IntroductionDiabetes and obesity are associated with increased risk of complications following total knee arthroplasty (TKA). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a modality for optimizing weight and glycemic control in the perioperative period. This study aims to compare 2-year postoperative complications between GLP-1 RA users and non-users, using laterality-verified methodology to ensure ipsilateral outcome attribution.MethodsA retrospective query of the TriNetX database identified patients who underwent TKA and used GLP-1 RAs within a 1-year preoperative period. GLP-1 RA patients were 1:1 propensity matched to non-user controls for demographics and confounding comorbidities. Laterality was assessed independently to ensure ipsilateral TKA and corresponding complication. Outcomes analyzed were TKA revision, periprosthetic joint infection (PJI), mechanical loosening, periprosthetic fracture, and other mechanical complications within a 2-year postoperative period. Results were further stratified to isolate outcomes among diabetic patients. Results were reported as risk ratios, 95% confidence intervals, and values.ResultsGLP-1 RA users experienced significantly lower rates of PJI (1.5% vs. 2.0%; RR 0.74; 95% CI 0.57, 0.96; = 0.02) compared to non-users in a 2-year postoperative period. Among diabetic patients, GLP-1 RA users had significantly lower PJI rates (1.7% vs. 2.5%; RR 0.68; 95% CI 0.52, 0.89; < 0.01). There were no significant differences between rates of revision, mechanical loosening, periprosthetic fractures, or other mechanical complications in the overall or diabetic-only cohorts.ConclusionGLP-1 RA use was associated with a reduced risk of PJI in a 2-year postoperative period without any significant differences in mechanical outcomes in both overall and diabetic-only cohorts. This laterality-verified analysis provides more accurate outcome attribution than prior database studies and supports a selective protective effect of GLP-1 RAs against infection-related rather than mechanical complications following TKA.

BACKGROUND: Indoor solid fuels, outdoor air pollution (PM, PM, and PM), and heatwave are all modifiable environmental factors. However, their mixed effects on Cardiometabolic Multimorbidity (CMM) and its core component diseases (diabetes, heart disease, and stroke) remain unclear. METHODS: In this study, four diseases analysis cohorts (CMM: n = 10,273; diabetes: n = 9,893; heart disease: n = 9,536; and stroke: n = 10,466) were constructed using data from the five waves (2011, 2013, 2015, 2018, and 2020) of the CHARLS. A time-varying Cox proportional hazards model was used to estimate the hazard ratio (HR) for environmental factor exposure. The Cumulative Risk Index (CRI) and the Quantile g-computation (Qgcomp) model were employed to assess the cumulative effect and component weights of coexposure to multiple environmental factors. RESULTS: The single-exposure analysis indicated that indoor solid fuels use significantly increased heart disease (HR = 1.118, 95% CI 1.016-1.231) and stroke (HR = 1.149, 95% CI 1.007-1.310) risks. PM, PM, and PM were the most consistent risk factors for CMM, diabetes, and heart disease (all HRs > 1, P < 0.001), and heatwave was sometimes associated with higher risks of CMM, diabetes, and heart disease. The CRI analysis demonstrated that coexposure to multiple environmental factors increased the CMM, diabetes, and heart disease risks. The Qgcomp model further showed that these coexposure increased the risk of four diseases, with ORs (95% CIs) (CMM:1.650, 1.375-1.979; diabetes: 1.675, 1.475-1.903; heart disease: 1.228, 1.080-1.397; stroke: 1.205, 1.011-1.437), with indoor solid fuels use as the primary contributor. CONCLUSIONS: In conclusion, long-term coexposure to indoor solid fuels, outdoor air pollution, and heatwave increased the risk of CMM and its core component diseases. Indoor solid fuels play a main role in these effects.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2i) may exert antiarrhythmic effects, but their association with ventricular arrhythmias remains unclear. OBJECTIVE: We conducted a systematic review to evaluate the association between SGLT2i use and the risk of ventricular arrhythmias, cardiac arrest, and sudden cardiac death compared with other antidiabetic medications or no SGLT2i use among patients with type 2 diabetes mellitus. METHODS: MEDLINE, EMBASE, and CENTRAL were searched for observational studies published between March 2013 and March 2026. Quality was assessed using the Risk of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool, alongside evaluation of pharmacoepidemiology-specific biases. RESULTS: A total of 17 studies (16 cohort and one nested case-control) were included. Based on ROBINS-I, seven studies had moderate, eight serious, and two critical risks of bias. Eleven studies had at least one pharmacoepidemiology-specific bias. For ventricular arrhythmias, estimates ranged from a protective effect (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.04-0.97) to a potential increased risk (odds ratio 1.87, 95% CI 0.89-3.95) with SGLT2i use. For cardiac arrest, estimates consistently reported a lower risk with estimates that ranged from HR 0.63 (95% CI 0.59-0.68) to HR 0.85 (95% CI 0.82-0.88). The only study on sudden cardiac death reported a potential risk reduction (HR 0.62, 95% CI 0.38-1.01). CONCLUSIONS: While the association between SGLT2i and ventricular arrhythmias remains inconsistent, the use of SGLT2i likely reduces cardiac arrest and may reduce sudden cardiac death, suggesting a possible protective effect on ventricular arrhythmias among patients with type 2 diabetes.

INTRODUCTION: Heart failure with reduced ejection fraction (HFrEF), defined by a left ventricular ejection fraction ≤ 40%, remains a major global health challenge, associated with substantial morbidity, mortality, and impaired quality of life (QoL), particularly in patients with higher NYHA class. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone therapy for HFrEF, significantly reducing hospitalizations and mortality regardless of glycemic status, sex, race, or comorbidities. METHODS: EVOLUTION-HF was an observational, multi-center, longitudinal cohort study involving 257 consecutive patients diagnosed with HFrEF who initiated dapagliflozin in a routine clinical setting in Greece. The primary objectives were to characterize baseline demographic and clinical features of patients newly initiated on dapagliflozin for HFrEF and to evaluate dapagliflozin treatment patterns, including discontinuation timing, reasons for discontinuation, and concomitant heart failure and glucose-lowering therapies over time. The secondary objectives are to describe patient-reported outcomes using the KCCQ-23 and to assess adherence to dapagliflozin among patients with HFrEF. RESULTS: A total of 257 patients were enrolled and the follow-up period lasted for 12 months. Significant improvements among all KCCQ-23 scores were observed from baseline to 12-months post dapagliflozin initiation, revealing that the initiation and optimization of guideline-directed medical therapy in routine clinical practice provides improvement to quality of life over time. CONCLUSIONS: Dapagliflozin was safe and well-tolerated throughout the observation period. Although benefits are observed in most patients, individuals aged > 65 years, with prior myocardial infarction, or recent hospitalizations show a diminished response, underscoring the need for tailored management and closer follow-up in these higher-risk groups.

Cardiovascular-kidney-metabolic (CKM) syndrome encompasses obesity, type 2 diabetes, cardiovascular disease, and chronic kidney disease. Insulin resistance has traditionally been considered the primary driver, with hyperinsulinemia viewed as a compensatory response. However, emerging evidence suggests that hyperinsulinemia may precede insulin resistance in specific phenotypes and contribute to early disease mechanisms. We conducted a narrative review of the role of hyperinsulinemia in CKM syndrome. Literature searches were performed in PubMed/MEDLINE, Embase, and Scopus through December 2025. We prioritised prospective cohort studies, meta-analyses, Mendelian randomisation studies, and randomised controlled trials, and synthesised evidence across cardiovascular, renal, and metabolic domains. Sustained hyperinsulinemia is associated with myocardial hypertrophy and fibrosis through selective preservation of mitogenic signalling, contributing to heart failure phenotypes. In the kidney, it enhances sodium and glucose reabsorption, increases intraglomerular pressure, and promotes podocyte dysfunction, potentially accelerating CKD progression. Epidemiological evidence consistently shows associations between elevated fasting insulin levels and cardiovascular events, renal outcomes, and mortality across diverse populations, with meta-analytic estimates reporting a pooled relative risk of 1.46 (95% CI 1.16-1.84) for incident cardiovascular events. However, available data are largely observational and heterogeneous in exposure definitions and adjustment models. Hyperinsulinemia represents a clinically relevant and potentially modifiable component of CKM syndrome, with effects extending beyond glucose homeostasis. While causality is biologically plausible and supported by genetic and epidemiological evidence, it remains to be established through interventional studies. Recognition of hyperinsulinemia may support earlier risk stratification and mechanism-based interventions, although prospective validation is required before routine clinical implementation.

Renal biopsy is widely performed worldwide, but reported bleeding risks vary due to differences in technique, devices, operators, and patient populations. This study aimed to define the bleeding risk associated with current spring-loaded biopsy guns in a South-Asian population, identify relevant risk factors, and quantify the additional cost and hospital stay from bleeding complications. In this six-month prospective observational cohort study, all adult patients undergoing kidney biopsy at a tertiary hospital were enrolled. Demographic, clinical, radiological, procedural, and histopathological data were collected. Bleeding was defined as gross haematuria, perinephric hematoma, hemoglobin drop, transfusion requirement, or need for intervention. Factors associated with bleeding were evaluated using univariate analysis and multivariate logistic regression. Among 980 patients, overall bleeding incidence was 4.9%, with 1.6% clinically significant events. On univariate analysis, higher creatinine, urea, dialysis dependence, and ischemic heart disease were associated with bleeding, whereas diabetes mellitus was associated with lower bleeding risk. On multivariate analysis, ischemic heart disease remained independently associated with bleeding, while diabetes mellitus remained associated with lower bleeding risk. Histopathological chronicity, including glomerulosclerosis and interstitial fibrosis, was also associated with clinically significant bleeding events (requiring transfusion or intervention). Bleeding after kidney biopsy was infrequent in this cohort. Ischemic heart disease and histopathological chronicity were associated with increased bleeding risk, while procedural and operator-related factors were not significantly associated in this cohort, although these findings should be interpreted cautiously. Bleeding was associated with increased hospital stay and healthcare costs.

BACKGROUND: Hypertension is frequently accompanied by metabolic abnormalities that increase cardiovascular risk. The triglyceride-glucose (TyG) index is a practical surrogate marker of insulin resistance. This study aimed to compare TyG index values and related metabolic parameters between patients receiving RAAS blockers plus thiazide/thiazide-like diuretics and those receiving RAAS blockers plus calcium channel blockers (CCBs) as antihypertensive regimens. METHODS: In this retrospective observational study, 157 of 189 screened patients met eligibility criteria and were included (RAAS blocker plus thiazide/thiazide-like diuretic, n=95; RAAS blocker plus CCB, n=62). Multivariable linear regression models and inverse probability of treatment weighting (IPTW) analyses were performed to assess the independence of findings from clinical confounders. RESULTS: The TyG index was significantly higher in the diuretic group than in the CCB group [9.21 (9.01-9.73) vs 8.95 (8.66-9.40); p<0.001], as were triglyceride [186.00 vs 142.35 mg/dL; p<0.001] and uric acid levels [5.70 vs 5.00 mg/dL; p=0.004]. Blood pressure control rates were similar. The treatment group effect remained significant across all adjusted models, including IPTW-weighted regression (β=0.385, p=0.0003). A significant treatment group × diabetes mellitus interaction was observed (p=0.042), suggesting a stronger association in diabetic patients. A dose-stratified analysis within the diuretic group showed a significant dose-response relationship: higher hydrochlorothiazide (25 vs 12.5 mg/day) and indapamide (2.5 vs 1.25 mg/day) doses were both associated with significantly higher TyG index, fasting glucose, and uric acid levels. In an exploratory diuretic subgroup analysis, urea and BUN levels were higher with hydrochlorothiazide than indapamide; however, this analysis was underpowered (indapamide n=24) and should be interpreted with caution. CONCLUSIONS: RAAS blocker plus thiazide/thiazide-like diuretic regimens were associated with a significantly higher TyG index and a less favorable metabolic profile than RAAS blocker plus CCB regimens, independent of multiple clinical confounders. Metabolic risk profiles should be considered when selecting antihypertensive combination therapy; prospective studies are needed to establish causality.

Periodontitis is a chronic inflammatory disease associated with obesity, type 2 diabetes, and cardiovascular disease, and has become a serious public health issue. Antibacterial treatment and mechanical debridement are the main treatment strategies for periodontitis. However, side effects and bacterial resistance might lead to treatment failure. Nanotechnology systems have new opportunities for the management of periodontitis. With benefits including superior targeting and fewer side effects, drug delivery systems constructed with nanoparticles (NPs) may provide local, delayed, and regulated drug release. When combined with immunomodulatory therapy, tissue regeneration, and antibacterial therapy, a high drug loading capacity of individual medications or therapeutic combinations is made possible by the large surface area to volume ratio of nanoparticles, providing synergistic beneficial effects. This paper reviews the progress in the research and application of nanoparticle-based drug delivery systems in the treatment of periodontitis. We focused on the pathophysiology of periodontitis, introduced the rational design of nano-drug delivery systems, and concentrated on the local approaches to treatment for periodontitis. Furthermore, the future challenges and research prospects for nanoparticle-based drug delivery systems in the treatment of periodontitis are also covered in this paper.

BACKGROUND: Blood-brain barrier (BBB) disruption is a key pathological mechanism of cerebral small vessel disease (CSVD). White matter hyperintensities (WMH), a major imaging feature of this disease, show unclear regional and severity-related differences in BBB leakage, along with uncertain independent risk factors. Conventional understanding that leakage increases steadily with lesion severity has not been validated with refined stratification. This study aimed to characterize the heterogeneous patterns of BBB leakage in periventricular (PWMH) and deep WMH (DWMH) stratified by Fazekas grade and identify their independent risk factors using quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters. METHODS: This single-center retrospective study included 75 patients with sporadic CSVD who underwent 3.0-tesla (3.0T) DCE-MRI. WMH were classified into PWMH and DWMH locations and graded by the Fazekas scale (0/1, 2, 3). The volume transfer constant (K) and plasma volume fraction (Vp) were derived from the Extended Tofts two-compartment model to assess BBB permeability and local perfusion, respectively. Group comparisons were performed using Mann-Whitney U tests, correlations were evaluated with Spearman rank analysis, and independent predictors of K were identified via stepwise multiple linear regression, with a significance threshold of α=0.05 (two-sided). RESULTS: K was significantly higher in Fazekas grade 2 PWMH than in grade 0/1 (P=0.0014) and significantly lower in grade 3 (P<0.0001). For DWMH, K was significantly higher in grade 2 (P=0.037) and significantly lower in grade 3 (P=0.0002) relative to grade 0/1. PWMH showed significantly higher K than DWMH at identical grade 0/1 and grade 2 (both P<0.05), but not at grade 3 (P>0.05). Vp declined progressively with increasing Fazekas grade: in PWMH, Vp was significantly lower in both grade 2 (P=0.027) and grade 3 (P<0.0001) versus grade 0/1; in DWMH, only grade 3 showed significantly lower Vp than grade 0/1 (P=0.021). Spearman correlation analysis revealed that K was positively correlated with Vp in most subgroups (PWMH grade 0/1: r=0.444, P=0.014; DWMH grade 0/1: r=0.288, P=0.043), except for PWMH grade 3 (r=0.274, P=0.367). Multiple linear regression (Fazekas grades 0-2) showed that age [β=-0.526, 95% confidence interval (CI): -0.944 to -0.108, P=0.015], Vp (β=0.870, 95% CI: 0.031-1.709, P=0.043), and Fazekas grade 2 classification (β=20.970, 95% CI: 12.01-29.94, P<0.0001) were independent predictors of K in PWMH. For DWMH, type 2 diabetes mellitus (β=9.770, 95% CI: 3.870-15.670, P=0.002) and Fazekas grade 2 classification (β=6.845, 95% CI: 0.977-12.710, P=0.023) were independent positive predictors of K. CONCLUSIONS: BBB leakage in WMH presents clear regional and severity-dependent heterogeneity. Moderate lesions represent the active stage of barrier disruption. Reduced leakage values in severe lesions may mainly stem from diminished local perfusion restricting contrast agent delivery instead of restored barrier function. Periventricular and deep lesions are regulated by distinct risk factors. These results support refined risk evaluation and targeted intervention for CSVD.

BACKGROUND: Non-valvular atrial fibrillation (NVAF) carries a high risk of left atrial appendage thrombus (LAAT) and dense spontaneous echo contrast (dense SEC), the primary triggers of cardioembolic stroke. Conventional CHADS [congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke/transient ischemic attack (TIA) score] and CHA2DS‑VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke/TIA, vascular disease, age 65-74 years, Sex category score) scores lack left atrial appendage (LAA) morphological features, yielding limited predictive accuracy for dense SEC/LAAT. This study constructed a nomogram based on quantitative LAA parameters derived from three-dimensional transesophageal echocardiography (3D-TEE) to predict dense SEC/LAAT in NVAF patients and compared its performance with the two conventional clinical risk scores. METHODS: We retrospectively enrolled 159 NVAF patients who underwent 3D-TEE from July 2024 to December 2025, stratified into a dense SEC/LAAT positive group (n=50) and a negative group (n=109). Variables with severe multicollinearity [variance inflation factor (VIF) ≥10] were excluded. Univariate logistic regression (P<0.10) screened candidate predictors, followed by forward stepwise multivariate logistic regression to identify independent risk factors and construct a nomogram. Model discrimination, calibration and clinical utility were assessed via receiver operating characteristic (ROC) curves, calibration curves, 10-fold cross-validation, decision curve analysis (DCA) and clinical impact curves; inter-model area under the curve (AUC) comparisons used P<0.05 as the statistical significance threshold. RESULTS: Four independent predictors of dense SEC/LAAT were identified: D-dimer >0.550 mg/L [odds ratio (OR) =7.805, 95% confidence interval (CI): 2.044-29.795, P=0.002]; European Heart Rhythm Association (EHRA) score ≥ IIb (OR =6.255, 95% CI: 1.458-26.833, P=0.013); LAA poor echogenicity (OR =23.037, 95% CI: 5.651-93.909, P<0.001); LAA orifice morphology (OR =0.537, 95% CI: 0.296-0.975, P=0.041). The nomogram achieved an original AUC of 0.892 (95% CI: 0.839-0.945) at an optimal cutoff value of 0.29, with sensitivity 0.82, specificity 0.83, accuracy 0.82, and negative predictive value 0.91. It significantly outperformed CHADS (AUC =0.629) and CHADS-VASc (AUC =0.606) (all P<0.05). Ten-fold cross-validation yielded an optimism-corrected AUC of 0.868 and a mean Brier score of 0.127; however, marked overfitting was observed (calibration slope =4.175, mean maximum calibration error =0.385). DCA confirmed sustained positive net clinical benefit within the 10-50% threshold probability range. CONCLUSIONS: The 3D-TEE-based nomogram shows acceptable discrimination for dense SEC/LAAT in NVAF patients and addresses the limitations of traditional risk scoring systems. Nevertheless, prominent overfitting prevents its direct clinical use without external validation and recalibration; it can serve as an auxiliary research tool for LAAT risk stratification.

In humans, hypersecretion of amyloidogenic amylin (islet amyloid polypeptide, IAPP) in the setting of insulin resistance and type 2 diabetes (T2D) promotes systemic oligomerization and tissue deposition, with deposits identified in failing human hearts and the cerebrovasculature of patients with Alzheimer's Disease. In the renal vasculature, amylin aggregation disrupts microvascular integrity, activating hypoxia signaling pathways and contributing to maladaptive erythropoietic responses, including excess erythrocytosis. We hypothesized that amyloid-forming amylin would activate hypoxia-inducible factor (HIF) signaling, leading to metabolic alterations in liver and heart during T2D pathogenesis. To investigate this, we used the HIP rat, which expresses human amylin specifically in pancreatic β-cells, comparing tissues from 14 to 16-month-old rats with those from age-matched wild-type, hyperglycemic UCD and amylin-knockout (AKO) rats. We found greater accumulation of HIF-1α and HIF-2α in HIP rat livers compared with those in other groups, alongside increased expression of HIF-1 target genes. Mitochondrial ETS capacity was elevated in HIP rat livers, in conjunction with the formation of mitochondrial supercomplexes. Amylin aggregates formed in the hearts of HIP rats, alongside HIF-1α and HIF-2α accumulation. This was associated with suppression of ETS capacity, and increased p-AMPK/AMPK, indicating possible cardiac energetic impairment. Pancreatic secretion of amyloidogenic amylin is thus associated with HIF activation in key metabolic organs beyond the renal vasculature, and occurs alongside mitochondrial alterations in liver and heart that are consistent with sustained hypoxic stress. Our results, alongside previous work, suggest that amylin dysregulation is an overlooked, human-relevant aspect of diabetes pathogenesis, and as such, a potential therapeutic target.

BACKGROUND: Conventional computed tomography (CT)-based liver fat assessment relies mainly on mean attenuation or liver-to-spleen ratios, whereas a novel voxel-based approach enables whole-liver, voxel-level quantification of hepatic fat. However, its value for predicting incident type 2 diabetes (T2D) remains unclear. Therefore, this study aimed to validate whether voxel-based liver fat quantification derived from routine CT can be used to assess the risk of incident T2D in a health check-up population. METHODS: In this retrospective cohort study, individuals who underwent routine noncontrast abdominal CT examinations between January 2013 and December 2023 and were free of diabetes at baseline were included. Liver fat was quantified via an automated voxel-based method incorporating spleen-referenced attenuation criteria on the basis of whole-liver segmentation. The average liver fat fraction was defined as the proportion of liver voxels classified as fat. Incident T2D was identified through longitudinal review of outpatient, inpatient, and health check-up records. Associations between liver fat and incident T2D were evaluated via Cox proportional hazards models adjusted for demographic, anthropometric, and metabolic covariates. Restricted cubic spline (RCS) analysis was used to explore dose-response relationships. Predictive performance was assessed via time-dependent receiver operating characteristic (ROC) analysis at 3 and 5 years, calibration plots, and decision curve analysis (DCA). Incremental predictive value was evaluated by comparing liver fat-based models with hemoglobin A1c (HbA1c)-based and clinical models. RESULTS: Among 356 participants [median age, 57 years, interquartile range (IQR), 53-63 years; 56.5% male], 32 individuals (9.0%) developed incident T2D during a median follow-up of 4.5 years. A higher average liver fat fraction was significantly associated with an increased risk of incident T2D after multivariable adjustment [hazard ratio (HR) per standard deviation (SD), 1.65; 95% confidence interval (CI): 1.05-2.60, P=0.031]. RCS analysis demonstrated a monotonic increase in diabetes risk with increasing liver fat fraction. The liver fat fraction showed moderate discrimination for incident T2D, with time-dependent area under the curve (tAUC) values of 0.71 (95% CI: 0.59-0.84) at 3 years and 0.72 (95% CI: 0.60-0.82) at 5 years. Compared with clinical variables or HbA1c alone, the addition of liver fat improved predictive performance for incident T2D, increasing the C-index from 0.574 (0.453-0.680) to 0.740 (95% CI: 0.663-0.803). CONCLUSIONS: Voxel-based CT quantification of liver fat is independently associated with incident T2D and provides incremental value for diabetes risk assessment in a health check-up population.

UNLABELLED: Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a global health burden with limited therapies. Berberine (BBR) shows promise against MASLD, but its molecular mechanisms remain unclear. Network pharmacology predicted BBR-MASLD intersecting targets, followed by protein-protein interaction (PPI) network construction, GO/KEGG enrichment, and molecular docking. In vitro validation used FFA-induced HepG2 steatosis cells with Oil Red O staining, triglyceride assay, RT-qPCR, and Western blot for p-AKT/AKT. From 147 intersecting targets, six functional core targets were identified: AKT1, IL6, TP53, TNF, IL1B, and BCL2. Enrichment analyses implicated insulin resistance, lipid metabolism, and inflammation. Molecular docking confirmed strong BBR-core protein binding. In vitro, BBR dose-dependently reduced lipid accumulation and triglyceride levels, downregulated lipogenic (SREBP-1c) and pro-inflammatory (IL-6, IL-1β, TNF-α) genes, and restored insulin signaling (AKT1) and apoptosis-related (TP53) gene expression.BBR increased the p-AKT (Ser473)/total AKT ratio as shown by Western blot. BBR attenuates lipid accumulation and partially reverses steatosis-related transcriptional changes in an FFA-induced HepG2 model, including restoration of AKT1 signaling at both mRNA and protein phosphorylation levels. These findings suggest that BBR exerts protective effects againstearly hepatocellular steatosist hrough coordinated regulation of lipid metabolism, inflammation, and stress-related targets. This study provides a network-based rationale for further in vivo and mechanistic investigation in MASLD, and identifies potential pharmacodynamic biomarkers for future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s10616-026-01057-w.

BACKGROUND: This study examined the associations of estimated glucose disposal rate (eGDR), a surrogate of insulin sensitivity, and the insulin resistance indices TG/HDL-C and TyG with gastrointestinal (GI) cancer mortality in the UK Biobank. METHODS: We included 369,447 participants without cancer at baseline and recorded 4,305 GI cancer-related deaths over a mean follow-up of 13.5 years. Fine-Gray models assessed associations of eGDR, TG/HDL-C, and TyG with GI cancer mortality. RESULTS: Higher eGDR was associated with lower pooled GI cancer mortality (sHR, 0.67; 95% CI, 0.61-0.74; P < 0.001); associations with EC, ESCC, CRC, LC, and PC mortality remained significant after false discovery rate (FDR) correction. TyG, but not TG/HDL-C, remained associated with pooled GI cancer mortality, and both markers remained associated with LC mortality. Subgroup analyses were exploratory. CONCLUSIONS: Higher eGDR was associated with lower pooled and several site-specific GI cancer mortality outcomes, whereas TG/HDL-C and TyG associations were modest and site-specific. These findings do not establish clinical utility.

The relationship between diabetes mellitus and prostate cancer (PC) represents one of the most intriguing paradoxes in cancer epidemiology, with diabetic individuals exhibiting a reduced incidence of PC yet poorer prognosis following diagnosis. This apparent contradiction underscores the need for an integrated understanding of how systemic metabolic dysfunction influences prostate carcinogenesis and disease progression. The present review critically synthesizes contemporary epidemiological, mechanistic, and translational evidence to establish metabolic convergence as a unifying framework linking diabetes-associated metabolic abnormalities with PC biology. Current evidence indicates that chronic dysglycemia, hyperinsulinemia, insulin resistance, and endocrine perturbations orchestrate interconnected intracellular signaling networks involving PI3K-AKT-mTOR, AMPK, AGE-RAGE signaling, oxidative stress, mitochondrial dysfunction, and epigenetic reprogramming, collectively driving metabolic adaptation and tumor evolution. Beyond tumor-intrinsic mechanisms, diabetes profoundly remodels the prostate tumor microenvironment through alterations in stromal metabolism, cancer-associated fibroblast activation, adipocyte-tumor crosstalk, extracellular matrix (ECM) remodeling, hypoxic adaptation, and vascular dysfunction, while simultaneously promoting immunometabolic reprogramming characterized by macrophage polarization, T-cell dysfunction, immune checkpoint activation, and immune evasion. The review further examines the bidirectional interactions between antidiabetic therapies and PC treatment, critically evaluating the translational potential of metformin and emerging glucose-lowering agents within the context of precision metabolic therapeutics. Finally, future directions encompassing biomarker-guided patient stratification, longitudinal metabolic profiling, multi-omics integration, artificial intelligence, and clinically relevant mechanistic validation are discussed as essential components of next-generation precision oncology. Collectively, this review reframes diabetes as an active metabolic determinant of PC rather than a coincidental comorbidity and highlights metabolism-centered precision strategies as promising avenues for improving risk stratification, therapeutic decision-making, and clinical outcomes in diabetes-associated PC.

Diabetic wounds pose significant healing challenges due to persistent inflammation, oxidative stress, and impaired tissue regeneration. This study developed bioinspired PLGA-gelatin nanofibrous scaffolds encapsulating Vitex negundo (VN) and Jatropha multifida (JM) phytoextracts to mimic the extracellular matrix, enhance drug release, and promote wound healing via anti-inflammatory and antioxidant mechanisms in in vitro (HUVEC cells) and in vivo (streptozotocin-induced diabetic rat) models. VN-JM nanofibers exhibited uniform nanoscale morphology (255-280 nm) with successful phytoconstituent incorporation, while XRD analysis confirmed crystalline-to-amorphous transformation, indicating enhanced solubility. The nanofibers demonstrated high porosity (83.6 ± 0.9%), excellent swelling capacity (450 ± 18% at 24 h), and controlled biodegradation (63.5 ± 4.5% weight loss at 28 days), supporting their suitability as bioresorbable wound dressings. Furthermore, the formulation provided sustained drug release over 168 h, achieving approximately 90% cumulative release, thereby ensuring prolonged therapeutic availability at the wound site. At optimal doses, nanofibers enhanced HUVEC viability, reduced ROS (DCFH intensity, boosted colony formation, and enhances migration wound closure. In diabetic rats, daily topical application for 21 days yielded better wound closure at day 21, markedly lowered TNF-α, IL-6, and diminished lipid peroxidation, DCF, nitrite levels compared to gels and extracts. Histology showed complete re-epithelialization, fibroblast proliferation, neovascularization, and organized collagen in nanofiber-treated groups, outperforming diabetic controls and matching standard groups. These findings demonstrate VN+JM-loaded nanofibers could be taken as a promising regenerative scaffold for diabetic wounds by mitigating oxidative stress and inflammation.

AIMS: The comparative association of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) with incident atrial fibrillation (AF) or atrial flutter remains uncertain, particularly with early use of both classes. We compared three initial treatment strategies in adults with type 2 diabetes. METHODS: We emulated a three-arm target trial using population-based healthcare data from 2015-2025. Participants were assigned to SGLT2i without GLP-1RA, GLP-1RA without SGLT2i, or early combined therapy according to dispensings during a 30-day treatment-assignment period. Follow-up began at the end of this period using a landmark design. Treatment groups were balanced using inverse probability of treatment weighting, and cumulative incidence was estimated using weighted Aalen-Johansen methods accounting for competing mortality. RESULTS: Among 216,293 participants, 114,572 received SGLT2i without GLP-1RA, 91,524 received GLP-1RA without SGLT2i, and 10,197 received early combined therapy. At 5 years, cumulative AF or atrial flutter incidence was 4.3%, 4.8%, and 4.2% among participants receiving SGLT2i without GLP-1RA, GLP-1RA without SGLT2i, and early combined therapy, respectively. SGLT2i without GLP-1RA was associated with lower risk than GLP-1RA without SGLT2i (RR 0.88, 95% CI 0.83-0.94), while risk was similar between SGLT2i without GLP-1RA and combined therapy (RR 1.00, 95% CI 0.84-1.19). CONCLUSIONS: Among adults with type 2 diabetes, treatment strategies incorporating SGLT2i were associated with a lower risk of incident AF or atrial flutter than GLP-1RA without SGLT2i. These findings extend the cardiovascular evidence supporting SGLT2i and provide new comparative data regarding early combined use of SGLT2i and GLP-1RA.

Gestational diabetes mellitus (GDM), traditionally defined as a disorder of hyperglycaemia with first onset or recognition during pregnancy, is a common condition which is complicated, costly, and controversial. Advances in understanding and awareness of GDM pathophysiology are resulting in an increasingly loud call for the application of personalised medicine approaches to both research in, and clinical care of, GDM. There is a shift away from viewing GDM as a condition to be diagnosed at 24 weeks of gestation and followed until 12 weeks postpartum, to a condition of metabolic vulnerability that precedes pregnancy, persists after pregnancy and requires a precision, life-course approach for health optimization facilitated by integrated, health system-wide supports. This article reviews emerging areas of focus in GDM with an emphasis on the relationship between the development of GDM and future health complications. The terms woman and women, mother and maternal are used in this paper to refer to all those, regardless of gender, who can or have become pregnant.

OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes, yet its effects in singleton pregnancies conceived via assisted reproductive technology (ART) remain unclear. This study evaluated the association between GDM and maternal and fetal outcomes in this population. METHODS: This retrospective study used the U.S. Nationwide Inpatient Sample 2008-2020 to identify singleton pregnancies conceived via ART. Propensity-score matching was performed to balance baseline characteristics between women with and without GDM. Logistic regression assessed associations between GDM and adverse maternal and fetal outcomes. RESULTS: After matching, 9,625 women were included (1,925 with GDM and 7,700 without GDM). GDM was associated with higher odds of preeclampsia (odds ratio [OR] = 1.24, 95% confidence interval [CI]: 1.03-1.50), placenta previa (OR = 1.34, 95% CI: 1.08-1.66), cesarean delivery (OR = 1.30, 95% CI: 1.18-1.44), induction of labor (OR = 1.14, 95% CI: 1.02-1.28), extended hospital stay (OR = 1.48, 95% CI: 1.24-1.76), preterm birth (OR = 1.30, 95% CI: 1.10-1.53), and large for gestational age/fetal macrosomia (OR = 1.54, 95% CI: 1.26-1.90). Stratified analyses showed generally similar associations across subgroups, while formal interaction analyses identified significant interactions for selected outcomes. CONCLUSION: GDM was significantly associated with adverse maternal and fetal outcomes in singleton pregnancies conceived via ART. These findings highlight the importance of vigilant clinical monitoring for complications such as preeclampsia, excessive fetal growth, preterm birth, and delivery-related complications in this high-risk population.

Non-alcoholic fatty liver disease (NAFLD) frequently coexists with type 2 diabetes mellitus (T2DM), posing a significant metabolic disorder with limited dietary intervention options. Cordycepin, a food‑derived nucleoside from the edible fungus Cordyceps militaris, exhibits hypoglycemic and hypolipidemic effects, but its role in T2DM combined with NAFLD remains unknown. Here, we established a mouse model of T2DM combined with NAFLD in male KM mice using high-fructose and high‑fat diet, and streptozotocin. Both cordycepin (COR) and Cordyceps militaris water extract (CWE) attenuated glucose intolerance, dyslipidemia, hepatic steatosis, liver injury, inflammatory response and oxidative stress, with cordycepin showing superior efficacy. Multi‑omics analysis revealed that cordycepin uniquely reshaped the gut microbiota by significantly enriching the c__Clostridia, including g__Acetatifactor, g__Anaerovorax, g__Monoglobus, s__Acutalibacter_muris, and further affected liver metabolism, which was characterized by enrichment of bile acid metabolism-related pathways. Targeted bile acid metabolomics demonstrated that cordycepin specifically promoted the production of cholic acid‑7‑sulfate (CA7S), a gut‑restricted secondary bile acid, through activation of the hepatic PXR/Sult2a1 pathway. Notably, integrated correlation analysis revealed a significant positive association between CA7S and c__Clostridia (e.g., g__Monoglobus, g__Lachnoclostridium, and g__Anaerovorax), suggesting that cordycepin enhances CA7S production by enriching these Clostridia members. And CA7S activated TGR5 to stimulate glucagon‑like peptide‑1 (GLP‑1) secretion, thereby improving glucose and lipid homeostasis. Therefore, these findings demonstrate that dietary cordycepin improves T2DM combined with NAFLD by modulating gut microbiota, particularly Clostridia, and affecting the PXR/Sult2a1/CA7S/GLP‑1 pathway, thereby exerting beneficial effects on glucose and lipid homeostasis.

AIMS: To examine associations of temporal coordination among 24-h light exposure, physical activity and eating patterns with prevalent diabetes and glycaemic traits. METHODS: We analysed 7,133 adults (1397 with diabetes) from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Phasor analysis generated magnitude and phase for Light-Activity, Light-Energy and Activity-Energy pairs. Survey-weighted models assessed associations with prevalent diabetes and glycaemic traits. RESULTS: In primary Model 3, higher Light-Activity and Activity-Energy magnitudes were associated with lower odds of prevalent diabetes (odds ratio [OR] per 0.01-unit increase 0.964, 95% confidence interval [CI] 0.937-0.993; and 0.889, 0.816-0.968, respectively), whereas the Light-Energy 95% CI included 1.0 (OR 0.910, 95% CI 0.822-1.007). Larger Light-Activity phase was associated with higher odds (OR per 1 h 1.065, 95% CI 1.001-1.133). In Model 4, all three magnitude estimates moved towards 1.0 and their 95% CIs included 1.0. Among participants without diabetes, all three magnitudes were inversely associated with fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and 2-h oral glucose tolerance test (OGTT) glucose, but not fasting glucose. CONCLUSIONS: Prospective studies should evaluate temporality, reproducibility and clinical relevance.

OBJECTIVE: To investigate the efficacy and safety of dapagliflozin-insulin combination in patients with Type 2 Diabetes Mellitus (T2DM). METHODS: In this 3-month, randomized controlled trial, 86 T2DM patients were allocated to either insulin monotherapy (Group A) or dapagliflozin-insulin combination (Group B). Primary endpoints included glycemic control (Fasting Blood Glucose [FBG], 2-hour Postprandial Blood Glucose [2hPBG], Hemoglobin A1c [HbA1c]), lipid profile (Total Cholesterol [TC], Triglycerides [TG], Low-Density Lipoprotein Cholesterol [LDL-C], High-Density Lipoprotein Cholesterol [HDL-C]), anthropometrics (Body Mass Index [BMI], Body Weight [BW]), blood pressure (Systolic Blood Pressure [SBP], Diastolic Blood Pressure [DBP]), and adverse events. RESULTS: After treatment, the combination therapy (Group B) demonstrated significantly greater improvements than insulin alone (Group A). Reductions in Group B versus Group A were: HbA1c (24.9%vs. 10.3%), FBG (23.6%vs. 5.6%), 2hPBG (25.1%vs. 13.7%), TC (35.1%vs. 16.9%), TG (15.9%vs. 11.0%), LDL-C (15.7%vs. 6.5%), SBP (7.3%vs. 3.2%), DBP (12.6%vs. 7.8%), BMI (9.8%vs. 4.3%), and BW (5.4%vs. 3.3%); while HDL-C increased more in Group B (16.3%vs. 9.9%). Group B demonstrated superior benefits in glycemic control, lipid profile, anthropometrics parameters and blood pressure reductions. All post-treatment between-group comparisons were statistically significant (p < 0.05). Critically, the incidence of adverse events was 71.4% lower in Group B, a statistically significant difference (p = 0.007). CONCLUSIONS: Dapagliflozin as an adjunct to insulin provides superior multi-faceted metabolic benefits encompassing glycemic control, weight reduction, lipid improvement, and blood pressure lowering, coupled with a more favorable safety profile, supporting its inclusion in standard insulin regimens for T2DM.

AIM: To determine the cross-sectional associations between type of diabetes neuropathy (DN) symptoms and self-reported neuropathy-specific quality of life (NS-QoL) in people (N = 1324) with type 1 or 2 diabetes (T1D or T2D), and to assess demographic and clinical determinants of NS-QoL. METHODS: DN-symptoms and NS-QoL were assessed with the Neuropathy and Foot Ulcer-specific Quality of Life measure. Bootstrapped multivariate linear regression analyses were conducted to assess associations of DN-symptoms (pain, reduced sensitivity, diffuse sensory-motor symptoms, multiple types of symptoms or no DN-symptoms) with NS-QoL, adjusting for demographic and clinical variables. RESULTS: In the total group, the multiple symptoms group had the lowest NS-QoL. There were no significant differences in NS-QoL between the pain, reduced sensitivity and diffuse sensory-motor symptoms groups. All symptom groups (besides reduced sensitivity in T2D) reported a significantly lower NS-QoL. Furthermore, in T1D, lower NS-QoL was associated with more complications, higher age, and higher body mass index, while in T2D, it was associated with more complications, higher anxiety, and male sex. CONCLUSIONS: Compared to people without DN symptoms, those with pain, reduced sensitivity, diffuse sensory-motor symptoms or multiple symptoms reported a lower NS-QoL in both T1D and T2D, with the strongest impairment among those reporting multiple symptoms.

BACKGROUND Rabson-Mendenhall syndrome (RMS) is an extremely rare autosomal recessive disorder caused by pathogenic variants in the insulin receptor gene, leading to severe insulin resistance and compensatory hyperinsulinemia. Classical features include acanthosis nigricans, non-obese or underweight body habitus, hirsutism, dental abnormalities, dysmorphic features, and variable growth abnormalities. Early recognition may be difficult when the initial presentation is dominated by non-specific symptoms rather than classical metabolic complaints. CASE REPORT A 10-year-old Saudi girl presented to a family medicine clinic with intermittent bilateral leg pain and excessive hunger, without polyuria or polydipsia. Examination revealed extensive acanthosis nigricans, moderate hirsutism, deep voice, high-arched palate, and dental enamel defects. Laboratory evaluation showed severe hyperinsulinemia with insulin level of 3522.5 µU/mL, elevated HbA1c of 8.4% (68 mmol/mol), and biochemical hyperandrogenism. Although RMS is classically associated with growth restriction, the patient was tall for age and had a family history of tall stature, requiring cautious interpretation of growth-related findings. Whole-exome sequencing confirmed a homozygous pathogenic insulin receptor variant (c.433C>T, p.Arg145Cys), establishing the diagnosis of RMS. Treatment included vitamin D supplementation, metformin, basal-bolus insulin therapy, dapagliflozin, home glucose monitoring, diabetes education, dietary counseling, and multidisciplinary follow-up. Glycemic control remained suboptimal despite treatment intensification, reflecting the severe receptor-level insulin resistance associated with RMS. CONCLUSIONS In this patient, marked acanthosis nigricans, severe hyperinsulinemia, hyperglycemia, and hyperandrogenic features supported evaluation for a genetic insulin resistance syndrome despite the absence of classical diabetic symptoms.

INTRODUCTION: This study evaluated the efficacy and safety of luseogliflozin (TS-071), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, in Japanese children and adolescents with type 2 diabetes (T2D). METHODS: In this multicenter, randomized, double-masked, placebo-controlled phase 3 trial, patients aged 10-17 years with hemoglobin A1c (HbA1c) levels of 7.0%-12.0%, with or without prior metformin use, were enrolled. Participants were randomized (2:1) to receive luseogliflozin 2.5 mg or placebo for 12 weeks (period I), followed by a 40-week open-label extension (period II), allowing dose escalation to 5 mg. RESULTS: Forty-eight participants were randomized and received luseogliflozin (n = 31) or placebo (n = 17). The primary endpoint-change in HbA1c from baseline at the end of period I-was -1.45% (95% CI, -1.78% to -1.11%) in the luseogliflozin group. The between-group difference in HbA1c change was -1.76% (95% CI, -2.49% to -1.02%). Luseogliflozin maintained efficacy through 52 weeks, with a mean HbA1c change of -0.92% ± 1.74% at the end of period II. Adverse events (AEs) and adverse drug reactions (ADRs) occurred in 85.4% and 29.2% of patients, respectively. No deaths occurred; three serious AEs and one mild hypoglycemic event were reported. Urinary and genital infections were the most frequent ADRs. CONCLUSION: Luseogliflozin significantly improved glycemic control and was well tolerated, supporting its potential as an effective and safe treatment option for children and adolescents with T2D.