How to improve implant osseointegration in type 2 diabetes mellitus (T2DM) represents a severe challenge worldwide. Currently, extracellular vesicles (EVs) play an essential role in intercellular communication and the execution of various biological functions, and are often employed as an ideal natural endogenous nanomedicine for repairing the structure and function of damaged tissues. Accumulating evidence suggests that exosomes derived from genetically modified ADSCs play an important role in tissue repair and regeneration, particularly in the context of bone healing. However, the role of EVs derived from genetically modified T2DM ADSCs (mTADSCs-EVs) in T2DM implant osseointegration remains largely unknown, with limited research being conducted on this aspect. In the present study, we investigated the effects of exosomes derived from TADSCs of Pten low expression on TBMSCs and the underlying molecular mechanisms, as well as the potential application of mTADSCs-EVs in T2DM implant osseointegration. Our results demonstrated that mTADSCs-EVs significantly enhanced the proliferation and osteogenic differentiation of TBMSCs in vitro. Furthermore, mTADSCs-EVs promoted implant osseointegration in T2DM rats, which is likely attributable to the effect of mTADSCs-EVs in promoting the expression of key osteogenic proteins in TBMSCs. In conclusion, our findings reveal the crucial role of mTADSCs-EVs in promoting TBMSCs proliferation and osteogenic differentiation during T2DM implant osseointegration. Moreover, this study proposes a novel strategy to enhance T2DM implant osseointegration by utilizing extracellular vesicles extracted from genetically modified TADSCs.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare, autoinflammatory skin disorder characterized by painful ulcers, with scarce treatment options. Adalimumab is a recently approved tumor necrosis factor-alpha inhibitor for PG, for which real-world data remain limited. This study evaluated the long-term safety and effectiveness of adalimumab in patients with PG. METHODS: This multicenter, prospective, open-label, single-arm, postmarketing observational study enrolled patients with PG who were prescribed adalimumab and were monitored for 52 weeks. The primary outcome was safety, assessed as the incidence proportion of infections reported as adverse drug reactions (ADRs). Secondary outcomes included other safety measures and effectiveness, estimated using the Physician Global Assessment (PGA), Investigator Inflammation Assessment, and Verbal Rating Scale (VRS) for pain. Relapse rates after remission and changes in PG subtype during the observation period were also examined. RESULTS: Sixty-seven patients with PG were enrolled in the study. The mean age was 61.9 years, and 77.6% of the patients had comorbidities, including diabetes mellitus (19.4%), ulcerative colitis (16.4%), and hypertension (14.9%); 59.7% were concomitantly receiving systemic steroids. The PG subtypes among the enrolled patients were ulcerative (n = 62), pustular (n = 2), vegetative (n = 2), and bullous (n = 1). The incidence proportions of infections reported as ADRs and serious ADRs were 14.9% and 9.0%, respectively. The proportions of patients with a PGA score (total lesions) of 0/1 at weeks 12, 26, and 52 were 36.0%, 46.2%, and 57.7%, respectively, and with a VRS score of 0 at weeks 26 and 52 were 45.7% and 52.4%, respectively. No relapses occurred among patients who discontinued treatment due to symptom improvement. CONCLUSIONS: This real-world study demonstrated no new safety concerns with adalimumab and demonstrated its effectiveness, including pain relief, across a heterogeneous PG population. These findings support its use as a standard treatment for PG, including in patients receiving concomitant systemic steroid therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04750213.

AIMS: Heart failure (HF) is a common sequela of type 2 diabetes (diabetes), and models have been developed for its prediction. We aimed to synthesize the available evidence by performing a systematic review and meta-analysis of models predicting incident HF and HF hospitalization (HFH) in individuals with diabetes. METHODS: We searched MEDLINE and EMBASE for multivariable models predicting HF or HFH in patients with diabetes from inception to 2 December 2025. Discrimination metrics from models validated in ≥3 cohorts were pooled using Bayesian meta-analysis. Heterogeneity was assessed using 95% prediction intervals (PI), and risk of bias with PROBAST. RESULTS: In total, 65 studies describing 56 HF and 44 HFH prediction models were included. Following exclusion of studies at high risk of bias, two HF models (RECODe (0.711, 95% CI 0.651-0.767) and DMRS (0.758, 95% CI 0.684-0.827)) and two HFH models (WATCH-DM 2022 (r) (0.705, 95% CI, 0.624-0.795), WATCH-DM 2022(i) (0.718, 95% CI 0.587-0.850)) had acceptable prediction performance, while one HFH model had good performance (DM-CURE (0.837, 95% CI 0.757-0.913). Of these, none reported a prediction horizon of less than ten years. For all models, regardless of risk of bias, none were prospectively tested, and only three underwent clinical utility analysis. CONCLUSION: While some HF and HFH models in diabetes show acceptable/good long-term discriminative performance, the scarcity of utility analyses and prospective testing limits translation to clinical settings. Prospective evaluation of these models is required to establish clinical utility.

BACKGROUND: Since 2019, Dutch hospitals have been developing approaches aiming to bridge the gap between hospital care and community-based lifestyle support. This has led to the introduction of the so called 'Lifestyle Front Office" (LFO) in 2022. The LFO enables healthcare professionals to refer patients for lifestyle and (psycho)social support adjacent to medical treatment in the context of specialist medical care. After a consultation at the LFO, patients are referred to the appropriate community-based lifestyle interventions. LFOs have been quickly adopted in Dutch hospitals, leading to conceptual differences. This study aimed to evaluate similarities, differences and future needs of LFOs in the Netherlands, striving for a more unified concept. METHODS: A cross-sectional survey was sent out between December 2023 and September 2024 to all Dutch hospitals with an operational LFO (n = 17 hospitals). The survey focused on referral processes, patient eligibility criteria, departmental involvement, screening methods, consultation practices, follow-up procedures, financing, and capacity. The collected data were analyzed quantitatively and qualitatively to identify common practice, challenges, and opportunities for improvement. RESULTS: The survey response rate was 82% (14/17). Primary referral groups were patients with lifestyle-related conditions such as obesity, type 2 diabetes mellitus and cardiovascular diseases. Most LFOs conducted pre-visit screenings by using questionnaires, employed lifestyle care coordinators with diverse professional backgrounds, utilized structured tools during consultations and used the electronic patient records for screening and communication. Future needs included the need for (long-term) funding, which was only secured in 21% of the LFOs. Furthermore, inconsistent eligibility criteria, limited capacity, and follow-up procedures were seen as priorities for future attention. CONCLUSION: This study highlights the similarities, differences and future needs of LFOs in the Netherlands. To achieve a more unified concept, LFOs need to better align patient-related eligibility criteria, use of structured tools, referral to community-based support, follow-up strategies and long-term funding. While the LFO concept emphasizes strong inter-organizational collaboration, further research is needed to assess its impact by investigating success rate of referrals and (long-term) health outcomes after referral. Additionally, for maintaining LFOs in the Dutch healthcare system, additional research is required to better understand the barriers and facilitators regarding structural implementation.

BACKGROUND: Cardiovascular-Kidney-Metabolic (CKM) syndrome is a newly recognized condition characterized by systemic inflammation, a process also implicated in depression. The Dietary Inflammatory Index (DII) quantifies the inflammatory potential of diet, yet its association with depression among individuals with CKM syndrome remains underexplored. METHODS: Utilizing data from 11,847 adults with CKM syndrome stages 0-3 enrolled in seven NHANES cycles (2005-2018), we examined the relationship between DII and depression. The DII was computed using 24-hour dietary recall data. Weighted logistic regression and restricted cubic spline (RCS) analyses were applied to evaluate linear and nonlinear associations. Subgroup and sensitivity analyses were also conducted to assess consistency and robustness. RESULTS: Elevated DII values were consistently associated with a greater likelihood of depression across all models. Participants in the highest DII quartile (Q4) exhibited significantly higher odds of depression than those in the lowest quartile (Q1). RCS models revealed a positive, nonlinear dose-response relationship. Additionally, a significant interaction was observed between DII and diabetes mellitus status. CONCLUSION: A pro-inflammatory dietary profile, reflected by higher DII scores, is positively associated with depression among individuals with CKM stages 0-3. These findings highlight the potential benefits of adopting anti-inflammatory dietary interventions to mitigate depression risk in this population.

BACKGROUND: The optimal approach for transitioning hospitalized patients with type 2 diabetes (T2DM) from continuous subcutaneous insulin infusion (CSII) to second-generation basal insulin analogues remains unclear. This exploratory study aimed to: (1) evaluate whether a smooth transition from CSII to each second‑generation basal insulin analogue (insulin degludec [IDeg] or insulin glargine U300 [IGlar U300]) could be achieved; (2) compare post‑transition glycemic outcomes between IDeg and IGlar U300; and (3) identify patient characteristics associated with transition outcomes. METHODS: This single-center retrospective analysis included 135 hospitalized adults with T2DM who received CSII therapy upon admission and were transitioned to basal insulin analogues before discharge (IDeg, n = 77; IGlar U300, n = 58). Among these, 90 patients (IDeg: 50; IGlar U300: 40) were insulin-naive at admission. Glycemic outcomes were assessed using continuous glucose monitoring metrics. RESULTS: Within‑group comparisons showed significant improvements from CSII to post‑transition in both groups: time in range increased from 56.4% to 73.0% in the IDeg group (P < 0.001) and from 58.3% to 73.6% in the IGlar U300 group (P < 0.001). Between‑group comparisons after transition revealed comparable profiles between IDeg and IGlar U300 across key metrics: overall control (time in range: 73.0% vs. 73.6%, P = 0.912), glycemic variability (coefficient of variation: 29.8% vs. 29.2%, P = 0.629), and hypoglycemia risk (time below range: 0.8% vs. 0.5%, P = 0.915). IDeg demonstrated lower fasting glucose variability (coefficient of variation of fasting glucose: 23.8% vs. 28.3%, P = 0.024) and a later nocturnal glucose nadir. Lower body mass index correlated strongly with poorer post-transition outcomes, coinciding with more frequent use of multiple daily injection regimens in these patients (36.1% vs. 6.3%, P < 0.001). Lower serum albumin consistently associated with greater glycemic variability. CONCLUSIONS: Transition from CSII to either IDeg or IGlar U300 is effective and safe. IDeg may provide greater fasting glucose stability. Transition success requires personalized discharge planning based on BMI and albumin levels. CLINICAL TRIAL NUMBER: Not applicable.

BACKGROUND: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is widely used for neovascular retinal diseases. Intraocular inflammation is a recognized adverse event and typically occurs in the injected eye. Inflammation in the fellow, uninjected eye is exceptionally rare and may be misinterpreted as sterile immune-mediated inflammation, potentially delaying appropriate treatment. We report a case of polymerase chain reaction (PCR)-confirmed herpes simplex virus type 1 (HSV-1) uveitis presenting in the fellow eye shortly after intravitreal bevacizumab administration. CASE PRESENTATION: An 84-year-old man with well-controlled type 2 diabetes mellitus received intravitreal bevacizumab (1.25 mg) in the left eye for neovascular age-related macular degeneration. Three days later, he developed acute granulomatous anterior uveitis with dense vitritis in the right, uninjected eye, while the treated eye remained quiescent. Best-corrected visual acuity decreased to 20/400. Given the severity of inflammation and limited fundus visualization, viral retinitis was suspected. Empirical systemic valacyclovir and topical corticosteroids were initiated. Aqueous humor PCR detected HSV-1 DNA, confirming herpetic uveitis. Inflammation resolved within 40 days with recovery of visual acuity to 20/20 and no progression to acute retinal necrosis. The patient remained recurrence-free under antiviral prophylaxis at last follow-up. CONCLUSIONS: Severe fellow-eye inflammation following intravitreal bevacizumab may reflect viral reactivation rather than sterile inflammation. Early diagnostic evaluation, including aqueous humor PCR when clinically indicated, is essential to guide appropriate therapy and prevent sight-threatening complications.

BACKGROUND: Diabetes mellitus type 2 (T2D) is a growing burden in Switzerland, where general practitioners (GPs) face increasing workload. To evaluate the quality of T2D care, the Swiss Society of Endocrinology and Diabetology (SGED) developed the SGED score to help GPs overview aggregated patient parameters at the practice level. However, the practical use of the SGED score is hampered by paper-based workflows and fragmented documentation. Currently, no dashboard exists to specifically visualize the SGED score, which overviews aggregated population parameters such as HbA1c or blood pressure. To address this gap, this study examined: (1) what functional requirements healthcare professionals consider essential for such a potential SGED dashboard, and (2) how do healthcare professionals evaluate the usability and clinical relevance of an iteratively developed dashboard prototype. METHODS: We employed an iterative, user-centered three-step approach involving 10 semi-structured interviews with 14 Swiss T2D healthcare professionals. Step 1 involved defining the project scope, identifying predefined functional requirements, and developing an initial SGED score dashboard prototype. Step 2 collected user-generated requirements and prioritized all requirements using the "Must Have", "Should Have", "Could Have", "Won't Have" (MoSCoW) method. In step 3, the high-fidelity Figma dashboard prototype was iteratively refined based on the requirements and interviewee feedback. RESULTS: Key functional requirements of the digital SGED score included reminder and alert functions for missing or overdue SGED-relevant assessments, color-coded critical values such as low nephropathy screening rates, demographic overviews, trend analyses of SGED indicators at practice level, benchmarking within practice networks, and exportable reports. Additional needs emerged for patient-level views, integrated checklists, inclusion of comorbidities, and personal or practice-specific goal-setting features. Iterative refinements based on user feedback improved clarity, usability, and visual appeal. Some participants highlighted the dashboard's intuitive design, clear and diverse visualizations, and benchmarking functionalities, describing it as both engaging and efficient. Others raised concerns about limited suitability for daily clinical workflows, potential integration challenges with existing systems, and the need for interactive, patient-centered features to support routine care. CONCLUSION: The proposed SGED score dashboard could enhance T2D care through features like population overviews, long-term visualizations, and anonymized benchmarking, meaning the ability to compare a practice's SGED performance with those of other practices. Successful clinical adoption will heavily depend on interoperability and seamless integration into existing workflows. The identified requirements provide a foundation for future digital T2D management systems.

BACKGROUND: Air pollution exposure is increasingly recognized as a risk factor for chronic kidney disease (CKD), but the underlying mechanisms, especially the complex gene-environment interactions as reflected in genetic susceptibility, transcriptomic, and proteomic signatures, remain to be elucidated. METHODS: We conducted a large-scale prospective cohort study including 330,002 UK Biobank participants with an average follow-up of 13.0 years. Annual average concentrations of PM, PM, PM, NO, and NO were assessed. Cox proportional hazards models were applied to estimate CKD risk associated with long-term air pollution exposure. We further evaluated non-linear relationships using restricted cubic splines (RCS), potential mediators via mediation analyses, and CKD susceptibility through additive interaction analyses with baseline comorbidities and polygenic risk scores (PRS). Additionally, transcriptome-wide association study (TWAS) and proteome-wide two-step Mendelian randomization (MR) were integrated to explore potential molecular pathways. RESULTS: Higher exposures to PM (HR: 1.36, 95% CI: 1.22-1.51, per 5 µg/m³), PM (HR: 1.25, 95% CI: 1.07-1.46, per 5 µg/m³), PM (HR: 1.20, 95% CI: 1.06-1.36, per 10 µg/m³), and NO (HR: 1.04, 95% CI: 1.02-1.07, per 20 µg/m³) were significantly associated with increased CKD risk, whereas NO showed no significant association (HR: 0.98, 95% CI: 0.95-1.00, per 10 µg/m³). RCS revealed non-linear relationships for PM and PM. Mediation analyses indicated that incident hypertension and type 2 diabetes mellitus (T2DM) acted as potential mediators in these associations. Crucially, additive interaction analyses revealed that participants with pre-existing hypertension or type 1 diabetes mellitus (T1DM) were significantly more vulnerable to specific pollution-driven CKD. Compared to individuals with low genetic risk and low air pollution exposure, those with both high genetic risk and high exposure exhibited the highest CKD risk, demonstrating a clear gradient effect across categories. TWAS identified shared genes potentially linking air pollutants with CKD, including upregulated transcripts (STX2, PHOSPHO2, NECAB3) and downregulated transcripts (CDK3, MEIOB, NDUFAF1, CRIPAK). Furthermore, proteome-wide MR analyses identified ALDH3A1, F12, and SNCG as potential risk proteins, and GNLY and MEGF10 as protective proteins. CONCLUSIONS: This study provides comprehensive evidence that long-term air pollution exposure is associated with increased CKD risk and offers exploratory insights into the potential molecular pathways underlying this association, advocating the incorporation of renal health considerations into air quality control policies.

BACKGROUND: Latent autoimmune diabetes in adults (LADA) shares core genetic and immunological features with type 1 diabetes (T1D) but is frequently misdiagnosed as type 2 diabetes (T2D). With few biomarkers for its timely diagnosis and management, this study integrated proteome-wide Mendelian randomisation (MR) and observational clinical analysis to identify potential LADA biomarkers. METHODS: We performed proteome-wide MR using cis-protein quantitative trait loci (cis-pQTLs) for 1,389 plasma proteins from the deCODE study (n = 35,559) and genome-wide association study (GWAS) data for LADA (2,634 cases and 5,947 controls, European ancestry). Robustness was enhanced via multiple sensitivity analyses. Pathway enrichment analysis, druggability evaluation, phenome-wide MR, and interaction analyses were performed to investigate the clinical relevance and biological context of candidate proteins. Candidate proteins were further evaluated using enzyme-linked immunosorbent assays in a matched Chinese clinical study (n = 241) to assess their discriminative ability for LADA. RESULTS: Proteome-wide MR and colocalisation analyses indicated associations between genetically predicted plasma levels of C-X-C motif chemokine ligand 10 (CXCL10; OR [95% CI] per 1-SD increase in protein levels: 5.49 [1.74,17.32]), serum amyloid A1 (SAA1; 1.28 [1.14,1.45]), and SAA2 (1.22 [1.11,1.34]) with LADA risk. Replication, multi-tissue eQTL, and multivariable MR supported CXCL10's association. Druggability evaluation suggested CXCL10 as a drug target under investigation, and phenome-wide MR of 1,006 diseases and traits indicated no major safety concerns for CXCL10 as a potential biomarker. In the observational clinical study, CXCL10 differentiated LADA from healthy controls (area under the receiver operating characteristic curve [ROC-AUC]: 0.889; precision-recall area under the curve [PR-AUC]: 0.919) and T2D (ROC-AUC: 0.838; PR-AUC: 0.921), with both models showing adequate calibration. CONCLUSIONS: This study suggests that CXCL10 is a putative biomarker associated with LADA, demonstrating discriminative ability to distinguish LADA from T2D in an observational clinical cohort. These findings contribute to understanding the autoimmune molecular aetiology of LADA and support its diagnostic potential in resolving the clinical ambiguity between LADA and T2D.

BACKGROUND: Kidney failure is a growing global health concern, affecting 9-10% of the population and contributing to rising mortality. In the Dominican Republic, a national dialysis registry was created in 2020 to monitor patients receiving kidney replacement therapy (KRT). Yet no comprehensive national epidemiological report has been published to date. METHODS: We conducted a nationwide, cross-sectional study using data from the 2022 Dominican National Dialysis Registry, encompassing all patients, both private and public, on hemodialysis (HD) or peritoneal dialysis (PD) in National Health Service, authorized units. Data were collected via a standardized digital form (August-September 2023) and analyzed using IBM SPSS Statistics v22. RESULTS: A total of 4,690 patients were recorded, median age 56 years (SD ± 15.6), 69% male. HD predominated (78.4%). Hypertension (93.9%) and diabetes mellitus (44.4%) were the most frequent comorbidities, with diabetes more common in PD than HD (52.5% vs. 42.2%). In HD, arteriovenous fistula was the primary access (61.2%); in PD, continuous ambulatory peritoneal dialysis (CAPD) was predominant (80.4%). National prevalence reached 421.8 patients per million population (91.1 ppm PD, 330.7 ppm HD), a 6% increase from 2022. CONCLUSIONS: This first nationwide analysis provides a comprehensive characterization of the epidemiological profile of KRT in the Dominican Republic, revealing the dominance of HD, the high burden of cardiovascular and metabolic comorbidities, and rising prevalence rates. These findings underscore the urgent need to strengthen kidney failure prevention, improve early detection, and enhance the integration of PD within a balanced renal care strategy aligned with regional best practices.

Activated charcoal is widely used in the medical management of acute intoxications, yet its gross appearance at autopsy is poorly described and may represent a diagnostic pitfall. We report a case highlighting this issue. An elderly man with a history of cardiovascular disease, diabetes mellitus, and prostate cancer was found unresponsive in his closed residential garage after making suicidal statements. Open bottles of amlodipine and glimepiride were found on his person. He was hospitalized, where routine toxicology screening was negative, and he died in the intensive care unit less than 24 h after admission. At autopsy, the stomach contained an abundant amount of dense, black, odorless, thick material adherent to the gastric mucosa which wiped off after gentle cleaning. After removal, the underlying mucosa was intact, without hemorrhage or ulceration. Review of medical records indicated that activated charcoal had been administered during hospitalization due to concern for intentional medication ingestion. Subsequent expanded toxicology testing demonstrated a markedly elevated amlodipine concentration, consistent with acute toxicity. The cause of death was certified as amlodipine toxicity, and the manner of death as suicide. This case illustrates the characteristic gross appearance of activated charcoal in the stomach and discusses its potential to mimic other causes of black gastric contents, including gastrointestinal hemorrhage, caustic ingestion, Wischnewsky spots, hydrocarbons, black esophagus, and iron deposition. Awareness of this finding and careful correlation of gross autopsy findings with medical history and toxicologic results are essential to avoid misinterpretation and diagnostic error in forensic practice.

Polycystic ovary syndrome (PCOS) is a common, heterogeneous condition that is tightly linked to obesity, visceral adiposity and insulin resistance. Lifestyle intervention and off-label use of metformin provide only modest and unsustained weight loss, insufficient to reverse obesity-driven pathophysiology in most women with PCOS and obesity. Incretin-based anti-obesity medications, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (dual GIP/GLP-1RAs), offer a biologically plausible way to target adipose dysfunction, hyperinsulinemia and chronic inflammation that drive PCOS in a large subset of patients. In this narrative, product-segmented review, we map the evidence for liraglutide, semaglutide and tirzepatide in PCOS across mechanistic, clinical, and safety domains, and highlight key evidence gaps that limit current practice. Liraglutide has the densest PCOS-specific evidence, demonstrating reproducible weight loss across small and heterogeneous cohorts, reductions in visceral adiposity and hepatic fat, improved glycemia and inflammatory markers, and early signals for androgen and fertility benefits in selected phenotypes. Semaglutide data remain sparse but conceptually rich, demonstrating weight-loss efficacy and mechanistic insights, alongside preliminary signals of increased likelihood of natural conception. Tirzepatide currently has no PCOS-specific evidence and cannot be recommended beyond extrapolation from obesity and diabetes trials. Across all agents, reproductive outcomes, periconceptional and pregnancy safety, adolescent use, long-term cardiovascular-kidney-metabolic trajectories, obstructive sleep apnea, musculoskeletal health and phenotype-stratified response remain major evidence gaps. We propose a multidimensional, metabolic high-risk PCOS phenotype as the most rational current target for incretin therapy, while emphasizing that well-designed, PCOS-specific trials are essential before these drugs can be viewed as PCOS-modifying therapies rather than powerful, but still adjunctive, weight-loss agents.

Diabetes mellitus significantly impacts perioperative anesthetic management. Patients with diabetic neuropathy exhibit increased sensitivity to local anesthetics, yet the underlying mechanisms, particularly regarding the median effective dose (ED) of ropivacaine and the role of voltage-gated sodium channels (Navs), remain incompletely elucidated. This study investigated the role of Navs in mediating the ED of ropivacaine in streptozotocin (STZ)-induced diabetic rats. Using the Dixon up-and-down method, the ED for sciatic nerve motor block was significantly lower in diabetic rats (0.100%) than in controls (0.142%), indicating heightened local anesthetic sensitivity. This pharmacodynamic shift was associated with underlying neuropathic changes, including reduced motor nerve conduction velocity (MNCV), decreased axon density, and downregulated expression of key Nav subtypes (Nav1.7, Nav1.8, Nav1.9) and the contactin-associated protein (CASPR) in the sciatic nerve and dorsal root ganglia (DRG). Crucially, administration of ropivacaine at the identified ED dose did not exacerbate neurophysiological dysfunction, histological damage, or alter Navs/CASPR expression in diabetic nerves compared with saline-treated diabetic group, demonstrating a favorable safety profile. These findings elucidate the mechanism underlying reduced local anesthetic requirements in diabetic neuropathy, which involves Navs downregulation and structural nerve alterations, and support the clinical use of lower, effective ropivacaine doses in diabetic patients to achieve successful analgesia without increasing neurotoxicity risk.

To investigate the role of LncRNA MALAT1 in insulin resistance (IR) and and oxidative stress injury in hunman glomerular endothelial cells (HGECs) under high glucose and insulin (HG/Ins) conditions, and to elucidate its regulatory mechanism involving the Nrf2 pathway. HGECs were exposed to 25 mM glucose and 100 nM insulin for 48 h to induce insulin resistance. MALAT1 was silenced by siRNA, with knockdown efficiency verified via qPCR. Given the critical role of Nrf2 in oxidative stress regulation, Nrf2 inhibitor ML385 and activator SFN were used to explore the pathway-dependent mechanism. Accordingly, experimental groups included control, ML385, and SFN. Groups included control, ML385, and SFN. Protein expression, Reactive Oxygen Species (ROS), apoptosis, and Nrf2 translocation were assessed by Western blot, flow cytometry, and immunofluorescence. Following IR induction in HGECs (25 mM glucose + 100 nM insulin, 48 h) and siRNA-mediated MALAT1 knockdown, effects on proteins, ROS, apoptosis, and Nrf2 translocation were assessed in control and modulator groups. MALAT1 exacerbates IR and oxidative stress-induced injury in HGECs by inhibiting Nrf2 nuclear translocation. Targeting the MALAT1-Nrf2 axis may serve as a novel strategy for diabetic kidney disease (DKD).

OBJECTIVES: To investigate associations of the bioelectrical impedance analysis (BIA)-derived phase angle (PhA), an indicator of body cell mass, hydration status, and cell membrane integrity, with type 2 diabetes (T2D), prediabetes, and glycemic and insulin-related traits. METHODS: Using data from the Cooperative Health Research in the Region of Augsburg (KORA) S3/S4 studies, we analyzed 7728 participants aged 25-74 years for prevalent T2D and 7006 participants who did not have diabetes at baseline for incident T2D. A subsample aged 55-74 years at S4 was followed to assess incident oral glucose tolerance test (OGTT)-defined prediabetes or T2D (prediabetes/T2D), and glycemic and insulin-related traits (S4/F4/FF4). The PhA was calculated from BIA 2000-S at 50 kHz. Logistic and Cox regressions were applied for binary outcomes, and two-level growth models for continuous traits. RESULTS: In S3/S4, 324 participants had prevalent T2D at baseline, and 707 developed T2D during a median 15.7-year follow-up. In S4/F4/FF4, during up to 14 years of follow-up, 251 out of 626 normoglycemic participants at S4 developed incident prediabetes/T2D, and 792-804 participants without diabetes at S4 had three repeated measurements of continuous traits. The PhA (per 1-degree) was positively associated with incident T2D (hazard ratio [HR] and 95% confidence interval [CI] in S3/S4: 1.37 [1.21-1.54]) and incident prediabetes/T2D (HR [95% CI] in S4/F4/FF4: 1.33 [1.07-1.67]) without sex differences. The PhA (per 1-degree) was also positively associated with fasting glucose (beta [95% CI]: 1.2% [0.1-2.2%]) and insulin resistance (beta [95% CI]: 7.0% [2.3-11.7%]) cross-sectionally, and with changes in 2-h glucose longitudinally (beta [95% CI]: 4.5% [2.3-6.7%]) (S4/F4/FF4). In contrast, the PhA (per 1-degree) was inversely associated with prevalent T2D (odds ratio [95% CI] in S3/S4: 0.72 [0.56-0.93]) in men only. CONCLUSIONS: The PhA at 50 kHz had stage-dependent associations with glucose metabolism, with higher values observed during subclinical stages and lower values after diabetes manifestation.

Animal reproduction is closely linked to energy metabolism, and ovarian glycolipid metabolism disorders can lead to follicular abnormalities, reduced fertility, and infertility. Granulosa cells (GCs), as key energy suppliers in the ovary, directly influence oocyte development, hormone secretion, and reproductive function. However, the interaction between reproductive regulatory factors and ovarian energy metabolism is unclear. Our prior studies showed that gonadotropin-inhibitory hormone (GnIH) causes ovarian degeneration and glycolipid metabolism disorders in female piglets, but its ovarian-level mechanism remains unknown. We explored GnIH's effects on porcine ovarian and GC glycolipid metabolism via in vivo and in vitro experiments. In vivo, intraperitoneal GnIH (0.1, 1 mg/mL) administered for 14 days inhibited glucose transport and gluconeogenesis, but promoted glycolysis, fatty acid synthesis, and β-oxidation. It inhibited the AKT-GSK-3β pathway and activated AMPK, causing abnormal glucose to use and ATP deficiency. Metabolomics showed increased adenosine and D-glyceroldehyde 3-phosphate, and decreased citrate, glucuronic acid, and testosterone. In vitro, transcriptomics revealed 5253 differentially expressed genes (956 glycolipid-related) in GnIH-treated GCs, enriched in Wnt and AMPK pathways. GnIH promoted glucose transport, glycolysis, and glycogen synthesis while simultaneously inhibiting mitochondrial ATP synthesis - effects that were closely associated with the activation of the Wnt signaling pathway and the inhibition of the AMPK pathway. GnIH inhibited AMPK and activated Wnt, promoting glucose transport and glycolysis but suppressing mitochondrial ATP synthesis. Furthermore, functional intervention experiments demonstrated that GnIH effectively reversed the metabolic effects induced by either the AMPK activator AICAR or the Wnt inhibitor IWP2 in GCs, reinforcing that GnIH acts as a dominant regulator upstream of both pathways. In addition, GnIH exacerbated oxidative stress, induced insulin resistance, and disrupted mitochondrial dynamics. In conclusion, GnIH disrupts energy metabolism via Wnt and AMPK pathways, causing GC glycolipid disorders and dysfunction, offering new targets for reproductive disorder interventions.

ETHNOPHARMACOLOGICAL RELEVANCE: Wumei Pill (WMP) is a classic traditional Chinese medicine formula recorded in Zhang Zhongjing's Treatise on Febrile Diseases for the treatment of "Xiao Ke" (consumptive thirst, analogous to diabetes mellitus). Historically, it has been used to treat diabetes mellitus and neurological dysfunction. However, its therapeutic effect on diabetic encephalopathy (DE) and the underlying mechanisms remain unclear. AIM OF THE STUDY: To explore the therapeutic effect of WMP on diabetic encephalopathy and elucidate whether it exerts neuroprotective effects via CXCL1/CXCR2 signaling-mediated neuroinflammation, particularly given the lack of effective treatments for DE and the unclear neuroprotective mechanism of WMP. MATERIALS AND METHODS: Leptin receptor-deficient (db/db) mice and high-fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetes mellitus (T2DM) mice were administered WMP intragastrically for 8 weeks. A validated HPLC method was applied to ensure consistent and stable contents of representative bioactive components in all WMP preparations used throughout the study. Cognitive function was evaluated using Morris water maze and novel object recognition tests, while metabolic parameters including body weight (BW) and fasting blood glucose (FBG) were assessed. Hippocampal pathological changes were observed via HE and Nissl staining. Network pharmacology and transcriptomics were performed to screen active components, potential targets, and key differentially expressed genes (DEGs) of WMP against DE. Western blot, ELISA, and immunological assays were used to quantify key protein and cytokine levels. In vitro assays were further conducted to verify the dependence on the target signaling pathway. RESULTS: WMP reduced BW and FBG, ameliorated cognitive impairments as shown by shortened escape latency, increased platform crossings, and an improved novel object recognition index. It also increased the number of neurons in the hippocampal CA1 and CA3 regions and upregulated the expression of synaptic proteins. Network pharmacology and Transcriptomics analysis revealed that the C-X-C motif chemokine ligand 1 (CXCL1)/C-X-C motif chemokine receptor 2 (CXCR2) axis played a key role in WMP-mediated protection against DE. In vivo, WMP significantly inhibited the hippocampal CXCL1/CXCR2 axis and reduced the release of pro-inflammatory cytokines (TNF-α/IL-1β) in diabetic mice. In vitro experiments further demonstrated that WMP exerted neuroprotective effects indirectly rather than directly acting on hippocampal neurons: it notably suppressed high glucose-induced CXCL1 upregulation and protein secretion in astrocytes. Notably, the neuroprotective effect of WMP was abolished by exogenous recombinant CXCL1, confirming the essential role of astrocyte-derived CXCL1. CONCLUSIONS: WMP ameliorates metabolic disorders and cognitive dysfunction in DE by targeting the astrocyte-neuron CXCL1/CXCR2 axis. This action is mediated by inhibiting astrocytic CXCL1 secretion and subsequent CXCL1/CXCR2-driven neuroinflammation, thus preserving hippocampal neuronal integrity. Our findings reveal a novel mechanism for WMP and provide a promising therapeutic strategy for DE.

Major depressive disorder (MDD) is a leading cause of disability worldwide, and currently available antidepressants remain limited by delayed onset of action, incomplete response, and adverse effects. Ketamine is a rapid-acting antidepressant, whereas xanomeline, an M1/M4 muscarinic receptor agonist, may represent a mechanistically distinct non-monoaminergic strategy. However, the molecular basis by which xanomeline may influence depression-related pathways, and its relationship to ketamine, remain unclear. We used network pharmacology and molecular docking to compare the shared and distinct molecular mechanisms of xanomeline and ketamine in MDD. Potential drug targets were collected from public databases and intersected with MDD-related targets. Protein-protein interaction analysis was performed to identify hub genes, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Drug-pathway-target-disease networks were constructed, and shared core targets were further evaluated by molecular docking. We identified 368 overlapping targets for xanomeline-MDD and 714 for ketamine-MDD. Three KEGG pathways were shared between the two networks: EGFR tyrosine kinase inhibitor resistance, Ras signaling, and Rap1 signaling. EGFR, insulin-like growth factor 1 receptor (IGF1R), and SRC proto-oncogene, non-receptor tyrosine kinase, emerged as common core targets. Xanomeline was more strongly associated with receptor tyrosine kinase and PI3K/AKT-related signaling, whereas ketamine was more strongly linked to synaptic transmission, NMDA receptor-related functions, and glutamatergic signaling. Molecular docking supported structurally plausible binding of both drugs to EGFR, IGF1R, and SRC. These findings suggest partial convergence on downstream plasticity-related signaling nodes despite distinct upstream mechanisms and warrant further experimental investigation. However, the results should be interpreted as hypothesis-generating rather than as evidence of shared functional target engagement.

OBJECTIVE: Transmetatarsal amputation (TMA) is a functional foot reconstruction for limb salvage following extensive forefoot infection and/or ischemic gangrene. Unfortunately, up to 30% of TMAs progress to major amputation. This study evaluates the effects of diabetes and peripheral artery disease (PAD) on long-term TMA outcomes. METHODS: This was a retrospective review of a single-surgeon, single-institution consecutive series of TMAs performed between 2006 and 2024. Patients with PAD and perioperative hemoglobin A1c (HbA1c) ≤6.5 (euglycemic PAD), PAD and HbA1c >6.5 (hyperglycemic PAD), and diabetes without PAD (DM only) were compared for ipsilateral major amputation, primary healing, and all-cause mortality. RESULTS: Among 230 TMAs, 189 healed primarily. Of intact TMAs, 48 were euglycemic PAD, 71 hyperglycemic PAD, and 70 DM only. There were no differences in sex, race, or comorbidities aside from smoking history (P=.043) and history of prior revascularization (P<.001). Mean HbA1cs were 5.7, 8.3, and 9.1 (P<.001). The PAD groups were older (67.1, 66.7, 57.3 years; P<.001), had lower toe pressures (34.7, 43.0, 99.0 mmHg; P<.001), and higher WIfI scores (69.1%, 76.0%, 43.6% stage 4; P=.009). Primary healing rates were 85.7%, 74.0%, and 89.7% (P=.021), with similar 90-day all-cause mortality (P=.364). Kaplan-Meier analysis demonstrated superior intact TMA survival in euglycemic PAD (P=.049), with 5-year TMA survival rates of 97.8%, 83.6%, and 78.8%. Modeled continuously, each 1% rise in HbA1c increased major amputation odds by 24% (P=.005). CONCLUSION: Uncontrolled diabetes is a distinct marker of poor long-term outcomes following TMA for limb salvage.

BACKGROUND: Acute intestinal ischemia is a severe postoperative complication of abdominal aortic surgery, and delayed diagnosis markedly limits therapeutic options. At present, no reliable biochemical marker for early detection is available. This study assesses whether perioperative changes in glucagon-like peptide-1 (GLP-1) may serve as an early biomarker of postoperative intestinal ischemia. METHODS: This prospective single-centre cohort study enrolled 80 patients undergoing elective abdominal aortic surgery. Total serum GLP-1 concentrations were measured at eight perioperative time points spanning the preoperative, intraoperative, and postoperative periods. Intestinal ischemia was diagnosed using contrast-enhanced magnetic resonance imaging or surgical confirmation. RESULTS: The perioperative time course of GLP-1 was similar across all patients, with peak concentrations consistently observed 24 hours after complete declamping during vascular reconstruction. Six patients developed intestinal ischemia; these individuals exhibited significantly higher GLP-1 levels at all postoperative time points compared with patients without ischemia (p<0.02). GLP-1 demonstrated the highest predictive ability at 24 hours after complete declamping (AUC 0.993); similarly, measurements obtained at 6 hours after complete declamping exhibited excellent predictive performance (AUC 0.919). CONCLUSIONS: Perioperative elevation of GLP-1 demonstrates high specificity for intestinal ischemia, independent of diabetes mellitus or age. Serum GLP-1 concentrations show promise as reliable predictive biomarkers for postoperative intestinal ischemia, with the best diagnostic accuracy observed at 6 and 24 hours after complete declamping during vascular reconstruction.

Obesity is a major global health burden with profound cardiovascular implications, contributing to morbidity, mortality, and healthcare costs. Excess adiposity promotes atherosclerosis, hypertension, atrial fibrillation, heart failure, stroke, and venous thromboembolism through entangled mechanisms, including adipose tissue dysfunction, chronic low-grade inflammation, immune dysregulation, endothelial impairment, insulin resistance, and neurohormonal activation. Dysfunctional adipose tissue, including perivascular and epicardial fat, actively contributes to vascular inflammation, cardiac remodeling, and arrhythmogenesis. Although the "obesity paradox" has been described, obesity remains strongly associated with earlier and more severe cardiovascular events. Recent therapeutic advances, particularly incretin therapies, have improved the management of obesity and its consequences by realizing notable weight loss and metabolic benefits. However, important gaps in obesity phenotyping, cardiovascular risk stratification, and individualized therapy persist, supporting integrated precision-medicine and public-health strategies to reduce obesity-related cardiovascular burden.

The N-myc downstream-regulated gene (NDRG) family comprises four proteins (NDRG1-4) that lack intrinsic catalytic activity and participate in diverse cellular processes, including differentiation, stress responses, and metabolic regulation. Although NDRGs have been studied primarily in the context of development and cancer, emerging evidence indicates that they both influence components of the canonical insulin signaling pathway and are regulated by insulin. NDRGs are highly expressed in nervous tissue, where insulin signaling is essential for neuronal function and brain metabolism. This mini-review summarizes current knowledge on NDRG function in the nervous system, with emphasis on their links to insulin signaling and insulin-resistance.

AIMS: To investigate: i) the association of sedentary time (ST) and moderate-to-vigorous physical activity (MVPA) during pregnancy with placental interleukin-6 (IL-6) expression and cord venous IL-6 content in women with obesity; and ii) cord venous markers mediating the relationship of ST/MVPA and placental IL-6 with neonatal adiposity. METHODS: Among 134 participants, ST and MVPA were assessed using accelerometry at three gestational periods. Placental IL-6 mRNA was quantified using Nanostring technology. Cord blood concentrations of glucose, leptin, insulin, C-peptide and IL-6 were determined. Neonatal fat percentage was calculated from skinfold measurements. RESULTS: Increasing MVPA from inclusion (<20 weeks) to 24-28 or 35-37 weeks, and reducing ST to 24-28 weeks, were associated with higher IL-6 expression in female placentas (p < 0.05). Increasing MVPA from inclusion to 24-28 weeks was associated with lower cord venous IL-6 levels in male fetuses (p = 0.006). Lower cord glucose and insulin concentrations and insulin resistance mediated the association between increased placental IL-6 and reduced neonatal adiposity (p < 0.05). CONCLUSIONS: In women with obesity, increasing MVPA and reducing ST during pregnancy is associated with higher IL-6 expression in female placentas and lower cord IL-6 in male fetuses. Higher placental IL-6 expression is linked to reduced fetal insulinemia and insulin resistance, contributing to lower neonatal adiposity. TWITTER SUMMARY/SOCIAL MEDIA: In pregnant women with obesity, higher moderate-vigorous physical activity and lower sedentary time upregulate placental IL-6 expression, which in turn is related to lower neonatal adiposity through reduced fetal insulinemia and insulin resistance. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN70595832.