Diabetic wound (DW) is a severe and disabling complication of diabetes mellitus (DM), generally characterized by delayed healing, persistent inflammation, and insufficient reliable biomarkers for early diagnosis. These clinical limitations emphasize the urgent need for sensitive, non-invasive, and real-time analytical strategies to monitor disease progression. In this study, we developed LRX, an activatable fluorescent molecular probe designed for the selective detection of peroxynitrite (ONOO). Systematic evaluations demonstrated that LRX exhibited excellent selectivity toward ONOO, high chemical stability, and favorable biocompatibility. By applying this probe in a DW mouse model, dynamic changes in ONOO levels were successfully visualized and monitored in vivo. These results indicate that LRX can serve as a sensitive and practical platform for real-time imaging of ONOO fluctuations under diabetic pathological conditions. Overall, this work provides new insight into nitro-oxidative stress-related mechanisms involved in diabetic complications and offers a useful molecular imaging tool for future diagnostic and therapeutic studies.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) frequently overlaps with hepatitis C virus (HCV) infection, yet the recently proposed combinatorial MASLD (cMASLD) classification remains poorly characterized in this setting. This study aimed to evaluate the prevalence, metabolic profile, and virological determinants of cMASLD in an Italian cohort of HCV-infected patients. METHODS: We conducted a cross-sectional study on 169 HCV-infected patients evaluated at two referral Centers in Southern Italy (between 2020 and 2024). All subjects underwent transient elastography, and cMASLD was diagnosed according to international guidelines. Group comparisons were performed using ANOVA or Kruskal-Wallis tests with appropriate post-hoc analyses, categorical variables by Chi-square or Fisher's exact test, and multivariate logistic regression to identify factors independently associated with cMASLD (p<0.05). RESULTS: Among 169 patients, n=52 (31%) fulfilled cMASLD criteria, n=14 (8%) had HCV with liver steatosis, and n=103 (61%) had HCV infection alone. Compared with other groups, cMASLD patients showed higher body mass index (28±8 kg/m²; p<0.001), larger waist circumference (p<0.001), increased controlled attenuation parameter (298±41 dB/m; p<0.001), and higher fasting insulin (p=0.029). HCV RNA levels were significantly elevated in the cMASLD group (p=0.014). Multivariate logistic regression identified HCV RNA as independently associated with cMASLD (OR=1.48; 95%CI: 1.01-2.17; p=0.045). CONCLUSIONS: Applying the cMASLD nomenclature emphasizes the need for a multidisciplinary management approach integrating antiviral and metabolic care. This classification provides a more comprehensive understanding of liver injury mechanisms in patients with overlapping metabolic and viral etiologies.

BACKGROUND AND AIMS: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) may have favorable hepatic effects, but long-term outcomes in cirrhosis are uncertain. We investigated the relationship between SGLT2i exposure and 5-year outcomes among adults with cirrhosis. METHODS: We performed a retrospective cohort study in the TriNetX US Collaborative Network (March 2013- January 2025). Adults (≥18 years) with cirrhosis were classified as SGLT2i users (first exposure on/after cirrhosis diagnosis) or non-users (no SGLT2i exposure) and propensity score matched 1:1. Outcomes were assessed over 5 years beginning 1 day after index. Primary outcomes were all-cause mortality and hospitalization burden (inpatient encounters per patient). Secondary outcomes included hepatic decompensation complications and prespecified adverse events; tertiary outcomes were the most recent liver- and kidney-related laboratory values during follow-up. RESULTS: After matching, 24,559 patients were included per cohort. SGLT2i use was associated with lower all-cause mortality (11.8% vs 26.0%; OR=0.381, 95%CI: 0.363-0.399; p<0.001) and fewer hospitalizations (mean 3.6±10.7 vs 5.4±13.4; p<0.001). Composite hepatic decompensation was less frequent (OR=0.617, 95%CI: 0.580-0.656; p<0.001), including lower odds of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome; hepatic encephalopathy did not differ. Acute kidney failure and urinary tract infection were less frequent, while diabetic ketoacidosis did not differ. Laboratory profiles favored SGLT2i use (lower aspartate aminotransferase and bilirubin, higher albumin, lower international normalized ratio, and improved renal indices). CONCLUSIONS: In this matched real-world cohort, SGLT2i exposure after cirrhosis diagnosis was associated with an improved 5-year survival, fewer hospitalizations, and fewer decompensation events.

Accumulating evidence indicates that tryptophan metabolism plays important roles in insulin resistance, and glucolipid metabolism. Our preliminary study revealed a significant decrease in the serum levels of the tryptophan metabolite 5-methoxytryptamine (5MT), in both high-fat diet (HFD)-fed and db/db mice. Notably, these levels were restored following treatment with the hypoglycemic agent, the dipeptidyl peptidase-4 inhibitor (DPP-4i) sitagliptin, suggesting a potential relationship between 5MT and metabolic homeostasis. In the current study, we demonstrated that 5MT treatment ameliorated insulin resistance and hepatic steatosis in HFD and db/db mice. Specific inhibition of the aryl hydrocarbon receptor (AHR) attenuated the beneficial effects of 5MT on insulin resistance in HFD mice. Transcriptome sequencing and subsequent validation revealed that 5MT significantly upregulated the expression of C-X-C motif chemokine ligand 14 (Cxcl14) in hepatic macrophages. Myeloid-specific knockout of Cxcl14 demonstrated that 5MT inhibited hepatic inflammatory response to improve insulin resistance in a macrophage CXCL14-dependent manner. Furthermore, molecular mechanism exploration revealed that 5MT promoted the AHR-mediated transcriptional activation of Cxcl14, which inhibited glycolysis in macrophages, subsequently suppressing their proinflammatory classical activation (M1 phenotype). Collectively, these data reveal a novel beneficial role of 5MT in insulin resistance and metabolic homeostasis, providing a rationale for new therapeutic strategies targeting insulin resistance-associated metabolic disorders, such as obesity and diabetes.

OBJECTIVE: To evaluate the efficacy and safety of adding pioglitazone as a third-line agent in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin and sodium-glucose cotransporter-2 inhibitors. DATA SOURCES: A systematic search of PubMed, Scopus, the Cochrane Library, and Google Scholar was conducted through February 2026 for randomized controlled trials (RCTs). STUDY SELECTION AND DATA EXTRACTION: Eligible RCTs reported outcomes on glycemic control and cardiometabolic parameters. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane Risk-of-Bias tool 2, with certainty of evidence evaluated using the Grading of Recommendations Assessment, Development, and Evaluation tool. DATA SYNTHESIS: Four RCTs (n = 1213) were included. Using a random-effects model, pioglitazone significantly reduced glycated hemoglobin (HbA1c) (mean difference [MD]: -0.56%; 95% confidence interval -0.74 to -0.38; < 0.00001) and increased the likelihood of achieving HbA1c <7% (risk ratio: 2.37; 95% CI 1.87-3.01). Subgroup analysis demonstrated a dose-dependent effect, with 30 mg providing greater glycemic reduction than 15 mg. Significant improvements were also observed in fasting plasma glucose, homeostasis model assessment of insulin resistance, triglycerides, high-density lipoprotein cholesterol, and diastolic blood pressure. However, pioglitazone was associated with weight gain (MD: 2.38 kg) and a higher risk of adverse drug reactions. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: These findings suggest that pioglitazone is an effective add-on therapy for patients with T2DM who remain uncontrolled on metformin and SGLT2 inhibitors, particularly in those with significant insulin resistance. However, its use should be individualized, with careful consideration of predictable adverse effects such as weight gain and tolerability, rather than routine escalation for all patients. CONCLUSIONS: Adding pioglitazone to metformin and SGLT2 inhibitors significantly improves glycemic control and metabolic parameters. While the 30 mg dose offers greater efficacy, clinicians must balance these benefits against predictable side effects like weight gain.

Type 1 diabetes (T1DM) is an autoimmune disorder marked by a characteristic dysfunction of insulin-secreting beta-cells in the pancreatic islets. This destructive process is not a single event but a chronic inflammatory cascade, propelled by immune cells-including T-lymphocytes and macrophages-that release potent pro-inflammatory cytokines. This review delves into the growing body of evidence implicating specific inflammation-promoting mediators-including Interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α) and Interferon-γ (IFN-γ) -as master regulators of beta-cell death. We also explore how modern analytical techniques enable precise mapping of cytokine patterns in the blood, revealing a dynamic and ongoing disease process long that precedes clinical symptoms onset. By weaving together findings from clinical and preclinical studies, this article argues that profiling these inflammatory signals provides a crucial real-time, functional readout of autoimmune activity that complements traditional, static autoantibody measurements. We conclude by discussing the significant potential of integrating cytokine data into existing models to create more robust risk stratification tools and to pave the way for interventions that could intercept the disease pathway before critical beta-cell mass is lost.

BACKGROUND: Conducting diet-focused interventions in rural, American Indian (AI), and/or under-resourced communities is critical to improve health. However, interventions that may work in urban or suburban settings may not work in rural or under-resourced communities due to differences in types of locally available food, food preferences, food insecurity, and/or limited access to grocery stores or supermarkets. This paper describes the acceptability of recruitment strategies used in the Cooking for Health (CFH) study, a culturally targeted healthy food budgeting, purchasing, and cooking skills intervention for AIs with type 2 diabetes who live on or around a large reservation in the North-Central United States. METHODS: CFH was a two-armed parallel group randomized controlled trial (RCT) designed to evaluate the effectiveness of a 12-month intervention on diet, healthy food self-efficacy, food budgeting and cooking skills, and healthy food purchases. The intervention consisted of monthly lessons and videos related to cooking healthy foods, food budgeting skills, and optimal nutrition for diabetes management. AI men and women 18 + years old with diagnosed type 2 diabetes were eligible to participate. Recruitment strategies included passive, active, and word-of-mouth (refer-a-friend) methodologies. Additionally, research staff worked closely with a community partner, the Tribal Diabetes Program, to facilitate enrollment. RESULTS: Of the 276 individuals screened for eligibility for the study, 226 individuals were deemed eligible to participate. Of these, 176 enrolled, 25 individuals scheduled a baseline study visit but did not show up, and 25 individuals declined participation. Reasons for declining participation included: no longer interested; too busy/employed full-time; already managing diabetes with own healthcare provider; or moved out of the area. CONCLUSIONS: These results support a multi-strategic recruitment approach of passive, active and word-of-mouth strategies for successful recruitment and enrollment of AIs in diet-focused RCTs. It is likely that the recruitment successes were largely due to community involvement and ownership in the study. The importance of trusting mutually beneficial and shared decision-making is also critical to project success. TRIAL REGISTRATION: ClinicalTrials.gov, TRN: NCT03699709. Registered on 5 October 2018, https://clinicaltrials.gov/study/NCT03699709.

BACKGROUND: Insulin resistance has been linked to increased breast cancer risk through mechanisms involving metabolic dysfunction and chronic inflammation. This study aimed to investigate the association between the metabolic score for insulin resistance (METS-IR) and breast cancer incidence in a large cohort of Korean women. METHODS: We conducted a retrospective cohort analysis using data from 2,731,416 women aged ≥ 40 years, obtained from the 2009-2010 Korean National Health Screening Program. Participants had no prior history of breast cancer at baseline. METS-IR scores were calculated and stratified into quartiles. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer incidence according to METS-IR quartiles. RESULTS: During 31,633,123 person-years of follow-up, 43,526 new breast cancer cases were identified. Women in the highest METS-IR quartile demonstrated a significantly increased breast cancer risk (HR: 1.07, 95% CI: 1.03-1.12) compared to those in the lowest quartile. This relationship exhibited a non-linear association, with the increased risk of breast cancer primarily driven by the highest quartile of metabolic dysfunction. CONCLUSIONS: Our findings validate METS-IR as a useful tool for breast cancer risk assessment among Korean women, highlighting the importance of insulin resistance as a modifiable metabolic risk factor. These results emphasize the need for targeted preventive interventions focusing on metabolic health to reduce breast cancer incidence.

BACKGROUND: Metabolic syndrome (MetS) is a major global public health problem associated with cardiovascular disease, type 2 diabetes mellitus (T2D), and increased mortality. Chronic psychological stress has been proposed as a contributor to metabolic dysfunction; however, evidence linking perceived stress to MetS and its individual components remains inconsistent. The Perceived Stress Scale (PSS) is a widely validated instrument for assessing subjective stress, yet its association with metabolic outcomes has not been systematically synthesised. AIMS: The objective of this study was to systematically review the evidence and evaluate the association between perceived stress, measured using the PSS, and metabolic parameters related to MetS. METHODS: A systematic search of peer-reviewed literature identified studies assessing perceived stress using the PSS-10 or PSS-14 and reporting metabolic outcomes in adults. Associations between perceived stress and metabolic parameters were examined using random-effects meta-regression models, with stress scores standardised to allow comparability across PSS versions. Outcomes included anthropometric measures, blood pressure, glycaemic markers, lipid profile, and insulin resistance. RESULTS: Thirty studies comprising 12,491 participants were included. Most metabolic parameters, including body mass index, waist circumference, blood pressure, fasting glucose, and triglycerides, showed no significant association with perceived stress. In contrast, insulin resistance assessed by HOMA-IR was positively associated with perceived stress (β = 0.463, 95% CI: 0.159-0.767). Borderline associations were observed for high-density lipoprotein cholesterol and total cholesterol. Although substantial heterogeneity was present across analyses, the HOMA-IR association was exploratory and sensitive to the inclusion of individual studies. CONCLUSIONS: Higher perceived stress may be associated with insulin resistance (HOMA-IR) but not with traditional anthropometric, glycaemic, or blood pressure measures; this finding is exploratory and causal inferences cannot be established. These results highlight the potential relevance of psychosocial stress as a contributor to metabolic vulnerability; stress assessment may be considered in preventive and clinical strategies pending higher-certainty evidence.

BACKGROUND: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus (T2DM), imposing a substantial burden on healthcare systems. This systematic review and network meta-analysis evaluated the comparative efficacy of antidiabetic medications and combination therapies in reducing cardiovascular outcomes in patients with T2DM. METHODS: PubMed (Medline), Embase, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to December 30, 2024, for randomized controlled trials (RCTs) assessing cardiovascular outcomes in adults with T2DM treated with metformin, sulfonylureas, thiazolidinediones (TZDs), dipeptidyl peptidase‑4 (DPP‑4) inhibitors, glucagon‑like peptide‑1 (GLP‑1) receptor agonists, sodium-glucose cotransporter‑2 (SGLT2) inhibitors, or insulin. Outcomes included cardiovascular mortality, myocardial infarction (MI), stroke, heart failure, hospitalization for cardiovascular events, and unstable angina. Risk of bias was assessed using the Cochrane RoB 2.0 tool, and analyses were conducted with a random-effects model in Stata (version 18). RESULTS: From 10,514 records, 133 RCTs involving 289,558 participants (mean age: 64.7 years) were included. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduced cardiovascular mortality (RR = 0.85, 95% CI: 0.75-0.98; high-certainty evidence) and stroke (RR = 0.83, 95% CI: 0.74-0.93; high-certainty evidence). SGLT2 inhibitors significantly reduced heart failure (RR = 0.64, 95% CI: 0.53-0.77; high-certainty evidence) and hospitalization for cardiovascular events (RR = 0.72, 95% CI: 0.68-0.77; high-certainty evidence). An indirect comparison suggested lower cardiovascular mortality with DPP-4 inhibitors versus GLP-1 receptor agonists, although this finding should be interpreted cautiously due to network imbalance. CONCLUSIONS: GLP-1 RAs and SGLT2 inhibitors are associated with significant reductions in specific cardiovascular outcomes in patients with T2DM, particularly in reducing cardiovascular mortality, stroke, heart failure, and hospitalization. Treatment decisions should integrate patient-specific risk profiles and cost-effectiveness to optimize outcomes.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) significantly exacerbates the prognosis of patients with type 2 diabetes mellitus (T2DM). We aimed to compare metabolic and adiposity-related surrogates for MASLD using data-driven feature selection and to validate a parsimonious risk model across distinct populations. METHODS: We included 449 T2DM patients from the WMU cohort (discovery) and 306 from the Japanese NAGALA cohort (external validation). A two-stage data-driven feature-selection framework (Boruta and LASSO) was implemented to identify a parsimonious two-variable signature (TyG-BMI and SGLT2i). Based on these results, TyG-BMI was prioritized for systematic evaluation. Association and dose-response relationships were assessed via multivariate logistic regression and restricted cubic splines. Multiplicative and additive interactions between TyG-BMI and LDL-C were further explored. Clinical utility was evaluated via AUC, NRI, IDI, and decision curve analysis. RESULTS: The Boruta algorithm ranked TyG-BMI as the feature with the highest importance score for MASLD classification. Subsequently, LASSO regression (utilizing the 1-standard-error criterion λ1se) identified a parsimonious two-variable signature comprising TyG-BMI and SGLT2i. In the WMU cohort, TyG-BMI exhibited a potent association with MASLD (T3 vs. T1: OR = 7.36, 95% CI 3.89-13.94) and a significant linear dose-response relationship (P for overall < 0.001). Incorporation of TyG-BMI into the baseline model improved discriminative performance (AUC increased from 0.7288 to 0.7920) and was associated with improved continuous reclassification (NRI: 0.6088, P < 0.001). DCA and calibration plots confirmed high clinical net benefit and accuracy. Furthermore, a significant synergistic interaction was observed between TyG-BMI and low-density lipoprotein cholesterol (LDL-C). CONCLUSIONS: TyG-BMI, selected through data-driven feature selection, may serve as a practical candidate predictor of MASLD in patients with T2DM. The observed interaction between TyG-BMI and LDL-C suggests that their joint assessment may further refine MASLD risk stratification. The derived parsimonious model offers a high-performing, non-invasive tool for early MASLD risk stratification across Asian populations.

BACKGROUND: As the global prevalence of obesity rises, the clinical focus is shifting from simple BMI to a systemic perspective that integrates body composition and metabolic health. This study evaluates the association between Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and the combined influence of insulin resistance and obesity-related body shape indices. METHODS: Utilizing the KoGES cohort (n = 3,196), participants were categorized into four groups based on the median values of HOMA-IR and the Body Roundness Index (BRI). MASLD was defined by an HSI score > 36, at least one metabolic component, and controlled alcohol consumption (< 30 g/day for men, < 20 g/day for women). Cox proportional hazard regression was conducted to assess the risk across groups, including interaction and subgroup analyses to determine the independence of these markers. RESULTS: Both HOMA-IR and BRI were significant predictors of MASLD risk even when fully adjusted, with Hazard Ratios (HR) of 1.80 (95% CI: 1.52-2.12) and 2.33 (95% CI: 1.96-2.76), respectively. In the joint analysis, the group with both high HOMA-IR and high obesity-related body shape index (BRI) showed a 3.58-fold (95% CI: 2.84-4.51) increased risk compared to the reference group. Notably, no significant additive or multiplicative interactions were found, confirming that these two factors serve as independent and distinct predictive markers. CONCLUSIONS: Combining HOMA-IR with body shape-related obesity markers like BRI provides a more robust prediction of MASLD risk than individual indices. These findings suggest that integrated monitoring of metabolic and morphological profiles is essential for the early identification of high-risk populations.

BACKGROUND: Persistently poorly controlled type 2 diabetes mellitus (PPDM) affects 10-15% of patients with diabetes and disproportionately contributes to morbidity, mortality, and expenditure. Unresponsive to standard outpatient treatment, PPDM requires intensified and comprehensive approaches that lend themselves to a telehealth delivery modality. Despite the recognized need for these types of comprehensive telehealth care models, little is known about factors that influence their implementation in real-world care settings. The objective of this study was to use a secondary qualitative analysis approach to understand implementation barriers and facilitators of a comprehensive virtual care program that has demonstrated superiority in comparison to standard telehealth for patients with PPDM. METHODS: Patients (n = 19) and clinical and administrative staff (n = 8) participated in interviews to discuss their first-hand experience with implementation of comprehensive telehealth as part of a comparative effectiveness randomized controlled trial. Using the Health Equity Implementation Framework, we conducted a secondary analysis using rapid qualitative methods to identify factors that may influence the implementation of this approach into routine care delivery. RESULTS: The comprehensive diabetes telehealth intervention complemented primary care goals to support diabetes self-management but required novel, complex patterns of communication with the existing care team. The approach was perceived as effective, but the intensity of the program introduced challenges with maintaining ongoing patient engagement. Adaptations related to standardizing provider training and integrating locally available resources and complementary programs may amplify the benefit of the approach to patients. Staffing the approach may require new clinical roles or substituting existing responsibilities to ensure sufficient capacity to deliver the approach with fidelity. CONCLUSION: Comprehensive diabetes telehealth intervention implementation is facilitated by using existing infrastructure and care team organization. Opportunities exist to improve fit of the program as part of routine delivery at scale. Findings have implications for the design of strategies to improve implementation efforts required to offer the program at scale to patients with PPDM. CLINICAL TRIAL NUMBER: Not applicable.

BACKGROUND: Low birth weight (LBW) remains a critical global health challenge, yet the differential contributions of risk factors in pregnancies with and without gestational diabetes mellitus (GDM) are poorly characterized. This study aimed to identify modifiable first-trimester risk factors for LBW in GDM and non-GDM subpopulations within a Chinese context, and quantify the preventable LBW burden by population attributable fraction (PAF) estimation adjusted for risk factor interdependence. METHODS: This prospective cohort study enrolled 34,031 pregnant women from Central China (2013-2019), stratified by GDM (n = 5414) and non-GDM (n = 28,617) groups. Early-pregnancy exposures included advanced maternal age, passive smoking, alcohol intake, no folic acid used, low education, and pre-pregnancy underweight. Multivariable logistic regression and principal component analysis-adjusted PAFs were used to quantify preventable LBW burdens while accounting for risk factor overlap. RESULTS: Five risk factors were identified in both GDM (advanced maternal age, passive smoking, underweight, no folic acid used, and low education) and non-GDM (advanced maternal age, alcohol intake, underweight, no folic acid used, and low education) pregnancies. It was found that 18.4% and 33.4% of LBW cases could be theoretically prevented through these five identified risk factors in both GDM and non-GDM cohorts, respectively. Among four shared contributors, low education emerged as the primary modifiable risk factor (adjusted PAF: 9.3% in GDM; 20.1% in non-GDM), followed by underweight (adjusted PAF: 3.7% in GDM; 5.8% in non-GDM), advanced maternal age (adjusted PAF: 3.3% in GDM; 4.8% in non-GDM), no folic acid used (adjusted PAF: 0.9% in GDM; 2.2% in non-GDM). Passive smoking and alcohol intake are specific risk factors for pregnant women with GDM and non-GDM, respectively, with adjusted PAF of 1.1% and 0.5%. CONCLUSION: This study significantly contributes to the advancement of precision public health approaches by elucidating modifiable risk profiles associated with LBW in both GDM and non-GDM populations. These findings highlight population-specific heterogeneity in preventable disease burdens, revealing that a significant proportion of LBW cases could be reduced through targeted antenatal interventions.

BACKGROUND AND AIM: This study aimed to assess the prospective association between zinc (Zn) deficiency and the risk of cardiovascular diseases (CVD), CVD mortality and all-cause mortality in adults with type 2 diabetes (T2DM). METHOD: This prospective cohort study, embedded in the Tehran Lipid and Glucose Study (TLGS), including 632 adults with T2DM (mean age = 59.6 ± 12.4 years, 38% men) enrolled at 2009-2011 and followed until 2020. Serum zinc (SZn) concentrations were measured using flame atomic absorption spectrometry (FAAS), and Zn deficiency was defined as SZn < 85 µg/dL. Multivariable Cox proportional hazard models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of outcomes in the Zn-deficient compared to Zn-sufficient group. RESULTS: Mean baseline SZn concentration was 116 ± 44.5 µg/dL, and 22% were Zn-deficient. Over a median follow-up of 9.3 years, 34.7% of participants experienced incident CVD events, while 6.3% and 18.5% died from CVD and all causes, respectively. Zn deficiency was associated with a significantly increased risk of CVD events (HR = 1.86, 95%CI = 1.06-3.28, P = 0.031) in the fully adjusted model. Each 10 µg/dL increase in SZn was associated with a borderline-significant reduced risk of CVD (HR = 0.97, 95%CI = 0.93-1.00, P = 0.050). Zn status was not associated with CVD mortality or all-cause mortality. CONCLUSION: Zn deficiency is associated with a significantly increased risk of CVD events in patients with T2DM. Increased SZn concentration was associated with reduced risk of CVD events in patients with T2DM.

BACKGROUND: Cognitive development is associated with diet, activity, sleep, metabolic health, and socioeconomic status. However, evidence remains limited, as most studies have focused on clinical groups or single factors. We examined the combined associations of these variables with cognitive function in school-aged children from the general population. METHODS: We evaluated 170 school-aged children from a population-based cohort (mean age 6.33 ± 0.03 years; 49% female). Children were evaluated after an overnight fast (>8 h), and anthropometric, metabolic, and socioeconomic variables were evaluated. Diet and physical activity were assessed using validated questionnaires (Vioque FFQ and enKid). Cognitive function was assessed using NEPSY-II and TONI-2 subsets. Correlation and regression analyses were performed. RESULTS: Cognitive function was positively associated with Mediterranean diet adherence, sleep duration, socioeconomic status, and negatively associated with ultra-processed food intake, TV viewing, and metabolic markers including insulin resistance (HOMA-IR), C-reactive protein, and gamma-glutamyltransferase (all p < 0.05). Multivariate analyses showed that Mediterranean diet adherence (OR 2.18, 95%CI 1.08-4.40), economic status (OR 2.50, 95%CI 1.13-5.49), sleep duration (OR 2.90, 95%CI 1.42-5.92), and HOMA-IR (OR 0.47, 95%CI 0.23-0.96) as independently associated with cognitive outcomes, particularly in attention, language, and memory. CONCLUSIONS: Lifestyle factors and socioeconomic conditions are independently associated with cognitive function in children. IMPACT: Key message: Diet, sleep, metabolic health, and socioeconomic status are associated with cognitive function in school-aged children. Novelty: Simultaneously examines multiple factors associated with cognition in school-aged children from a population-based cohort. Impact on cognition: Mediterranean diet adherence, sleep duration, and metabolic health were positively associated with several cognitive domains, including attention, language, and memory. Practical use: Highlights the potential relevance of healthy lifestyles and social equity in relation to cognitive development. Broader significance: Highlights the multifactorial nature of cognitive development in children.

The triglyceride-glucose (TyG) index represents a pioneering approach to assessing insulin resistance. The objective of this study was to investigate the potential association between the TyG index and muscle strength in a Chinese middle-aged and older adults without comorbid chronic diseases. A total of 2,086 participants were identified in the China Health and Retirement Longitudinal Study (CHARLS). Muscle strength was assessed using two methods: absolute handgrip strength (HGS) and relative HGS, which was normalised by body weight or BMI. To evaluate the correlation between the TyG index and muscle strength, a range of analytical techniques was employed, including linear regression models, logistic regression models, and restricted cubic spline (RCS) analyses. A reduction in relative HGS was observed in the high TyG population compared to the low TyG population, whereas no such reduction was observed for absolute HGS. Regression analyses revealed a significant negative correlation between TyG and relative HGS, after controlling for a range of potential confounding variables. Conversely, no such relationship was observed between TyG and absolute HGS. The RCS results indicated that no nonlinear relationship existed between TyG and absolute HGS. In Chinese middle-aged and older adults, a negative correlation was observed between the TyG index and relative HGS, but not absolute HGS, in individuals without comorbid chronic diseases.

Circadian rhythms orchestrate a wide array of behavioral and physiological functions, coordinating cellular and organismal processes on an approximately 24-h cycle through an intrinsic timekeeping system. Among the many processes subject to this temporal regulation, mitochondrial function has emerged as a critical and dynamic target of circadian control. Mitochondria, far from being static organelles, undergo continuous morphological remodeling through cycles of fusion and fission, collectively termed mitochondrial dynamics, that are essential for maintaining metabolic homeostasis, energy production, and cellular quality control. Disruptions in circadian rhythmicity, such as those arising from sleep disturbances or irregular feeding patterns, have been associated with impaired glucose tolerance, insulin resistance, and increased risk of metabolic syndrome, diabetes, and cardiovascular disease. Emerging evidence suggests that the circadian clock and mitochondrial dynamics are engaged in a bidirectional interplay, whereby clock-controlled gene expression shapes mitochondrial morphology and function, while mitochondrial metabolic states in turn feedback to influence circadian timing. This review explores the evolutionary origins of mitochondrial rhythmicity, synthesizes current evidence on how the circadian clock regulates mitochondrial dynamics, and examines the physiological and pathological implications of their interconnection. A particular focus is placed on how disruptions in this circadian-mitochondrial axis may contribute to the development of common diseases, including neurodegenerative disorders, metabolic diseases, and cancer, highlighting novel avenues for chronobiologically informed therapeutic strategies.

BACKGROUND: The prevalence of type 2 diabetes (T2D) is rapidly increasing worldwide, particularly in low- and middle-income countries, and can lead to severe health complications. Dietary polyphenols may help prevent T2D and support metabolic health. OBJECTIVE: To investigate the longitudinal associations between dietary polyphenol intake and the risk of incident T2D and changes in glycemic markers (fasting glucose, glycated hemoglobin - HbA1c, and homeostatic model assessment of insulin resistance - HOMA-IR) in participants of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: A total of 8,781 participants (mean age 58.8 years, 61.3% female) free of diabetes at baseline were followed for a median of 7.6 years. Dietary polyphenol intake was assessed via a semiquantitative food frequency questionnaire at two time points, with polyphenol content estimated from the Phenol-Explorer database. Cox proportional hazards regression with time-varying exposure was used to assess associations between polyphenol intake tertiles and incident T2D. Linear regression models were used to examine associations with changes in glycemic markers between waves. RESULTS: During follow-up, 1,453 incident T2D cases were identified. In the fully adjusted model, participants in the highest tertile of total polyphenol intake had a 19% lower risk of incident T2D compared with the lowest tertile (HR 0.81, 95% CI 0.70-0.93). Significant inverse associations were also observed for phenolic acids, hydroxycinnamic acids, total flavonoids, flavan-3-ol monomers, flavan-3-ol dimers to polymers, flavones, anthocyanins, and stilbenes, with risk reductions ranging from 13% to 27%. Participants in the highest tertile of total polyphenols, phenolic acids, and stilbenes showed significantly smaller increases in HOMA-IR over follow-up. No significant associations were observed for fasting glucose or HbA1c. CONCLUSION: Higher dietary polyphenol intake was inversely associated with incident T2D and attenuated insulin resistance progression over time. These findings support polyphenol-rich dietary patterns as a strategy for T2D risk reduction.

Diabetic foot ulcers (DFUs) represent one of the most severe complications of diabetes mellitus, frequently leading to chronic infection, delayed wound healing, and lower-limb amputations. Despite advances in wound care, current therapeutic strategies largely rely on broad-spectrum antibiotics and mechanical interventions, which often fail to address the complex biological environment of non-healing wounds. Emerging evidence indicates that DFUs are strongly associated with alterations in the wound microbiome, including microbial dysbiosis, polymicrobial biofilm formation, and persistent inflammatory responses. These factors collectively contribute to impaired tissue regeneration and resistance to conventional therapies. Consequently, microbiome-targeted therapeutic strategies are gaining increasing attention as a promising approach for DFU management. Novel interventions such as bacteriophage therapy, probiotic and postbiotic-based wound dressings, and CRISPR-mediated genome editing provide precise tools for disrupting pathogenic biofilms, attenuating microbial virulence, and overcoming antimicrobial resistance while preserving beneficial microbial communities. In parallel, advances in rapid microbiome diagnostics, smart wound dressings, nanotechnology-based drug delivery systems, and data-driven personalized treatment platforms are enabling more adaptive and targeted wound management. By shifting the perspective from treating DFUs as simple infections to understanding them as complex microbial ecosystems, these emerging strategies offer new opportunities to enhance healing outcomes.

Substance use disorders and affective disorders frequently coexist and share overlapping neurobiological mechanisms involving reward processing, stress regulation, neuroinflammation, and metabolic dysfunction. However, few pharmacological approaches currently target these interconnected pathways simultaneously. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for the treatment of type 2 diabetes and obesity, have recently attracted interest because of their central nervous system effects extending beyond metabolic regulation. This narrative review summarizes preclinical, translational, and emerging clinical evidence regarding the potential role of GLP-1 receptor signalling in addiction and affective disorders. Experimental studies suggest that GLP-1 receptor activation may influence dopaminergic, glutamatergic, and GABAergic neurotransmission within mesolimbic and corticolimbic circuits involved in reward-related behaviours. In animal models, GLP-1 RAs have been associated with reductions in drug-seeking behaviours and cue-induced reinstatement across several substances. Early clinical studies, particularly in alcohol use disorders, have reported reductions in alcohol intake, craving, and cue-reactivity. Additional preliminary evidence from metabolic and psychiatric populations suggests possible effects on depressive symptoms, cognitive function, and neuroinflammatory pathways, although findings remain heterogeneous and direct evidence in dual-disorder populations involving co-occurring substance use and affective disorders remains limited. Overall, current evidence supports further investigation of GLP-1 receptor signalling as a potential mechanistic link between metabolic, reward, and affective processes. Nevertheless, the available clinical literature remains preliminary, and adequately powered randomized controlled trials specifically targeting populations with co-occurring substance use and affective disorders are needed to clarify clinical efficacy, underlying mechanisms, and patient subgroups most likely to benefit.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed to adolescents for obesity and type 2 diabetes mellitus (T2DM), with growing interest in extending their use to conditions such as polyendocrine metabolic ovarian syndrome (PMOS, formerly known as polycystic ovary syndrome or PCOS). However, adolescence represents the critical window for peak bone mass acquisition, and the implications of pharmacologic weight loss during this developmental period have received limited attention. Furthermore, this commentary addresses potential concerns related to eating disorder risk and future reproductive outcomes in this population. METHODS: This commentary examines the emerging concerns regarding bone health, reproductive safety, eating disorder risk and endocrine development when GLP-1 RAs are used in adolescent populations. RESULTS: Adult studies demonstrate improvements in weight loss, insulin resistance, and menstrual regularity with GLP-1 RA therapy. In adolescents with obesity, clinical trials of liraglutide and semaglutide show significant weight reduction without short-term effects on growth or pubertal development. However, adolescence represents a critical period for peak bone mass acquisition, and rapid pharmacologic weight loss may theoretically impair bone mineral accrual. Evidence from adult populations suggests modest reductions in bone mineral density associated with weight loss, while structured exercise may mitigate these effects. GLP-1 RAs are not recommended during pregnancy, and no data exist on reproductive outcomes following adolescent exposure. Additionally, the potent appetite-suppressing effects of these agents raise concerns about potential misuse or exacerbation of eating disorders in adolescents, a population uniquely vulnerable to body image pressures. CONCLUSIONS: GLP-1 RAs represent a promising adjunct therapy for adolescents with obesity, T2DM, and PMOS, but long-term skeletal, reproductive, psychological, and endocrine outcomes remain uncertain. Careful patient selection, bone health monitoring, incorporation of resistance exercise, contraceptive counseling, and screening for disordered eating may be essential when these therapies are considered in adolescent populations.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome characterized by diastolic dysfunction (DD), impaired left ventricular relaxation and elevated left ventricular filling pressures (LVFP), with limited disease-modifying therapeutic options. Emerging evidence implicates the association between arterial stiffness and the development of HFpEF. This review aims to summarize current evidence on the relationship between arterial stiffness and HFpEF and to explore its potential implications for risk stratification and future therapies. Structural and functional vascular changes increase pulsatile afterload and disrupt ventricular-arterial coupling (VAC), leading to myocardial hypertrophy, fibrosis and DD. Arterial stiffening is closely associated with common HFpEF comorbidities including hypertension, diabetes mellitus, obesity and atrial fibrillation, reflecting shared mechanisms such as endothelial dysfunction and systemic inflammation. Several non-invasive indices of arterial stiffness correlate with DD, reduced exercise capacity and adverse clinical outcomes, underscoring their potential prognostic value. Additionally, emerging indices that integrate vascular and myocardial mechanics, providing a more comprehensive assessment of VAC, may offer incremental value in risk stratification. Although arterial stiffness represents a promising therapeutic target in HFpEF, it remains uncertain whether the reduction of arterial stiffness after pharmacological therapies translates into improved VAC and clinical outcomes. We need new insights into the interplay between arterial stiffness and HFpEF and novel therapeutic strategies should be tested.

The long-term stability of biomedical hard-tissue implants is closely associated with the homeostasis of the surrounding immune microenvironment. Wear particles generated from implants can trigger immune activation, leading to local inflammatory responses and inducing bone destruction, ultimately resulting in implant failure. In addition, in patients with diabetes, chronic metabolic disturbances can disrupt immune homeostasis around implants, thereby increasing the risk of implant-related complications. Although the immunological effects of wear particles under normal physiological conditions have been extensively studied, their behavioral characteristics and immunological effects under metabolic disorder conditions such as diabetes remain insufficiently elucidated. Previous studies have demonstrated that nanoparticles rapidly acquire a protein corona (PC) upon exposure to biological fluids, which determines their immune recognition and interactions with cells. However, how diabetes-associated metabolic abnormalities remodel the PC on wear particles and thereby modulate immune responses has not been fully elucidated. In this study, we found that diabetes induces the formation of a distinct PC, referred to as DM-PC (Diabetic-derived protein corona). The DM-PC was enriched in receptor signaling-related proteins, enhancing interactions between wear particles and macrophage membrane receptors and activating the downstream JAK1-STAT3 pathway. The resulting immune imbalance significantly enhanced particle-induced M1 polarization and osteoclast activation. Collectively, this study proposes a mechanism by which the DM-PC modulates macrophage recognition of wear particles and enhances their inflammatory effects through an inflammation-amplifying signaling axis. These findings provide insight into how diabetes-associated metabolic dysregulation drives the progression of implant complications and offer potential intervention targets for improving the long-term stability of hard-tissue implants in the context of metabolic diseases. STATEMENT OF SIGNIFICANCE: Although the immunological effects of wear particles generated from hard-tissue implants under normal physiological conditions have been extensively investigated, their behavioral characteristics and biological effects in the context of metabolic disorders such as diabetes remain insufficiently elucidated. Given this, from the perspective of the protein corona, this study demonstrates that the diabetic microenvironment alters the interfacial biological properties of wear particles and reshapes their interactions with macrophages, thereby exacerbating inflammatory responses and bone destruction. This study not only elucidates the potential biological basis underlying the increased risk of hard-tissue implant-related complications in patients with diabetes and provides mechanistic rationale as well as potential strategies for the prevention or intervention of implant-related complications in diabetic individuals.