Obesity-induced insulin resistance (IR) is closely associated with chronic inflammation and metabolic dysfunction in adipose tissue, in which macrophage polarization plays a pivotal role. Liquiritigenin (LQ), a natural flavonoid derived from licorice, exhibits potential metabolic regulatory effects; however, its role in high-fat diet (HFD)-induced obesity and insulin resistance, as well as the underlying mechanisms, remains unclear. In this study, an HFD-induced obese mouse model combined with multi-omics analyses and an in vitro co-culture system was employed to investigate the effects of LQ. LQ significantly improved glucose tolerance, insulin sensitivity, and lipid metabolism, and restored the expression of p-IRS1/IRS1, p-AKT/AKT, and GLUT4 in epididymal adipose tissue. Integrated analyses of network pharmacology, transcriptomics, and metabolomics revealed that LQ markedly reversed HFD-induced alterations in oxidative stress, mitochondrial dysfunction, and inflammatory pathways. Mechanistically, palmitic acid (PA) at physiologically relevant concentrations did not directly induce insulin resistance in adipocytes but instead promoted macrophage polarization toward the pro-inflammatory M1 phenotype, thereby impairing adipocyte insulin signaling. Further investigation showed that PA and HFD increased mitochondrial reactive oxygen species (mtROS), disrupted oxidative phosphorylation (OXPHOS), and induced mitochondrial dysfunction in macrophages, ultimately driving M1 polarization; these effects were markedly attenuated by the mtROS scavenger Mito-TEMPO. In contrast, LQ reduced mtROS levels, restored OXPHOS function, and maintained mitochondrial homeostasis, thereby suppressing pro-inflammatory macrophage polarization and improving insulin signaling and glucose uptake in adipocytes. Notably, these effects were more pronounced than those observed with dexamethasone under the same experimental conditions. These protective effects were abolished by the mtROS activator DMNQ. In conclusion, LQ alleviates adipose tissue insulin resistance by modulating macrophage polarization through the mtROS/OXPHOS axis, providing new mechanistic insights into immunometabolic regulation and supporting of applying LQ as a potential phytotherapy strategy for obesity-related metabolic disorders.

Type 2 diabetes mellitus and peripheral artery disease are pathophysiologically interlinked through shared mechanisms such as chronic inflammation and endothelial dysfunction, highlighting the imperative to identify common biomarkers for enhancing early detection and risk stratification. A review of PubMed through December 2025 was performed, culminating in the inclusion of 55 original studies. The synthesis revealed significant dysregulation of inflammatory markers including IL-6 and ICAM-1, endothelial and oxidative stress mediators such as TET3 and the PRDX family, along with coagulation markers such as von Willebrand factor and fibrinogen, all correlating with disease severity in comorbid patients. Multi-marker panels, exemplified by the HART PAD score and combined neutrophil-to-HDL ratio with systemic inflammation response index, demonstrated superior predictive accuracy compared to individual biomarkers. Subsequent investigations should prioritise prospective validation and clinical standardisation of these candidate markers. This scoping review offers a novel structured integration of biomarkers across fluid, cellular and functional domains, advocating for an integrated multi-marker strategy to facilitate personalised management in this high-risk population.

BACKGROUND: Red cell distribution width-standard deviation (RDW-SD), a measure of erythrocyte volume heterogeneity, has attracted increasing interest as a hematologic marker linked to inflammation, oxidative stress, and metabolic dysfunction beyond anemia evaluation. However, evidence on the relationship between glycated hemoglobin (HbA1c) and RDW-SD in newly diagnosed, treatment-naïve type 2 diabetes mellitus (T2DM) remains limited. This study investigated the association between HbA1c and RDW-SD after accounting for hematologic, nutritional, renal, and metabolic factors that are routinely available at diagnosis. METHODS: In this retrospective cross-sectional study, 202 adults aged 18-65 years with newly diagnosed, treatment-naïve T2DM were evaluated at a tertiary university hospital between September 2024 and January 2026. Patients with anemia, mean corpuscular volume abnormalities, advanced renal impairment, acute inflammation or infection, recent transfusion, prior antidiabetic therapy, active bleeding, or hematologic malignancy were excluded. Associations between HbA1c and RDW-SD were examined using correlation, partial correlation, and hierarchical linear regression analyses. Additional analyses assessed RDW-SD across HbA1c tertiles and tested the robustness of the association after inclusion of fasting glucose. RESULTS: HbA1c showed a positive correlation with RDW-SD (r = 0.664, p < 0.001), which remained essentially unchanged after adjustment for age, sex, body mass index, hemoglobin, mean corpuscular volume, creatinine, ferritin, and vitamin B12 (partial r = 0.662, p < 0.001). Mean RDW-SD increased stepwise across ascending HbA1c tertiles (40.40 ± 3.04, 42.96 ± 3.38, and 46.13 ± 3.85 fL; p-trend < 0.001). In hierarchical regression, HbA1c produced the largest incremental gain in explained variance (ΔR² = 0.323, p < 0.001) and remained the strongest correlate of RDW-SD in the fully adjusted model (B = 1.535, β = 0.674, p < 0.001). In sensitivity analysis, the association persisted after additional adjustment for fasting glucose. CONCLUSIONS: In newly diagnosed, treatment-naïve T2DM, higher HbA1c levels were associated with greater RDW-SD. These findings are hypothesis-generating and do not establish RDW-SD as a clinical marker of glycemic burden or dysglycemia assessment. CLINICAL TRIAL NUMBER: Not applicable.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and non-alcoholic fatty liver disease (NAFLD) are closely linked to insulin resistance and elevated cardiovascular risk, triglyceride-glucose (TyG)-related indices, the atherogenic index of plasma (AIP), and the cardiometabolic index (CMI) have emerged as practical surrogate markers for cardiometabolic risk assessment in these populations. However, it remains unclear whether the associations of these indices with adverse cardiovascular events remain consistent when transitioning from the NAFLD to the newly defined MASLD framework, and a comprehensive comparison of these indices across both diagnostic criteria is lacking. METHODS: This study included 4693/3266, 74,173/67,864, and 7823/10,576 individuals with MASLD/NAFLD from the National Health and Nutrition Examination Survey (NHANES), UK Biobank (UKB), and China Pudong cohort, respectively. Multivariate Cox proportional hazards models, restricted cubic spline analyses, and time-dependent receiver operating characteristic curves were employed to assess associations. Linear regression models evaluated relationships between TyG-related indices and cortical/subcortical structural volumes. Mediation analyses examined the role of oxidative stress, phenotypic aging, and inflammatory markers. RESULTS: Most IR-related indices demonstrated nonlinear, predominantly J-shaped associations with cardiovascular disease (CVD) and related mortality, especially within the UKB. TyG-WC optimally predicted 3-year CVD mortality in MASLD/NAFLD across UKB and NHANES, as well as ischemic stroke (IS) in UKB-MASLD. TyG-WHTR was the strongest predictor for CVD mortality in the Pudong cohort and myocardial infarction (MI) in UKB-MASLD. Notably, elevated TyG-WHTR was consistently associated with heightened risks across all endpoints: CVD mortality (NAFLD: UKB: HR 1.60, 95%CI 1.38-1.84, NHANES: 1.90, 1.34-2.70, Pudong: 1.24, 1.10-1.40; MASLD: UKB: 1.59, 1.38-1.82, NHANES: 1.86, 1.36-2.54, Pudong: 1.70, 1.43-2.03), MI (NAFLD: 1.20, 1.09-1.33; MASLD: 1.22, 1.11-1.34), and IS (NAFLD: 1.41, 1.24-1.61; MASLD: 1.39, 1.23-1.57). Structural neuroimaging analyses revealed significant negative correlations between TyG-WC/TyG-WHTR and subcortical volumes (P < 1 × 10). Mediation analyses indicated that oxidative stress, phenotypic aging, and inflammatory markers collectively accounted for 1.4-27% of the observed associations. CONCLUSIONS: Insulin Resistance-Related Indices demonstrate robust clinical utility in predicting CVD and mortality in NAFLD/MASLD across three distinct cohorts, with oxidative stress, inflammatory activation, and accelerated aging serving as potential mechanistic pathways.

BACKGROUND: China's Healthcare Security Diagnosis-Related Groups (CHS-DRG) framework anchors inpatient payment to a relative weight (RW) set by each hospitalization's severity stratum. That stratum depends on the complications and comorbidities (CC) and major complications and comorbidities (MCC) identified among recorded secondary diagnoses, so ICD-10 documentation carries direct payment consequences. Evidence on diagnostic coding combination patterns in clinically complex populations, and on the methodological hazards of analyzing an exposure defined by grouper logic, remains limited. METHODS: This single-center retrospective study used medical record front page and CHS-DRG grouping data (locally implemented national grouper, v2.0) for pneumonia hospitalizations discharged from Anhui Chest Hospital in 2025. The hospitalization was the unit of analysis; 131 met pre-specified criteria and were classified by recorded ICD-10 secondary diagnoses into three mutually exclusive coding patterns (basic-disease-only; basic disease with CC; enhanced complication). Because the exposure shares the grouper's own logic, its correspondence with the severity stratum is treated as definitional and the regressions as exploratory. Reporting follows STROBE and RECORD. RESULTS: Among 131 hospitalizations (mean age 70.4 ± 10.7 years; 91 of 131 male, 69.5%), 15 (11.45%), 20 (15.27%), and 96 (73.28%) fell into the basic-disease-only, basic disease with CC, and enhanced complication patterns. By construction each pattern mapped one-to-one onto its severity stratum. Total hospitalization expenditure, the only non-definitional outcome, rose across patterns (H = 43.57, P < 0.001): medians 5,938.62, 6,769.91, and 25,501.36 yuan (approximately US$827, US$943, and US$3,552); RW followed a parallel gradient (H = 42.96, P < 0.001). In exploratory regression, length of stay and the count of recorded chronic conditions co-varied with MCC entry (adjusted OR 1.234, 95% CI 1.101 to 1.384, and 1.411, 95% CI 1.144 to 1.741, respectively), both contemporaneous and partially coding-dependent rather than independent predictors. CONCLUSIONS: The structure of recorded ICD-10 diagnoses corresponded to CHS-DRG severity stratification and RW by definition rather than through an independent association, while realized expenditure rose in parallel. The study is best read as a cautionary illustration of definitional circularity: rule-conformant ICD-10 coding remains necessary for accurate stratification and equitable payment, but coding-pattern data alone cannot establish independent clinical or economic effects. CLINICAL TRIAL NUMBER: Not applicable.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) varies significantly among Tuberculosis (TB) patients from 25.3 to 44% in India. Correct knowledge regarding TB symptoms is a determinant for health-seeking behaviour among T2DM patients. However, there is limited literature regarding TB knowledge and risk perception among patients with T2DM in rural communities of coastal Karnataka, India. OBJECTIVES: To determine the association of correct knowledge regarding TB among patients with T2DM and their TB risk perception in a rural community in coastal Karnataka. METHODOLOGY: A cross-sectional study was conducted over 18 months in the rural villages under the rural health training centre of a tertiary care private medical college at Dakshina Kannada District, Karnataka, involving 202 T2DM patients. Data were collected via pretested semi-structured questionnaires administered through interviews. Descriptive statistics and chi-square tests were used to analyse demographic variables, TB knowledge and TB risk perception. RESULTS: Among the 202 participants, 116 (57.4%) demonstrated overall correct knowledge regarding TB. Participants with high risk perception showed significantly better recognition of specific TB knowledge components, including airborne transmission (p = 0.013), key symptoms such as cough (p = 0.029), fever (p = 0.049), and weight loss (p = 0.019), as well as awareness of asymptomatic disease (p = 0.003) and extrapulmonary involvement (p = 0.046). They were also more likely to correctly reject misconceptions related to TB transmission.However, overall correct TB knowledge was not significantly associated with perceived risk (χ² = 0.008, p = 0.927). High risk perception was significantly associated with being single/widowed (p = 0.003), higher education (p < 0.001), higher socio-economic status (p < 0.001), skilled occupation (p < 0.001), and a family history of DM (p = 0.008). Age, sex, and duration of DM were not significantly associated with risk perception. CONCLUSION: Although more than half of the participants demonstrated correct TB knowledge, this did not translate into higher perceived risk, highlighting a critical knowledge-perception gap among patients with T2DM. While specific and clinically relevant knowledge components were associated with higher risk perception, general awareness alone was insufficient to evoke a sense of personal vulnerability. Educational strategies should therefore move beyond general information dissemination and focus on personalised risk communication that explicitly links DM with increased susceptibility to TB. Such interventions should emphasise the possibility of asymptomatic disease and promote timely screening and care-seeking behaviour.

The aberrant aggregation of human islet amyloid polypeptide (hIAPP) or Amylin into toxic oligomers and fibrils leads to pancreatic β-cell dysfunction and progressive cell death, which is a key pathological feature of Type II diabetes mellitus (T2DM). In this study, we adopted a hybrid approach combining virtual screening and molecular dynamics (MD) simulation, with experimental validation, to identify inhibitors of hIAPP aggregation. Herein, we screened 2000 phytoconstituents from natural products using molecular docking, followed by in silico ADMET predictions. Withaferin A and Withanolide A (phytoconstituents of Ashwagandha) were found to be lead molecules with suitable drug-like properties. Next, we performed MD simulation to assess the stability and interaction dynamics of hIAPP-ligand complexes, and the effect of ligands on hIAPP fibrils. Building on the computational screening, we further carried out a comprehensive experimental analysis to validate the inhibitory effects of lead molecules. The collective experimental results from the Thioflavin T (ThT) assays, FTIR experiment, combined with Confocal and Transmission Electron Microscopy (TEM), suggest that the ligands (preferably Withanolide A) have a potent inhibitory effect against hIAPP aggregation by increasing the lag phase, reducing β-sheet content, and inhibiting fibril formation of hIAPP. For in vivo validation using Drosophila model, Withanolide A was found to mitigate hIAPP oligomer-induced toxicity by reducing apoptosis, necrosis, and oxidative stress in the Drosophila gut, as confirmed by multiple cell death staining assays and reactive oxygen species (ROS) analysis. Besides, in diabetic flies, Withanolide A lowered glucose levels, demonstrating anti-diabetic activity. Thus, this work, for the first time, suggests that Withanolide A may be a potential candidate for inhibiting hIAPP aggregation and as a T2DM drug.

BACKGROUND: Gestational diabetes mellitus (GDM) diagnosed early in pregnancy (before 20 weeks' gestation) is associated with increased metabolic risk, yet its molecular profile remains poorly defined. While disrupted lipid metabolism is an important feature of GDM, no previous study has characterized the lipidomic profile of women with early GDM (eGDM). METHODS: We performed untargeted liquid chromatography mass spectrometry on maternal plasma samples from a cohort of 180 women at risk of GDM, enrolled in the Treatment of Booking GDM (TOBOGM) multicenter randomized controlled trial. Oral glucose tolerance tests (OGTT) were conducted before 20 weeks' gestation to diagnose eGDM using World Health Organization (2013) criteria. Lipidomic data were analyzed using multivariable linear regression, unsupervised clustering, weighted gene co-expression network analysis (WGCNA), and logistic regression-based risk modeling. RESULTS: In 89 eGDM and 91 non-GDM controls, we quantify 543 lipid species across 18 lipid classes. We identify a distinct lipidomic signature of eGDM, comprising elevated concentrations of glycerolipids (diacylglycerols), fatty acids, and ethanolamine-containing glycerophospholipids (phosphatidylethanolamine and lysophosphatidylethanolamine), alongside lower concentrations of choline-containing glycerophospholipids (lysophosphatidylcholine and ether-linked phosphatidylcholine) and glycosphingolipids (hexosylceramides). Fatty acid and diacylglycerol species are the strongest and most consistent lipid predictors of eGDM and glycemic indices, independent of clinical risk factors. Lipid ontology-based enrichment analysis reveals perturbations in pathways related to lipid storage, membrane remodeling, and signaling. CONCLUSION: To our knowledge, this is the first study to characterize the lipidomic profile of women with eGDM. We identify a distinct lipidomic signature associated with eGDM, offering molecular insights into pathophysiology and highlighting candidate lipid biomarkers for future investigation and validation in this context.

Diabetic foot ulcers (DFUs) are a leading cause of morbidity in patients with diabetes mellitus and a major driver of multidrug-resistant (MDR) bacterial infection in low- and middle-income countries. This cross-sectional study characterised the clinical profile, microbial spectrum and phenotypic/genotypic resistance patterns of DFU-associated bacteria in 224 patients recruited from six tertiary hospitals in Islamabad, Pakistan, between November 2023 and December 2024. Wound swabs, pus aspirates and deep tissue biopsies were collected aseptically and processed on selective and non-selective media; isolates were identified by colony morphology, Gram staining and standard biochemical tests with ATCC reference strains as controls. Antimicrobial susceptibility was determined by Kirby-Bauer disc diffusion against 15 antibiotics following CLSI M100 (2023) guidelines. Plasmid DNA was extracted from all phenotypically β-lactam- or aminoglycoside-resistant isolates and screened by PCR for β-lactamase genes (blaTEM, blaCTX-M, blaSHV) and aminoglycoside-modifying enzyme genes (aac(6')-Ib, ant(4')-Ia, aph(3')-IIIa). Bacterial growth was obtained from 208/224 (92.9%) samples; six species were recovered: Staphylococcus aureus 41.3% (86/208), Escherichia coli 20.2% (42/208), Staphylococcus epidermidis 12.5% (26/208), Proteus vulgaris 10.6% (22/208), Proteus mirabilis 7.7% (16/208) and Pseudomonas aeruginosa 7.7% (16/208). Resistance to gentamicin was uniformly high (S. aureus 91.9%; E. coli 90.5%; S. epidermidis 84.6%); cefoperazone-sulbactam was the most active β-lactam against S. aureus (43.0% resistance) and colistin retained activity against E. coli (35.7% resistance). PCR detected aac(6')-Ib in 114/208 (54.8%), blaTEM in 91/208 (43.8%), blaCTX-M in 83/208 (39.9%), blaSHV in 82/208 (39.4%), ant(4')-Ia in 78/208 (37.5%) and aph(3')-IIIa in 76/208 (36.5%) of isolates. Fisher's exact test confirmed strong, statistically significant associations between aminoglycoside-modifying enzyme genes and gentamicin resistance, and between β-lactamase genes and cefotaxime resistance (specificity and positive predictive value = 100% at the reference antibiotic). DFUs in this Pakistani cohort were predominantly polymicrobial with a high burden of plasmid-mediated β-lactam and aminoglycoside resistance determinants. Strengthened antimicrobial stewardship, expanded molecular surveillance and patient-centred foot-care education are critical to reduce amputation risk and the public-health burden of DFU.

Studies linking mitochondrial DNA (mtDNA) with complex traits are often limited by small sample sizes or focused on specific phenotypes in clinically selected cohorts. Here, we use data from >600,000 participants in the Million Veteran Program (MVP) to perform a multi-ancestry analysis of mitochondrial DNA (mtDNA) variation and cardiometabolic phenotypes across European (EUR), African (AFR), Admixed American (AMR), and East Asian (EAS) populations. After validating 248 mtDNA loci, we identify 10 ancestry-stratified single-variant associations (8 EUR, 2 AFR) and 23 additional signals in sex- and type 2 diabetes (T2D)-stratified analyses. Four variants tagging haplogroup J, D-loop MT228G > A, MT-ND3 MT10398A > G (p.Thr114Ala), MT-ND5 MT13708G > A (p.Ala458Thr), and MT-CYB MT14798T > C (p.Phe18Leu), are associated with hypothyroidism in EUR and replicated in UK Biobank (UKBB) with concordant effects. In EUR females, MT-RNR1 MT1555A > G increases the risk of carditis and heart failure phenotypes, supporting prior reports of maternally inherited cardiomyopathy. Gene-based rare-variant tests (minor allele frequency ≤2%) yield 26 associations (12 EUR, 10 AFR, 2 AMR, 2 EAS), including mitochondrial tRNA burdens linked to primary cardiomyopathy (females) and exophthalmos (males). Twenty-three of the 33 single-variant signals map to the endocrine/metabolic category, indicating significant enrichment (Fisher's exact P = 0.003). These results define ancestry- and context-specific contributions of mtDNA to cardiometabolic disease, with a notable concentration in endocrine traits, and provide a framework for mtDNA analysis across diverse biobank cohorts.

BACKGROUND: Identifying differentially expressed miRNAs in plasma-derived exosomes associated with type 2 diabetes mellitus (T2DM) complicated by atherosclerosis (AS) and elucidating their roles in high-glucose/high-lipid-induced vascular endothelial dysfunction. METHODS: Plasma-derived exosomal miRNAs were isolated from people with T2DM complicated by AS and healthy controls. Followed by miRNA sequencing to characterize differential expression profiles between groups. GO and KEGG pathway enrichment analyses were performed on differentially expressed miRNAs. Human umbilical vein endothelial cells (HUVECs) were exposed to combined hyperglycemia and hyperlipidemia to establish an in vitro model of diabetic endothelial injury. HUVECs were subsequently transfected with miR-887-5p mimics, inhibitors or negative controls, and assessed for proliferation, migration, apoptosis, oxidative stress, and nitric oxide (NO) content. RESULTS: Sequencing revealed globally reduced plasma exosomal miRNA expression in people with T2DM and AS relative to healthy controls, with 21 upregulated and 23 downregulated miRNAs identified. Among these, hsa-miR-887-5p exhibited the greatest fold change of all detected miRNAs, while hsa-miR-96-5p and hsa-miR-183-5p (upregulated) and hsa-miR-410-3p (downregulated) harbored the most target genes implicated in diabetic atherosclerosis. Functionally, miR-887-5p enhanced HUVEC proliferation and migration under high-glucose/high-lipid conditions, elevated superoxide dismutase (SOD) activity, reduced lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, suppressed intracellular iNOS/NO and attenuated apoptosis. CONCLUSION: Plasma exosomal miRNA expression is broadly reduced in people with T2DM complicated by AS. hsa-miR-887-5p, hsa-miR-96-5p, hsa-miR-183-5p, and hsa-miR-410-3p may emerge as candidates with diagnostic and therapeutic relevance in this context. Specifically, miR-887-5p mitigates high-glucose/high-lipid-induced vascular endothelial injury, warranting further investigation as a therapeutic target.

PURPOSE: With little known about medication adherence for non-HIV chronic conditions in people living with HIV (PLHIV), this research evaluated antiretroviral (ART) adherence and non-ART composite medication adherence patterns among PLHIV and non-HIV chronic conditions (i.e., type 2 diabetes, hypertension, and hyperlipidemia) and their association with corresponding treatment goals. METHODS: Group-based multi-trajectory modeling of ART and non-ART adherence was used to identify medication adherence trajectories (MATs) over a 37-month observation period (9/2018-9/2021) in 525 continuously-enrolled PLHIV with multiple chronic conditions. ART and non-ART adherence were estimated using monthly proportion of days covered for diabetes, renin-angiotensin system antagonist, and statin medications. Relationships between MAT group membership and viral load, and a composite endpoint reflecting hemoglobin A1c, blood pressure, and/or total cholesterol control were evaluated using multivariable logistic regression. RESULTS: A six MAT model was identified: MAT-1 had inadequate, decreasing ART and non-ART adherence (6.3%); MAT-2 had inadequate, increasing ART and non-ART adherence (6.0%); MAT-3 had inadequate, divergent ART and non-ART adherence (11.5%); MAT-4 had inadequate, stable ART and non-ART adherence (17.6%); MAT-5 had low adequate ART and non-ART adherence (32.6%); and MAT-6 had high adequate ART and non-ART adherence (25.9%). Compared to MAT-6, MAT-1 (aOR = 0.24, p = 0.004) and MAT-2 (aOR = 0.24, p = 0.004) had decreased odds of achieving a viral load <20 copies/mL. Additionally, MAT-1 (aOR = 0.31, p = 0.038) and MAT-4 (aOR = 0.49, p = 0.033) had decreased odds of achieving the composite endpoint compared to MAT-6. CONCLUSIONS: Varying patterns of ART and non-ART adherence are differentially associated with achieving intermediate clinical endpoints suggesting tailored intervention to address unique medication adherence needs.

IMPORTANCE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used in adolescents with overweight or obesity, but their comparative effects on cardiometabolic outcomes across different agents remain uncertain. We aimed to compare the efficacy and safety of different GLP-1RAs on key cardiometabolic parameters in adolescents with overweight or obesity, with or without type 2 diabetes. METHODS: We searched PubMed, Embase, Web of Science, the Cochrane Library, and ClinicalTrials.gov from inception to May 1, 2026. Randomised clinical trials comparing GLP-1RAs with placebo or another active agent in eligible adolescents were included. Two reviewers independently extracted data and assessed risk of bias following PRISMA guidelines for network meta-analysis. We used a Bayesian random-effects model for data synthesis. RESULTS: 17 RCTs with 1230 participants were included. Semaglutide 2.4mg SC was associated with the largest reductions in body weight (mean difference -18.00kg; 95% credible interval -24.34 to -11.69, high confidence), BMI (-5.9kg/m^2, -10.5 to -1.3, high confidence), and waist circumference (-12.2cm, -21.67 to -2.67). For glycaemic control, dulaglutide 1.5mg SC showed the largest reduction in HbA1c (-1.50%, -1.84 to -1.15, high confidence), and lixisenatide 20 ug SC showed the largest reduction in fasting plasma glucose (-3.98mmol/L, -7.46 to -0.60); however, these rankings derive from networks with sparse head-to-head evidence and wide credible intervals for indirect comparisons. Exenatide 20 ug SC was associated with a reduction in systolic blood pressure (-6.64mmHg, -13.22 to -0.17) based on limited indirect evidence from early-phase trials. No agent improved lipid profiles in a statistically significant manner. CONCLUSION: In this network meta-analysis of adolescents with overweight or obesity, GLP-1RAs showed differential cardiometabolic profiles. Semaglutide 2.4mg produced the largest point estimates for weight-related outcomes, dulaglutide 1.5mg and lixisenatide 20 ug for glycaemic endpoints, and exenatide 20 ug for systolic blood pressure. These findings are hypothesis-generating: most active-treatment comparisons were indirect, many nodes were informed by single trials, and SUCRA rankings should not be interpreted as evidence of definitive clinical superiority.

OBJECTIVE: To assess the associations between the Dietary Inflammatory Index (DII) and obesity and dietary intake in adults with type 2 diabetes (T2DM), and to compare the findings with those obtained using the modified Japanese Diet Index (mJDI). METHODS: We conducted a cross-sectional study of 1,565 adults with T2DM in Japan between 2014 and 2019. Dietary intake was assessed using a validated food frequency questionnaire. The DII calculation was based on 25 nutrients. Participants were categorized into DII tertiles, and obesity was defined as BMI ≥ 25 kg/m. Logistic regression models were used to estimate associations between the DII and obesity with sequential adjustment for demographic, dietary, and lifestyle factors. Subgroup and sensitivity analyses were performed, and correlations between the DII and food group intakes were examined. RESULTS: Participants in higher DII tertiles were younger, more often male, and had higher BMI, lower energy intake, lower protein intake per kg of body weight, and lower physical activity. Higher DII scores were associated with greater odds of obesity (OR 2.412, 95% CI 1.751-3.323; P-trend < 0.001). The association was consistent across sex, age, energy intake, and physical activity categories. The DII was inversely correlated with intakes of vegetables, fruits, fish/seafood, soy products, and other nutrient-dense foods. Sensitivity analyses using BMI ≥ 30 kg/m showed similar but weaker associations. CONCLUSION: Higher DII scores were associated with obesity and lower intake of nutrient-dense foods in Japanese adults with T2DM, whereas higher mJDI scores were inversely associated with obesity. Associations appeared stronger for the DII.

AIMS: To characterize oral glucose tolerance test (OGTT)-derived metabolic phenotypes in children and adolescents with obesity, focusing on the clinical significance of elevated 1-hour plasma glucose. METHODS: This retrospective study included 726 children and adolescents with obesity who underwent an OGTT at a tertiary center. Participants were classified as NGT-Low (1-hour glucose < 155 mg/dL), NGT-High (≥155 mg/dL), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or advanced dysglycemia. OGTT-derived indices of insulin sensitivity and β-cell function were compared. ROC and multivariable logistic regression analyses identified determinants of dysglycemia. RESULTS: NGT-High showed lower insulin sensitivity (Matsuda index: 1.59 vs. 2.34, p < 0.001) and greater insulin exposure (insulin AUC: 19,845 vs. 13,048 µIU/mL × min, p < 0.001) than NGT-Low. Lower insulinogenic index at 30 min (IGI30), insulinogenic index at 60 min (IGI60), and Insulin Secretion-Sensitivity Index-2 (ISSI-2) indicated early β-cell dysfunction. Delayed insulin peak timing was observed in IGT and advanced dysglycemia groups. Fasting plasma glucose showed the highest discriminatory performance (AUC = 0.797); glycated hemoglobin (HbA1c) and ISSI-2 were independently associated with dysglycemia. CONCLUSIONS: A 1-hour glucose ≥ 155 mg/dL identifies a metabolically distinct phenotype with reduced insulin sensitivity and early β-cell dysfunction despite normal glucose tolerance, supporting 1-hour glucose incorporation into metabolic evaluation of youth with obesity.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a known risk factor for type 2 diabetes (T2D). However, whether MASLD onset age modifies T2D risk remains poorly understood. We aimed to determine the association of MASLD onset age and risk of incident T2D in a large prospective cohort. METHODS: 58,814 MASLD- and T2D- free participants at the first health examination (2006-2007) in the Kailuan Study were included. By December 31, 2015, 29,016 new-onset MASLD cases were identified. Each MASLD case was randomly matched to a MASLD-free control by age (±1 years) and sex. After excluding participants who developed T2D within first 2 years of follow-up, 19,378 MASLD cases and 19,483 controls were included. All participants were followed for incident T2D until 31 December 2020. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 11.8 years, 2,301 incident T2D cases were documented. Compared with non-MASLD, MASLD patients with onset age < 40 years had the highest risk of T2D (HR=6.18, 95% CI: 4.28, 8.93), followed by gradually attenuated elevated risks in older onset age groups: 40-<50 years (HR = 3.29, 95% CI: 2.70, 4.00), 50-<60 years (HR = 3.14, 95% CI: 2.69, 3.66), 60-<70 years (HR = 2.94, 95% CI: 2.39, 3.62), and ≥ 70 years (HR = 2.17, 95% CI: 1.56, 3.01). CONCLUSION: MASLD onset at any age is associated with increased risk of T2D, with earlier onset conferring progressively greater risk. This highlights the importance of preventing, or at least delaying MASLD onset, particularly in young adults.

OBJECTIVE: This study aims to evaluate changes in the epidemiology of major osteoporotic fractures(MOF) stratified by diabetes status over 15years in a population-based cohort. METHODS: Individuals aged≥50years who sustained MOF between 2009 and 2023 identified from territory-wide electronic health database, stratified by diabetes status. Records of HbA1c, hypoglycemic episodes, and osteoporosis screening and treatments were retrieved. Ratios of rates of MOF, osteoporosis screening and treatments between the diabetes and non-diabetes groups were calculated to reflect the disparity between two groups. Secular trends were reported in average annual percentage change(AAPC) using joinpoint regression. All rates were age-standardized to the 2021 Hong Kong Census mid-year population. RESULTS: 86263 hip fractures and 124268 non-hip fractures were recorded during the study period. Although annual age-standardized incidence of hip fractures decreased, rate ratios between diabetes and non-diabetes remained static at 4.1 for women(AAPC -0.16%,95%CI -0.65 to +0.35,p=0.54) and 2.5 for men(AAPC +0.07%,95%CI -0.58 to 0.71,p=0.83), suggesting persistent gap of diabetes-specific excess fracture risk. This gap was similarly observed for non-hip fractures. Over the years, age-standardized mean HbA1c improved from 59 mmol/mol(7.5%) to 53 mmol/mol(7%), along with fewer severe hypoglycemic episodes. Prevalence of individuals with screening dual-energy x-ray absorptiometry performed increased, more so in women with diabetes. Anti-osteoporosis medication prescriptions increased in both diabetes and non-diabetes, but increased to a lesser extent in the diabetes population. CONCLUSION: Diabetes-specific excess fracture risk persisted despite improved glycemic control. Despite increasing efforts of osteoporosis screening in diabetes, this has not translated into more aggressive treatment of bone fragility in diabetes.

OBJECTIVE: This exploratory study aimed to investigate whether combining preoperative intranasal insulin with pre-emptive analgesia is associated with a lower incidence of postoperative delirium (POD) in elderly patients undergoing lower extremity fracture surgery. METHODS: This prospective, randomized, exploratory trial involved 186 patients (aged ≥65 years and classified as ASA class II-III), who were allocated to one of three groups (n = 62): Group C (control: intranasal saline, 0.5 mL); Group I (insulin: intranasal insulin, 20 IU [0.5 mL]) and Group IP (insulin and pre-emptive analgesia: intranasal insulin as in Group I, plus a preoperative ultrasound-guided iliac fascia block with 0.375% ropivacaine [30 mL]). Intranasal administrations were given twice daily for two preoperative days and 20 min before anesthesia induction (five doses in total). The outcomes included NRS pain scores (at baseline [P1], 30 min after the intervention [P2] and 30 min after the third intranasal dose on day two [P4]), SRSS sleep scores (at baseline [P0] and on the night of the intervention [P3]), the incidence of postoperative delirium (assessed using the 3D-CAM on postoperative days one [T1], three [T2] and five [T3]), and serum biomarkers (insulin, glucose, insulin resistance [IR] and p-tau) at baseline [P1] and on postoperative day 1 [T1]). RESULTS: The incidence of POD was significantly lower in Group IP (17.74%) than in Group C (38.71%; corrected P = 0.009), while no significant difference was observed between Group I (27.42%) and Group C (corrected P = 0.181). For secondary exploratory outcomes, Group IP showed lower NRS scores at P2 and P4 (both nominal P < 0.001 vs. Group C) and lower SRSS scores at P3 (nominal P < 0.001 vs. Group C), suggesting potential improvements in pain and sleep. These patterns were not observed in Group I. Preoperative biomarkers were comparable across groups. Postoperatively, Group IP showed lower glucose (nominal P = 0.028), IR (nominal P = 0.001), and p-tau levels (nominal P < 0.001) compared with Group C, as well as lower insulin (nominal P < 0.001), IR (nominal P = 0.008), and p-tau (nominal P < 0.001) compared with Group I. Longitudinal analysis (T1 vs. P1) indicated an increase in p-tau in Group C and Group I (both nominal P < 0.001), whereas p-tau levels remained relatively stable in Group IP. A reduction in IR was observed only in Group IP (nominal P < 0.001). CONCLUSION: In this exploratory study, preoperative intranasal insulin alone showed no clear association with reduced POD or improved sleep. However, its combination with pre-emptive analgesia was associated with lower POD incidence, better pain and sleep profiles, and favorable biomarker changes. These hypothesis-generating findings warrant confirmation in future trials.

BACKGROUND: Metabolic syndrome is common in older adults and increases cardiometabolic risk. The fibroblast growth factor 21 (FGF21)-adiponectin axis regulates metabolic homeostasis, but its exercise responsiveness may differ by metabolic status. This study investigated the effects of exercise on circulating FGF21, adiponectin, and the FGF21/adiponectin ratio in older women with and without metabolic syndrome. METHODS: Sixty older women (75.2 ± 4.3 years) were classified by metabolic syndrome status and randomly assigned to control or exercise groups. Exercise groups completed a 10-week supervised combined exercise program consisting of body-weight resistance and cross-linked elastic resistance band training (3 sessions/week, 60 min/session), while controls maintained their usual lifestyle. Blood biomarkers, body composition, physical fitness, and metabolic parameters were assessed before and after the intervention and analyzed using two-way repeated-measures ANOVA. RESULTS: The FGF21-adiponectin axis was modulated by the intervention. Adiponectin increased in both exercise groups (NMSE: mean change, 1.23; 95% CI, 0.98-1.49; d = 1.04; MSE: mean change, 0.86; 95% CI, 0.31-1.40; d = 0.71). FGF21 increased in the NMSE group (mean change, 16.75; 95% CI, 5.46-28.05; d = 0.40) but decreased in the MSE group (mean change, -15.91; 95% CI, -28.35 to -3.48; d = -0.33). The FGF21/adiponectin ratio decreased in both exercise groups, with a greater reduction in MSE (NMSE: mean change, -2.18; 95% CI, -4.18 to -0.18; d = -0.29; MSE: mean change, -6.48; 95% CI, -9.82 to -3.15; d = -0.86). Secondary outcomes, including body composition, physical fitness, lipid profiles, insulin resistance markers, and inflammatory markers, also improved with small-to-large effect sizes. CONCLUSION: Combined exercise improved metabolic health and modulated the FGF21-adiponectin axis in older women, with differential FGF21 responses by metabolic status. The reduced FGF21/adiponectin ratio may indicate exercise-induced metabolic adaptation. TRIAL REGISTRATION: KCT 0011558.

OBJECTIVE: This study investigated the associations of intrinsic capacity, a multidomain measure of functional health, with the incidence and progression of ischemic heart disease, and the mediation of such associations by indices related to insulin resistance (IR). METHODS: We included 386,462 adults from the UK Biobank who were free of ischemic heart disease and its associated complications, including heart failure and arrhythmia, at baseline. Associations were estimated using Cox models, and multistate models for transitions. Mediation by IR-related indices was quantified in a counterfactual framework. RESULTS: Over a median 13.68 years of follow-up, 29,994 ischemic heart disease events occurred. Hazard ratios (95% confidence intervals) for ischemic heart disease were 1.15 (1.11-1.18), 1.38 (1.33-1.43), 1.68 (1.61-1.75), and 2.24 (2.12-2.37) for intrinsic capacity scores of 1, 2, 3, and ≥4 versus 0. Estimates from the multistate model for the transition from baseline to ischemic heart disease were consistent with the Cox results. Hazard ratios (95% confidence intervals) for transition from ischemic heart disease to death were 1.32 (1.14-1.53) for intrinsic capacity score 3 and 1.46 (1.21-1.74) for intrinsic capacity score ≥ 4, and 1.30 (1.09-1.56) from complications to death for intrinsic capacity score ≥ 4. IR-related indices accounted for 6.77-22.40% of the association between intrinsic capacity and ischemic heart disease, 5.38-24.24% for complications, and 2.22-10.04% for death. CONCLUSIONS: Lower intrinsic capacity was associated with higher risks of ischemic heart disease and its progression, partly through IR-related pathways, supporting metabolic dysfunction as a modifiable target for early risk stratification.

Current therapies cannot simultaneously address the interconnected metabolic, cardiac, and renal damage in Cardiovascular-Kidney-Metabolic (CKM) syndrome. This study investigated ACF210, a novel long-acting dual agonist targeting both GLP-1 and APJ receptors, as a potential treatment for type 2 diabetes (T2D)-induced CKM syndrome. ACF210 was synthesized by fusing the human IgG4 Fc fragment to the C-terminus of GLP-1 and the N-terminus of Elabela-21 (ELA). In vitro receptor activation assays confirmed that ACF210 effectively activated the GLP-1 and APJ receptor signaling simultaneously. db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced T2D were treated with dulaglutide, Fc-ELA, or ACF210 for 12 weeks. We assessed tissue morphology, organ function, and serum biomarkers. Compared to the diabetic control mice, ACF210 significantly improved blood glucose control and pancreatic β-cell function. Crucially, ACF210 demonstrated superior multi-organ protective effects over other treatments. Specifically, ACF210 reduced hepatic steatosis and provided comprehensive cardiac protection by lessening mitochondrial damage and fibrosis, enhancing diastolic function, reducing heart failure biomarkers such as NT-proBNP, and promoting microangiogenesis. In the kidneys, ACF210 alleviated podocyte damage and thickening of the glomerular basement membrane, while improving renal function as indicated by reduced levels of urinary albumin-to-creatinine ratio (UACR) and serum cystatin C. In conclusion, ACF210 not only effectively alleviates dysglycemia by potentially enhancing β-cell function but also significantly protects against diabetes-associated hepatic, cardiac, and renal damage, supporting its further exploration for the clinical management of CKM syndrome.

INTRODUCTION: The monoterpenoid eucalyptol (EUC; 1,8-cineole) has a vasodilatory effect on rat arteries; however, its effects on the human fetoplacental vasculature had not yet been described. Thus, the objective of this study is to evaluate the endothelium-independent vasorelaxant effect of EUC on human umbilical veins from normoglycemic parturients (HUV-NG) and parturients with gestational diabetes mellitus (HUV-GDM). METHOD: Denuded HUV rings were mounted in organ bath for isometric recordings under different experimental protocols in the presence of EUC (1-3000 μM). RESULTS: EUC (1-3000 μM) inhibited vasoconstriction induced by KCl (60 mM) and 5-HT (10 μM), exhibiting greater potency in HUV-GDM. EUC (3000 μM) prevented vasoconstriction induced by CaCl or BaCl (0.1-30 mM) in HUV-NG. However, its efficacy in preventing vasoconstriction induced by high concentrations of BaCl was attenuated in HUV-GDM. The presence of potassium channel blockers (TEA, 4-AP, GLI, and BaCl) reduced the vasorelaxant efficacy and potency of EUC, differentially in HUV-NG and HUV-GDM. DISCUSSION: The results suggest that EUC acts by modulating ion channels to induce vasorelaxation in HUV, possibly through the inhibition of voltage-operated calcium channels and the activation of potassium channels in vascular smooth muscle. Furthermore, the pathophysiological changes induced by GDM in HUV appear to alter the pharmacodynamics of EUC; nevertheless, the vasorelaxant effect of EUC was more potent via electromechanical and pharmacomechanical pathways in HUV-GDM. Thus, the current study provides a basis for the development of new pharmacological vasodilator strategies.

A central challenge in polygenic risk prediction is measuring and controlling for confounding due to population stratification. Standard approaches include adjusting for leading principal components (PCs) of genetic variation and using linear mixed models in genome-wide association studies (GWAS). Evidence of adequate control is typically inferred from reductions in the linkage disequilibrium score regression (LDSC) intercept and the preservation of polygenic risk score (PRS) performance in within-sibling settings. Here, we investigate how the number of PCs included during GWAS/PRS construction relates to the loss of predictive performance when moving from population-based analyses to that of discordant sibling pairs (within-sibling attenuation). This design detects confounding arising from environmental and genetic background effects correlated with population structure. Analyses were performed in the self-identified White subset of the UK Biobank (UKB) for coronary artery disease, type 2 diabetes, breast cancer, and prostate cancer, with educational attainment included as a comparison trait as it is known to exhibit substantial within-sibling attenuation. We find that increasing the number of PCs does not consistently reduce within-sibling attenuation across traits. Furthermore, reductions in attenuation do not closely correspond to decreases in the LDSC intercept, and mixed model-based methods offer little additional improvement in prediction or attenuation. Overall, our results suggest that confounding targeted by PC-adjustment and linear mixed models is either minimal in the UKB, or remains inadequately captured by current methods, reflecting limitations as to how much standard population structure correction improves the causal validity of PRS in the UKB.

PURPOSE: Gestational diabetes mellitus (GDM) is a common metabolic disorder of pregnancy associated with placental dysfunction and adverse maternal-fetal outcomes. LncRNAs have emerged as important regulators in metabolic diseases. The clinical significance and molecular mechanisms of lncRNA PANDAR in GDM remain unclear. METHODS: 117 GDM patients and 110 healthy pregnant women were enrolled. Relative expression of genes was measured by qRT-PCR. The diagnostic value of PANDAR was assessed using ROC analysis, and its association with adverse pregnancy outcomes was evaluated by logistic regression. High-glucose model was established in HTR-8/Svneo trophoblast cells to investigate the function of PANDAR. Cell apoptosis, viability, and invasion were assessed using flow cytometry, CCK-8, and Transwell assays. The regulatory relationships among molecules were validated by dual-luciferase reporter assays. RESULTS: PANDAR expression was upregulated in GDM patients and exhibited good diagnostic performance. PANDAR levels were higher in GDM patients with adverse pregnancy outcomes. Elevated PANDAR was independently associated factor for adverse pregnancy outcomes. High glucose induced PANDAR expression and promoted trophoblast apoptosis while inhibiting cell viability and invasion, effects that were alleviated by PANDAR silencing. PANDAR functioned as a ceRNA for miR-192-5p, thereby upregulating the pro-apoptotic target BCL2L11. Rescue experiments confirmed that a PANDAR/miR-192-5p/BCL2L11 axis mediated trophoblast dysfunction under hyperglycemic conditions. CONCLUSION: PANDAR is associated with adverse pregnancy outcomes and may reflect hyperglycemia-induced cellular responses by promoting trophoblast dysfunction via a miR-192-5p/BCL2L11 axis.

Type 2 diabetes mellitus (T2DM) complicated by muscle atrophy (diabetic sarcopenia) significantly increases mortality risk, with immunometabolic imbalance-driven disruption of the skeletal muscle microenvironment as a core mechanism. This review focuses on the immune cell-myocyte crosstalk network to elucidate the pathological mechanisms of T2DM-induced muscle atrophy, the local remodeling effects of exercise, and systemic organ crosstalk. In the T2DM state, M1/M2 imbalance and metabolic reprogramming of macrophages, dysregulated mast cell activation and histamine signaling, NLRP3 inflammasome-mediated pyroptosis, T-cell immunosenescence, and chemokine storms collectively disrupt muscle homeostasis. Exercise reverses these abnormalities by downregulating TRIB3/AKT to promote M2 polarization, restoring mast cell function, inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway, increasing Treg infiltration, and downregulating the chemokine network, thereby shifting the local microenvironment from a "pro-inflammatory/destructive" to a "reparative/regenerative" state. Furthermore, exercise exerts systemic regulation through multiple organ axes, including adipose tissue (adipokines and inflammation), gut microbiota, liver (SIRT1/FGF21 signaling), and the brain (hypothalamic-pituitary-adrenal axis and myokines such as BDNF and CTSB for bidirectional neuroimmune regulation). In summary, exercise directly remodels the local immune crosstalk network in skeletal muscle and synergistically improves T2DM-associated muscle atrophy through multi-organ interactions, providing a theoretical basis for precise exercise interventions.