed thinning in the postcentral gyrus. The study reveals that central fat (BRI/WHtR) is closely linked to neurocognitive risks, and longitudinal fat accumulation-rather than baseline adiposity-drives cortical alteration. Notably, fat reduction activated adaptive neural change in obese adolescents, underscoring the importance of weigh regulation during neurodevelopment.

Purpose: Polyethylene glycol-recombinant human growth hormone (PEG-rhGH) is the first commercial long-acting rhGH preparation approved in China. This study was designed to assess the efficacy and safety of PEG-rhGH in treating growth hormone deficiency (GHD) during the transition period. Methods: A prospective, multicenter and single-arm study was performed. The entire study duration spanned 66 weeks, comprising a 2-week trial screening phase, a 12week dose-adjustment period, and a 52-week PEG-rhGH treatment phase. A total of 10 interviews were conducted over the course of the study. The primary endpoint was change in body composition; secondary endpoints were changes in lumbar bone mineral density (BMD, L1-4) and lean body mass (LBM). Sex- and age-specific equations were developed to adjust body composition z-scores. Results: : A total of 31 subjects were included in this study. Throughout the 64-week therapy with PEG-rhGH, the insulin-like growth factor-1 (IGF-1) standard deviation score (SDS) demonstrated progressive elevation from baseline (-3.07 to -1.38; P<0.001). Significant alterations in body composition parameters were observed throughout the study. Body weight increased 3.96 kg (P<0.001), and the body weight SDS exhibited significant elevation from baseline (0.67) to 64 weeks (1.14; P=0.005). LBM significantly increased (4.54 kg; P<0.001), but there was a statistically significant reduction in fat percentage (Fat%) from 37.40% to 33.94% (P=0.008) and Fat% SDS from 1.91 to 1.47 (P= 0.009). The lumbar BMDz-score improved from-1.54 at baseline to-1.12 postintervention, but did not reach statistical significance (P>0.05). The triglyceride (TG) levels of the subjects decreased significantly at week 64 (P=0.018). There was no statistically significant difference in the changes of other lipid profile indicators. In this study, no adverse events attributable to direct drug-related causes were identified. Conclusion: Based on our study, PEG-rhGH can improve IGF-1 levels and alter body composition parameters by increasing LBM and decreasing body fat and TG levels in patients with GHD during the transition period, and it has a comparable safety profile and helps improve therapeutic adherence.

INTRODUCTION:Several studies have individually suggested that somapacitan, a once-weekly growth hormone (GH) treatment, has similar efficacy and safety to once-daily GH in children with GH deficiency. Here, we assessed the efficacy and safety of somapacitan versus daily GH after 52 and 156 weeks of treatment using pooled data from the REAL 3, REAL 4, and REAL 6 trials. METHODS:Participants receiving somapacitan 0.16 mg/kg/week or daily GH 0.034 mg/kg/day were included. Some participants switched from daily GH to somapacitan after 52 weeks of treatment, so data beyond week 52 were analysed separately. Outcomes, including height velocity (HV) and adverse events (AEs), were analysed by treatment group. An additional analysis was conducted in relation to puberty onset and Tanner stage. RESULTS:At week 52, HV was similar in participants receiving somapacitan and those receiving daily GH. At week 156, mean (SD) HV (cm/year) was 7.5 (1.6) in participants who had always received somapacitan, 7.6 (2.0) in those who had always received daily GH, and 7.8 (1.4) in those who switched to somapacitan from daily GH. Most AEs were mild and unlikely to be treatment-related. HV remained stable for up to 130 weeks in pubertal children, and was similar across treatment groups and Tanner stages. CONCLUSIONS:In this pooled analysis of clinical trial data, somapacitan demonstrated similar efficacy and safety to daily GH for up to 156 weeks of treatment. A dose of 0.16 mg/kg/week of somapacitan was able to maintain consistent growth in children and adolescents who reached puberty.

ABSTRACT Background Sarcopenic obesity (SO) is well‐characterized in older adults, but its impact on muscle development in children remains poorly understood. This study investigated the effects of childhood obesity on musculoskeletal health and the underlying mechanisms. Methods We enrolled 1447 children (31.4% girls; median age 11.10 years, IQR 9.39–12.50) for body composition assessment via dual‐energy X‐ray absorptiometry (DXA) and a separate cohort of 349 children (33.2% girls; median age 11.13 years, IQR 9.73–12.80) for grip strength measurement. A juvenile mouse model of high‐fat diet (HFD)‐induced obesity was established and compared to an adult‐onset model. Molecular pathways were examined via RNA sequencing and RT‐qPCR. Interventions included dietary reversal and vitamin C supplementation. Results In children, the appendicular skeletal muscle mass ratio (ASMR) Z‐score was inversely correlated with BMI‐Z score (ρ = −0.369, p < 0.001) and body fat percentage (ρ = −0.668, p < 0.001). According to weight‐specific reference criteria, most of children with obesity exhibited low grip strength (below the 25th percentile). In mice, 4 weeks of HFD feeding in juveniles, but not adults, significantly reduced muscle mass (−6%, p < 0.05), muscle fibre diameter (−8%, p < 0.001), grip strength (−14%, p < 0.01) and rotarod performance (−29%, p < 0.05). RNA sequence and RT‐qPCR revealed that HFD suppressed myogenic regulatory factors (e.g., Myod, Myog) and promoted adipogenic pathways specifically in juveniles. In stark contrast, adult mice showed no such impairments after 4 weeks of HFD. The muscle deficits caused by juvenile obesity were not resolved but persisted even after subsequent dietary weight loss. Vitamin C supplementation effectively mitigated HFD‐induced impairments, increasing muscle fibre diameter (~15%, p < 0.001, vs. HFD), grip strength (~10%, p < 0.001, vs. HFD) and expression of key myogenic genes (e.g., Myod, Myog, all p < 0.05). Conclusions Childhood obesity critically impairs muscle development during the juvenile growth period, driven by transcriptomic reprogramming that suppresses myogenesis. These deficits are persistent and not reversed by weight loss alone. Vitamin C supplementation presents a potential therapeutic strategy to protect muscle health in children with obesity. The juvenile mouse model established herein provides a novel tool for future research into childhood SO.

Background and aims:Food addiction (FA) likely contributes to obesity within a complex system of psychological, behavioral, and physiological factors. However, interactions among these factors remain incompletely understood. This study used a network approach to identify interrelationships among FA, eating motives, lifestyle habits, and weight indicators in a developmental youth cohort. Methods:A longitudinal panel study was conducted in Eastern China. Youth aged >8 years (mean ages 13-14 years) completed survey and anthropometric measurements. The Chinese version of the dimensional Yale Food Addiction Scale for Children 2.0 (dYFAS-C 2.0), Kids Palatable Food Eating Motive Scale (K-PEMS) and Mindful Eating Scale for Children (MEQ-C) were used to measure addictive eating motives and behaviors. Semi-quantitative food intake, physical activity and sleep duration were assessed, and height and weight were measured by trained researchers to calculate a Body Mass Index Z score (BMIZ). Body composition measurement utilized bioelectrical impedance for detecting subcutaneous fat content (FC) and a visceral fat level (VFL). Network analysis, including cross-sectional network estimation at each time point, longitudinal network comparison, and cross-lagged panel network (CLPN) modeling, was used to examine the centrality, connectivity, and temporal relationships among FA and key variables. Results:Among the 2680 participants enrolled, 2054 completed both waves of surveys (retention rate: 76.7%; 49.5% girls). In the baseline (T1) cross-sectional network, FA showed the highest closeness and betweenness and was linked to the weight-related subnetwork (BMIZ, FC, and VFL) primarily through VFL. The follow-up (T2) cross-sectional network showed a broadly similar overall pattern. Longitudinal comparison suggested generally stable centrality patterns across time, with lifestyle-related factors showing relatively greater prominence at T2. In the CLPN, the strongest directional paths primarily extended from FA to later eating motives, whereas direct longitudinal paths from FA to weight indicators were not observed. FA and mindful eating exhibited bidirectional relationships, and mindful eating was also negatively associated with subsequent reward-based eating motives. Conclusion:FA may represent an important intervention target within the broader obesity-related psychobehavioral system in youth, particularly in relation to eating motives and reward-driven eating processes. Interventions that address FA together with mindful eating and modifiable lifestyle factors may offer a more comprehensive approach to youth weight-related health.

The inhibition of estrogen receptor (ER)-mediated genomic signaling in ER-positive cancer cells has long been a primary focus of therapeutic strategies. Here, we introduce a switchable competitive inhibition system for ERα-mediated transcriptional regulation, termed DOCTER (Drug-induced On-Off Competitor for Transcription mediated by ERα). DOCTER integrates the Tet-On induced Cre-loxP recombination system to enable precise, reversible on/off switching. We demonstrate that DOCTER effectively inhibits ERα-mediated transcriptional regulation in breast cancer cells, modulating both exogenous and endogenous gene expression, and remains effective in cells harboring ERα ligand-binding domain (LBD) mutations. Upon drug induction, DOCTER exhibits controllable and reversible inhibition. To visualize these dynamic switching events in real time, we developed a multi-color fluorescent reporting system that enables monitoring of complete DOCTER switch-off within 24 hours. Our study provides a novel approach for time-specific transcriptional regulation and offers broad potential for applications in genetic research and therapeutic development.

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent pediatric disorder with limited treatment options, primarily due to an incomplete understanding of its molecular drivers. Recent research underscores the role of microbial guilds in metabolic health, but the mechanisms by which dysbiosis driven by core species and co-abundant symbionts disrupt metabolic homeostasis in pediatric MASLD remain unclear. Results Here, we conducted integrated metagenomic and metabolomic analyses on 285 pediatric subjects including MASLD patients, obese and healthy controls. The gut dysbiosis in MASLD was characterized by a depletion of Phocaeicola vulgatus , Bacteroides uniformis , Parabacteroides distasonis , and Bacteroides thetaiotaomicron . Co-abundance network analysis, integrating our cohort with four public datasets, identified these species as core guild members associated with MASLD. Microbial enrichment analysis showed significant disruptions in carbohydrate metabolism, particularly the downregulation of the tricarboxylic acid (TCA) cycle, fructose and sucrose metabolism, and pentose and glucuronate interconversions. P. vulgatus and B. uniformis were identified as dominant species linked to the downregulation of KEGG orthologs (KOs) in these disrupted pathways that were inversely correlated with hepatic injury biomarkers. CAZyme database analysis further emphasized P. vulgatus as the primary contributor to glycoside hydrolases involved in monosaccharide utilization. Finally, both untargeted and targeted metabolomics analysis validated a disrupted metabolic network centered on the TCA cycle and monosaccharide metabolism in pediatric MASLD. Conclusion Our findings suggest the core guild species P. vulgatus and B. uniformis may serve as critical regulators of carbohydrate metabolism in pediatric MASLD, offering potential mechanistic targets for gut microbiome-based interventions.

AIMS:One-hour postload plasma glucose (1h-PG) is an early marker of dysglycemia in adults, but its utility in children and adolescents is uncertain because insulin sensitivity changes during growth and puberty. We aimed to establish age- and pubertal stage-specific 1h-PG thresholds for identifying prediabetes and Type 2 diabetes (T2D) in children with overweight or obesity. MATERIALS AND METHODS:In this cross-sectional study, 4344 children and adolescents with overweight or obesity underwent an oral glucose tolerance test. Participants were classified into four groups: normal glucose tolerance (NGT) with normal 1 h-PG, NGT with elevated 1 h-PG, prediabetes and T2D. Insulin resistance and β-cell function indices were assessed. Participants were stratified by chronological age and pubertal stage. The optimal 1h-PG cut-offs were obtained via receiver operating characteristic (ROC) and age- and pubertal stage-based thresholds were compared for diagnostic performance. These thresholds were then validated in two independent cohorts. RESULTS:Among individuals with NGT, those with elevated 1h-PG exhibited greater insulin resistance, impaired β-cell function and a higher insulin area under the curve (29 916 vs. 23 524, p < 0.001). 1 h-PG levels increased with pubertal progression. Pubertal stage-specific thresholds showed superior discrimination compared with age-based stratification and adult cut-offs. Compared with adult thresholds (8.6 mmol/L for prediabetes and 11.6 mmol/L for T2D), a prepubertal cut-off of 7.78 mmol/L improved sensitivity for prediabetes (75.40% vs. 56.68%) and a pubertal cut-off of 10.48 mmol/L improved sensitivity for T2D (89.47% vs. 73.68%). CONCLUSIONS:Elevated 1h-PG proved to be a practical marker for identifying early metabolic dysfunction in children and adolescents with euglycemia. Given that widely used adult-derived cut-offs (8.6 and 11.6 mmol/L) are suboptimal for pediatric populations, we established pubertal stage-specific thresholds that outperformed both age-specific and adult-derived cut-offs. These stage-specific thresholds may serve as an effective screening tool for diabetes risk in children and adolescents with overweight or obesity.

Diabetic ketoacidosis (DKA) stands as the most common acute hyperglycaemic complication in children with type 1 diabetes (T1D) and remains associated with considerable morbidity and mortality. Although gut dysbiosis has been reported in newly diagnosed T1D, the gut microbiota and microbial metabolites during DKA onset remain poorly characterized. Shotgun metagenomic sequencing was performed on fecal samples from 96 newly diagnosed T1D children, including 32 presenting with DKA upon admission. Short-chain fatty acids (SCFAs) were quantified using gas chromatography/mass spectrometry (GC/MS). Comparative and correlation analyses were conducted to explore differences in gut microbial composition, SCFA levels, and their association with clinical indicators of DKA severity. Children with DKA exhibited distinct gut microbial compositions, with marked β-diversity separation from non-DKA individuals. The DKA group was characterized by an enrichment of potential pathogens and a significant depletion of SCFA-producing genera, including Anaerobutyricum, Dialister, Ruminococcus, Roseburia, Dorea, and Butyricicoccus. Correspondingly, fecal SCFA levels were significantly reduced in the DKA group. Moreover, SCFAs and their producing bacteria were strongly correlated with clinical indices of DKA severity. Mediation analysis suggested that reductions in SCFAs, particularly propionic acid and butyric acid, were associated with metabolic alterations linking SCFA-producing bacteria to DKA. This study provides a comprehensive characterization of gut microbiota and SCFA alterations in T1D children at DKA onset. The depletion of SCFA-producing bacteria and their metabolites reflects metabolic disturbances associated with DKA, and highlights SCFAs and their producers as candidate metabolic features warranting further validation as biomarkers and therapeutic targets.

Investigating the gene regulatory programs directing stem cell differentiation can provide new insights into cell fate decision. Recently, we have developed an expandable pancreatic progenitor (ePP) platform, but the detailed characterization is lacking. Here, we perform systems-level characterization of the ePP-islet system. We not only define the dynamic and coordinated transcriptomic and chromatin landscapes of pancreatic differentiation but also infer the sophisticated gene regulatory networks that govern ePP self-renewal, control endocrine cell fate bifurcation, and regulate islet function. In addition, we identify the essential roles of the NKX2.2-CLEC16A/endosomal pathway axis. Unexpectedly, we have developed an authentic human stem cell-based model with autoimmune-like characteristics for type 1 diabetes by CLEC16A knockout and further identified effective pharmacological rescuers for CLEC16A deficiency. Notably, this study provides rich information and highlights the ePP-islet system as a powerful platform for uncovering the molecular mechanisms of cell fate decision, paving the way for therapeutic applications.

OBJECTIVE:Food addiction (FA) is implicated in obesity, yet the potential moderating role of mindful eating and the underlying neural mechanisms in youth remain unclear. METHODS:This study integrated a multicenter cross-sectional survey, a longitudinal study with 6- and 12-month follow-ups, and an independent magnetic resonance imaging (MRI) sample. FA, eating motives, mindful eating, BMI z-score, fat content, and visceral fat level were assessed. Analyses utilized structural equation modeling, latent growth modeling, and voxel-based morphometry. RESULTS:Among 2071 screened, 1601 youth (55.5% boys; mean age = 12.69 ± 3.04 years) completed the baseline survey, with 880 and 564 completing the 6- and 12-month follow-ups, respectively. FA mediated the relationship between eating motives and weight status, and mindful eating moderated this pathway (p < 0.05). Longitudinally, baseline FA predicted accelerated accumulation of fat content and visceral fat level, but not BMI z-score (p > 0.05). The independent 75-MRI sample revealed that left insula gray-matter volume was negatively associated with FA but positively associated with mindful eating. CONCLUSIONS:FA may link eating motives to fat accumulation in youth, particularly abdominal fat; mindful eating may be protective, with left insula structure and left insula-striatum connectivity as possible neural correlates.

Obesity-related metabolic diseases include conditions linked to obesity, such as type 2 diabetes, hypertension, steatotic liver disease, and polycystic ovary syndrome. These disorders are primarily caused by insulin resistance, chronic inflammation, and excessive fat accumulation. They represent significant health challenges and often remain asymptomatic during their early stages. Traditional diagnostic tools, including blood glucose, lipid levels, blood pressure, and uric acid measurements, provide valuable insights but fall short of fully capturing the complexity of metabolic dysfunction. Consequently, there is a growing need for noninvasive, easily accessible biomarkers, especially those found in urine, to enable more accurate, sensitive, and patient-friendly diagnostic methods. Urine, with its diverse range of metabolites that reflect the body’s metabolic changes, is an ideal sample for early detection. Recent advancements in urine metabolomics and proteomics have highlighted the potential of urinary biomarkers for diagnosing obesity-related metabolic diseases. Despite challenges such as the need for standardized detection techniques and clinical validation, the integration of artificial intelligence and multi-omics approaches holds significant promise for enhancing diagnostic accuracy and advancing disease management strategies.