Diabetes mellitus is a chronic metabolic disorder that affects millions worldwide and continues to rise in prevalence. While conventional therapies such as insulin and oral hypoglycemic drugs provide glycemic control, they often fail to address underlying mechanisms like oxidative stress, inflammation, and β-cell dysfunction that drive disease progression. Metallic nanoparticles (MNPs) have emerged as promising multifunctional agents owing to their tunable physicochemical properties, high surface reactivity, and ability to be functionalized for targeted applications. Recent studies demonstrate that nanoparticles such as silver, zinc oxide, gold, titanium dioxide, copper oxide, and iron oxide can enhance insulin secretion and sensitivity, regulate glucose homeostasis, mitigate oxidative stress, and modulate immune and microbial pathways. Application-focused evidence highlights MNPs utility in drug delivery, glucose sensing, localized wound therapy, β-cell preservation/regeneration, and mitigation of diabetic complications (nephropathy, neuropathy, retinopathy). However, clinical momentum remains strongest for localized products and device prototypes, whereas systemic candidates are constrained by biodistribution/clearance, chronic safety requirements, and CMC/GMP reproducibility. Green-synthesized MNPs further offer eco-friendly and biocompatible alternatives, showing synergistic effects with phytochemicals. Despite these advances, translation to clinical practice is still in its infancy due to limited human trials, incomplete pharmacokinetic data, and safety concerns. This review consolidates current mechanistic insights, therapeutic applications, and clinical progress of MNPs in diabetes management, also highlights future research directions for a more translationally disciplined approach. By bridging laboratory research with translational strategies, MNPs hold strong potential to transform the therapeutic landscape of diabetes and its complications.

Blood-based non-invasive tests (NITs) in patients with T2DM/MASLD help in assessing the stage of hepatic fibrosis, but there is sparse data in the Indian population.

Fibrosis-4 (FIB-4) and NAFLD fibrosis score (NFS) were calculated for all individuals with T2DM with MASLD and compared to liver stiffness measurement (LSM) values obtained by vibration-controlled transient elastography (VCTE) with cut-offs of ≥9.7 kPa (rule-in cut-off for advanced fibrosis) and <6 kPa (as a rule-out cut-off for significant fibrosis).

The prospective study included 789 patients (238 females) with T2DM and MASLD, aged 53.3 ± 10.3 years. The LSM values were ≥9.7 in 102 (12.9%). Results for the whole group were as follows: The optimal rule-in cut-off for FIB-4 was 1.68 (AUROC 0.69, 95% CI 0.637-0.746, sensitivity 64.7%, specificity 65.2%). The optimal rule-in cut-off of NFS for advanced fibrosis was -0.389 (AUROC 0.619, 95% CI 0.560 to 0.678, sensitivity 61.8%, specificity 57.4%). Rule-out cut-offs also had poor AUROCs (0.586 for FIB-4 and 0.570 for NFS). The diagnostic accuracy of the earlier suggested rule-in (for advanced fibrosis) cut-offs of FIB-4 (>2.67) was 81.3% (sensitivity 22.1%, specificity 92.2%). The diagnostic accuracy of NFS (>0.675) for advanced fibrosis was 79.4% (sensitivity 21.3% and specificity 90.1%). The diagnostic accuracy of the rule-out cut-offs was 52.7% for FIB-4 (at value < 1.3) and 53.8% for NFS (at value < -1.455).

The performance of FIB-4 and NFS to predict or rule out advanced fibrosis was poor in Indian patients with type 2 diabetes mellitus and MASLD.

Although extensive clinical and basic research has been conducted on diabetic cardiomyopathy (DbCM), the therapeutic efficacy for this condition remains significantly limited. Ubiquitin-specific peptidase 20 (USP20), a deubiquitinating enzyme, plays an essential role in regulating protein ubiquitination and modulating various cellular processes. In this study, we aimed to investigate the effect of USP20 on the pathogenesis of DbCM, which may provide a novel therapeutic target for its treatment. The cardiomyocyte-specific USP20 conditional knockout (USP20CKO) mice were employed in this study. The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. USP20 expression was downregulated in the myocardium of diabetic mice. Cardiomyocyte-specific USP20 deficiency aggravated cardiac remodeling and myocardial dysfunction in diabetic mice. LC-MS/MS analysis, along with Co-IP results, demonstrated the interaction between stimulator of interferon genes (STING) and USP20. In mechanism, USP20 directly binds to STING and promotes its degradation through the autophagy pathway by deubiquitinating p62 via its active site C154, thereby alleviating the myocardial inflammation and improving ventricular remodeling and heart failure induced by diabetes.

Native vertebral osteomyelitis (NVO) is a life-threatening spinal infection with rising incidence and significant morbidity. Despite its growing burden, long-term data on clinical characteristics, management trends, and outcomes remain limited.

We conducted a 26-year multicenter retrospective cohort study of adults (≥18 years) diagnosed with NVO at Mayo Clinic sites between 1999-2024. Demographic, microbiologic, treatment, and outcome data were analyzed across five time periods. Predictors of treatment failure were assessed using a multivariable competing risk model.

Among 1,255 patients (median age 67; 66% male), lumbosacral involvement was most common (65%), and 21% had multilevel involvement. Pathogens were identified in 77%, most commonly S. aureus (49%; MSSA 37%, MRSA 13%). Over time from 1999-2004 to 2020-2024, Gram-negative bacilli increased from 6% to 14% (p=0.048).Comorbidities including chronic kidney disease (10% to 21%), active chemotherapy (6% to 11%), and immunosuppression (8% to 17%) increased significantly. Additionally, 1-year treatment failure declined (16% to 10%). In multivariable analysis, diabetes mellitus (sHR 1.92, 95% CI 1.18-3.13) and multilevel involvement (sHR 1.67, 95% CI 1.17-2.38) were associated with increased incidence of treatment failure, while concurrent infections (sHR 0.57, 95% CI 0.37-0.87) and higher Charlson Comorbidity Index (CCI) (sHR 0.62, 95% CI 0.43-0.90) were associated with lower failure.

This large multicenter cohort highlights increasing host complexity, shifting microbiology, and predictors of failure, emphasizing the importance of early risk stratification and tailored strategies, such as multidisciplinary evaluation and close follow-up of high-risk patients to improve outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with GLP1R gene variation potentially linked to therapeutic outcomes. A GLP1R natural missense variant, A316T, protects against T2D and cardiovascular disease. Here, we generated and characterized a human GLP1R A316T mouse model. Human GLP1R^A316T/A316T mice displayed lower fasting blood glucose versus wild-type littermates even under metabolic stress, as well as slower weight gain and alterations in islet cytoarchitecture, glucagon secretion, and liver metabolism under a high-fat, high-sucrose diet. This was however associated with blunted responses to pharmacological GLP-1RAs in vivo. Further investigations in β cell models demonstrated that human GLP1R A316T exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Results are further supported by cryo-EM analyses and molecular dynamics simulations of GLP-1R A316T structure, collectively demonstrating that the A316T variant governs basal GLP-1R activity and pharmacological responses to GLP-1R-targeting therapies.

Diabetes can cause serious complications such as liver damage and nerve pain. Unfortunately, existing treatment options for these problems often have limited effectiveness and unwanted side effects. To find better therapeutic alternatives with good efficacy and safety profile this study tested a novel quinazolinone derivative, (E)-1-benzoyl-3-((4(dimethylamino)benzylidene)amino)-2-(4-(dimethylamino)phenyl)-2,3 dihydroquinazoline-4(1H)-one, in diabetic mice's experiencing liver damage and neuropathic pain. Diabetes was induced in mice using alloxan (150 mg/kg). For possible antidiabetic effect, test compound was given in doses of 10 mg/kg and 20 mg/kg. The standard drugs used for comparison was Glibenclamide (5 mg/kg), Tramadol (50 mg/kg) and Diclofenac sodium (50 mg/kg) for pain relief, and Gabapentin (75 mg/kg) for nerve pain. Pain relieving effect was assessed using various test models (e.g., hot plate, writhing, allodynia, and hyperalgesia). Liver function was studied through blood tests and tissue examination. The test compound (at test dose of 20 mg/kg) led to a significant reduction in blood glucose even greater than the reduction seen with glibenclamide (5 mg/kg). Similarly, the test compound significantly reduced pain and showed protective effects on the liver. This new quinazolinone compound was found to be safe and effective in reducing diabetic nerve pain and liver damage in mice. It may offer a better alternative to currently available treatments like gabapentin and glibenclamide.

PurposeTo explore the relationship between systemic comorbidities and presenting tumor T category in patients with uveal melanoma.MethodsSingle-center, retrospective cohort study of patients with posterior uveal melanoma initially diagnosed between January 2000 and December 2016. Univariate and multivariate ordinal logistic regression analyses were performed to identify comorbidities associated with presenting tumor T category, as classified by AJCC criteria.ResultsInitial presenting AJCC T category was T1 in 190 (43%), T2 in 130 (29%), T3 in 89 (20%), and T4 in 38 (9%). The most common comorbidities present were hypertension (250 patients, 56%), hyperlipidemia (211, 47%), obesity (137, 31%), and diabetes mellitus (87, 19%). Of these, obesity (p = 0.034), hypertension (p = 0.017), and diabetes mellitus (p < 0.001) were associated with earlier presenting T category on univariate ordinal logistic regression. After multivariate regression, only diabetes mellitus (p = 0.01) and obesity (p = 0.04) remained significantly associated with earlier T category on initial presentation.ConclusionAmong patients presenting with uveal melanoma, diabetes mellitus and obesity were associated with earlier presenting T category, which could reflect earlier detection of uveal melanoma in patients undergoing annual diabetic retinopathy screening examinations or having more frequent contact with the healthcare system. Larger studies should further explore this association and examine the utility of increased ocular screening in early detection of uveal melanoma.

Non-alcoholic fatty liver disease (NAFLD) is a type of metabolic stress-induced liver injury that is closely related to type 2 diabetes mellitus (T2DM). Ursolic acid (UA), a natural pentacyclic triterpenoid compound, has anti-inflammatory, hypoglycemic and liver-protective effects. However, its role in regulating liver injury through the NLRP3 inflammasome pathway in a T2DM combined with NAFLD model has not been systematically elucidated. This study systematically evaluated the protective effect of UA on NAFLD and its molecular mechanism through in vivo (STZ + high-fat diet-induced NAFLD mouse model) and in vitro (high glucose + palmitic acid-induced LO2 cell oxidative stress model) experiments. The results showed that UA significantly improved hepatic lipid deposition, reduced serum ALT/AST levels, and effectively alleviated oxidative stress, as indicated by decreased malondialdehyde (MDA) content and increased activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in liver tissues. Further mechanism studies revealed that UA could significantly down-regulate the expression levels of pro-inflammatory factor IL-1β and pro-fibrotic factor TGF-β1 by inhibiting NLRP3 inflammasome activation, and simultaneously reduce the deposition of type IV collagen. This study demonstrated that ursolic acid (UA) has a protective effect on T2DM combined with NAFLD, and its mechanism of action may be related to the regulation of the NLRP3 signaling pathway by UA, which inhibits oxidative stress, inflammation and fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with type 2 diabetes (T2D) in adults; however, its epidemiology in the pediatric population remains unclear. We conducted a systematic review and meta-analysis to estimate the prevalence of MASLD among children and adolescents with T2D. We systematically searched PubMed and Embase databases from inception until March 18, 2025 to identify observational studies investigating the prevalence of MASLD (diagnosed by liver biopsy, imaging methods, or blood-based biomarkers) in children and adolescents (aged ≤ 21 years) with T2D. Data from eligible studies were extracted, and meta-analysis was performed using a generalized linear mixed model. This study was registered in PROSPERO (ID CRD420251013625). Eighteen unique studies with 3926 pediatric patients with T2D were included. The pooled prevalence of MASLD in pediatric T2D was 36.61% (95% confidence interval [CI] 26.45 to 48.12), with substantial heterogeneity (I² = 97.1%). Prevalence estimates differed significantly by the diagnostic method used for MASLD (p = 0.014) but remained consistent across subgroups based on world region, median year of enrollment, and sample size. Sensitivity analysis restricted to magnetic resonance-based studies showed a high prevalence (55.0%, 95% CI 38.20 to 70.78, I² = 73.7%). The funnel plot did not reveal any significant publication bias.

MASLD affects over one-third of pediatric patients with T2D. These findings support early liver health screening in this high-risk group. Future research is needed to validate non-invasive tests for liver disease assessment in pediatric diabetes care.

• Type 2 diabetes (T2D) is a strong risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). • The epidemiology of MASLD in children and adolescents with T2D remains poorly characterized.

• MASLD affects an estimated 36.61% of pediatric patients with T2D, with substantial variation according to the diagnostic modality used. • This high prevalence underscores the need for early liver health screening in pediatric T2D.

Protein kinase D1 (PRKD1), a serine/threonine kinase of the PKD family, has been implicated in tumor biology, but its role in hepatocellular carcinoma (HCC) remains unclear. We explored PRKD1 expression and function using immunohistochemistry, bulk and single-cell RNA sequencing, and in vitro functional assays. PRKD1 protein levels were significantly elevated in 339 HCC tissues compared to corresponding adjacent non-tumorous samples (11.390 ± 1.560 vs. 6.277 ± 2.357, P < 0.0001). Multicenter bulk transcriptomic data confirmed consistent PRKD1 mRNA overexpression (SMD = 0.26, 95% CI = 0.14-0.39), with single-cell transcriptomic profiling indicating specific enrichment in endothelial cells, smooth muscle cells, and hepatocytes. High PRKD1 expression was associated with advanced tumor stages and worse overall survival. Functionally, PRKD1-associated genes were enriched in extracellular matrix and focal adhesion pathways. Immune profiling revealed positive correlations with M2 macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), and negative correlations with CD8⁺ T cells and CD4⁺ Th1 cells, suggesting an immunosuppressive role. Mechanistic experiments demonstrated that conditioned medium from PRKD1-knockdown HCC cells promoted M1 polarization and reduced M2 markers in THP-1 cells, while PRKD1 silencing increased PD-L1 and IDO1 expression. In contrast, IFN-γ treatment did not induce PRKD1 expression, indicating that PRKD1 actively contributes to, rather than responds to, immunosuppressive cues. PRKD1 knockdown markedly impaired HCC cell proliferation and migration. Pharmacologically, nitidine chloride significantly reduced PRKD1 expression in a dose-dependent manner, and molecular docking suggested a potential direct interaction. With respect to drug response, PRKD1-high HCC cases exhibited increased predicted sensitivity to multiple tyrosine kinase inhibitors (TKIs), while in vitro PRKD1 knockdown reduced sorafenib sensitivity, and sorafenib treatment suppressed both PRKD1 and p-ERK1/2 levels. Collectively, our findings identify PRKD1 as a multifaceted contributor to HCC progression, immune microenvironment modulation, and TKI responsiveness. These results highlight PRKD1 as a promising therapeutic target warranting further mechanistic and translational investigation.