Chagas disease (ChD) and Type 2 diabetes (T2D) originate from distinct etiological processes -infectious and metabolic, respectively- yet both share a chronic inflammatory and metabolic imbalance that profoundly impacts immune-endocrine homeostasis. Persistent Trypanosoma cruzi infection in ChD induces sustained immune activation, altered adrenal steroid balance, and tissue remodeling, whereas T2D is characterized by metabolic inflammation, oxidative stress, and insulin resistance. When these two conditions coexist, their overlapping inflammatory, metabolic, and endocrine circuits may act synergistically, amplifying metabolic toxicity, immune exhaustion, and premature immunosenescence. In addition, this comorbidity thus represents the convergence of pathogen-driven and metabolism-driven inflammation, resulting in a disrupted neuroendocrine-immune dialogue and heightened susceptibility to tissue damage, particularly in the heart. Understanding the mechanistic basis of this interplay is crucial, as it highlights shared pathogenic pathways and potential molecular targets for integrated therapeutic interventions. Altogether, recognizing ChD+T2D coexistence as a mechanistic rather than merely epidemiological association provides new insights into the links between chronic infection, metabolic dysfunction, and immune aging-offering a conceptual framework for future studies aimed at restoring immune-metabolic balance and improving disease outcomes, particularly cardiac damage.

BACKGROUND: Diabetic wounds are a common complication and a debilitating condition of diabetes mellitus, which are characterized by chronic inflammation, persistence, and aggravation. Evidence suggests the beneficial influence of Loganin on diabetic complications and inflammation. However, the effectiveness of Loganin on diabetic wounds remains uninvestigated. METHODS: Network pharmacology was applied to identify the potential targets of Loganin in diabetic wound healing. Employing a streptozotocin (STZ)-induced diabetic mouse model, we conducted evaluations pertaining to the effects of Loganin on wound healing and assessment of macrophage-related phenotypes via ELISA, immunohistochemistry, Western blot and qPCR. In vitro, we used J774A.1 mouse macrophage cell line and induced differentiated Th17 cells for experiments. Molecular docking, biotin-labeled pull-down assays and cellular thermal shift assays were applied to investigate direct mechanisms. RESULTS: Loganin topical application accelerated wound healing in diabetic mice, reduced local inflammation, and inhibited NLRP3 inflammasome activation. The IL-17/NF-κB signaling pathway was suppressed by Loganin, thus inhibiting NLRP3 inflammasome. In particular, Loganin inhibited IL-17 A/F production in Th17 cells and targeted the NF-κB p50 subunit in macrophages, thus blocking its nuclear translocation and pro-inflammatory activation. CONCLUSION: Loganin may be considered as an adjuvant or a new therapeutic agent in the management of chronic non-healing diabetic wounds.

Corneal endothelial dysfunction is a major cause of global blindness, with an estimated 12.7 million patients awaiting corneal transplantation, and the severe shortage of donor grafts underscores the urgent need for non-surgical therapies. Gene therapy offers a promising alternative, but is hindered by the limitations in existing delivery systems and the scarcity of validated molecular targets capable of reversing core pathophysiology. To address this, we first employed multi-omics analysis and identified FOXO1 as a central and under-explored therapeutic target for corneal endothelial dysfunction. In vivo FOXO1 overexpression effectively improved corneal endothelial function by preserving mitochondria-associated endoplasmic reticulum membrane integrity and mitochondrial Ca homeostasis, yet its therapeutic potential was limited by low transfection efficiency. To overcome this, we engineered an AAV-Foxo1 delivery system using a viscous choline chloride-fructose-based deep eutectic solvent (DES) as the carrier. The DES-AAV-Foxo1 delivery system exhibited good biocompatibility, significantly prolonged anterior chamber retention, and enhanced transfection efficiency in corneal endothelial cells compared to conventional AAV delivery. Animal experiments confirmed that it effectively improved corneal endothelial pump activity and mitigates endothelial dysfunction in type 1 diabetes mellitus and Fuchs endothelial corneal dystrophy mouse models. Our findings demonstrated the therapeutic potential of DES-AAV-Foxo1 delivery system for corneal endothelial disorders.

OBJECTIVE: Gestational diabetes mellitus (GDM) refers to glucose intolerance, insulin sensitivity, and beta islet cell dysfunction during pregnancy. GDM pathogenesis is associated with hypertension, impaired placental and renal function, oxidative stress, and increased circulating CD4 T cells. There are limited animal models to explore GDM pathology and treatment. This study sought to determine a role for GDM placental CD4 T cells to parallel manifestations of the GDM phenotype in pregnant athymic nude rats. METHODS: GDM placental CD4+ T cells (GDM T cells) were isolated upon delivery and injected into pregnant nude rats on gestational day (GD) 12. Mean arterial pressure and markers of renal injury, proteinuria, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin, were assessed on GD19. Glucose, insulin tolerance, and glucose tolerance tests were also performed. Renal and pancreatic tissues were stained using Periodic acid Schiff and hematoxylin and eosin, respectively. A one-way ANOVA was used for statistical analysis. RESULTS: Adoptive transfer of GDMT cells increased blood pressure (120.8 ± 2.2 mmHg,  < 0.05) compared to controls (105.4 ± 2.8 mmHg) and normotensive Tcell recipients (96.3 ± 3.9 mmHg). Metformin or MitoTEMPO attenuated this response. GDM T cell recipients had elevated blood glucose ( < 0.05) and impaired glucose tolerance and insulin sensitivity, which improved with metformin or MitoTEMPO treatment. Renal injury was more severe in GDM T cell recipients, but attenuated with metformin or MitoTEMPO. Pancreatic morphology showed reduced beta islet numbers in GDM T cell recipients. CONCLUSION: GDM CD4 T cells contribute to hypertension, glucose intolerance, and renal dysfunction, improved byMitoTEMPO. These findings supports optional therapeutics that support mitochondrial function during pregnancy.

BACKGROUND: To compare the elastosonographic changes of the tibial nerve (TN) and Achilles tendon (AT) in patients with type 2 diabetes mellitus (T2DM) and explore their relationship and respective relevant factors. METHODS: This case-control study enrolled 165 subjects, comprising 126 patients with T2DM and 39 healthy controls matched for age and gender. The patients were further divided into those with and without diabetic peripheral neuropathy (PN-DM and NPN-DM groups). Clinical and laboratory data were collected. Conventional ultrasound and elastography were performed to assess the changes in the morphology and elasticity of the bilateral TN and AT. Sonographic features were compared across the three groups, relevant factors affecting the stiffness of TN and AT were analyzed, respectively. RESULTS: Diabetic patients exhibited significantly higher levels of HbA1C and a higher rate of smoking than healthy controls (P < 0.01 and P = 0.02, respectively). Their levels of body mass index (BMI) and total cholesterol have a significant difference between the NPN-DM group and healthy controls (both P = 0.02). The incidence of other microvascular complications in the NPN-DM group was significantly lower among diabetic patients (P = 0.04). Compared with healthy controls, the cross-sectional area (CSA) and transverse diameter of TN in diabetic patients were significantly larger (both P < 0.01), and CSA and anteroposterior diameter of AT were notably greater (P = 0.02 and P < 0.01). Besides, the stiffness of TN in the longitudinal section was significantly higher (P < 0.01), and the stiffness of AT in the cross-section was remarkably lower (P < 0.01). There was no significant difference in the morphology or elastography of TN or AT between NPN-DM and PN-DM groups. Furthermore, the stiffness of TN was not linearly related to that of AT, but independently correlated with age, HbA1C, and other microvascular complications (P < 0.05). The stiffness of AT was only independent of age (P < 0.01). CONCLUSIONS: The size of both TN and AT in diabetic patients was significantly larger. The stiffness of TN increased, and that of AT decreased; however, these changes were independent of each other. CLINICAL TRIAL NUMBER: Not applicable.

Pyogenic liver abscess (PLA) is a life-threatening infection rising in East Asia, especially among patients with type 2 diabetes. Although SGLT2 inhibitors improve glycemic control and offer extraglycemic benefits, their effect on PLA risk is unknown. Using Taiwan's National Health Insurance Research Database, we conducted a nationwide retrospective cohort study of adults with T2DM. After 1:1 propensity score matching, 258,800 SGLT2i users and 258,800 non-users were included. The primary outcome was incident PLA. Incidence rates were calculated per 1,000 person-years, and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards models. Additional analyses included subgroup analyses with interaction testing, a time-dependent Cox model, a competing-risks model, and a negative-control outcome analysis using fracture. During follow-up, 1,275 PLA events were identified. The incidence rate of PLA was 0.75 per 1,000 person-years in SGLT2i users and 0.83 per 1,000 person-years in non-users. In the primary multivariable Cox model, SGLT2i use was associated with a lower risk of PLA compared with nonuse (aHR, 0.88; 95% CI, 0.79-0.99). This inverse association was generally consistent across most subgroups. In the time-dependent analysis, SGLT2i use remained associated with a lower PLA risk (aHR, 0.72; 95% CI, 0.64-0.81). SGLT2i therapy was independently associated with reduced PLA risk in T2DM patients, particularly with prolonged exposure. These findings suggest an inverse association between SGLT2i use and the risk of pyogenic liver abscess in patients with T2DM.

BACKGROUND: Dyslipidemia remains a major modifiable contributor to China's cardiovascular disease (CVD) burden, yet large-scale evidence on risk-stratified management gaps is lacking. METHODS: In this nationwide study across 1,785 hospitals in 28 Chinese provinces, 604,250 outpatients with dyslipidemia were enrolled. We analyzed lipid levels, quantified control rate among treated population and rates of requiring lipid-lowering therapy (LLT) among untreated population across regions, socioeconomic status, and demographic groups. RESULTS: Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were higher among females, middle-aged individuals, and individuals with obesity. LDL-C levels were also higher among urban residents, while TC showed no significant urban-rural difference. Triglyceride (TG) levels were higher in males, middle-aged individuals, individuals with obesity, and rural residents. Among treated population, LDL-C/non-HDL-C control rates reached 95% in low-risk, 70-90% in moderate-risk, 40-50% in high-risk, and 5-15% in very-high-risk groups. Among untreated population, rates of requiring LLT reached about 20% in the low-risk group and over 70% in moderate- and high-risk groups. After adjusting for covariates, males, older individuals, smokers, patients with hypertension or type 2 diabetes mellitus, as well as those in rural and low-gross-domestic-product areas were associated with lower lipid control rates and higher treatment needs. CONCLUSIONS: Our findings highlight the urgent need for risk-stratified lipid management in primary care, improved access to LLT, and policies addressing regional and socioeconomic disparities to enhance lipid control and reduce CVD burden in China. Lessons from China can inform global strategies to improve lipid management and reduce the CVD burden.

BACKGROUND: Hypertension is common among patients with type 2 diabetes mellitus (T2DM) and represents a major contributor to cardiovascular and renal morbidity. Real-world data from primary care are essential to characterise associated clinical profiles and cardiometabolic multimorbidity patterns in routine clinical practice. OBJECTIVE: To assess the prevalence of hypertension among patients with T2DM managed in primary care, to characterise associated clinical profiles, and to explore sex-related differences using real-world data. METHODS: A cross-sectional study was conducted including 680 adults with T2DM receiving routine care in primary care settings. Clinical, sociodemographic and laboratory data were obtained from electronic health records, direct clinical assessment, and structured patient interviews. Hypertension was defined as a previously recorded clinical diagnosis, current antihypertensive treatment, or blood pressure ≥ 140/90 mmHg. Comparisons were performed according to sex. Factors independently associated with hypertension were analysed using bivariate analyses and multivariable logistic regression models adjusted for age, sex, duration of T2DM, pharmacologically treated dyslipidaemia, and established cardiovascular disease. RESULTS: The mean age of participants was 69.8 ± 13.3 years and the mean duration of diabetes was 9.9 ± 4.6 years; 52.1% were men. Overall hypertension prevalence was 84.3%, with no significant difference between men (85.9%) and women (82.5%). Hypertension prevalence increased with age in both sexes. Women had lower educational and socioeconomic levels, higher abdominal obesity, and higher lipid concentrations, whereas men showed higher fasting glucose, serum creatinine, and markers of renal damage. In multivariable analysis, hypertension was independently associated with older age (OR 1.04 per year; 95% CI 1.02-1.06), pharmacologically treated dyslipidaemia (OR 1.83; 95% CI 1.17-2.86), established cardiovascular disease (OR 2.03; 95% CI 1.16-3.55), and longer duration of T2DM (OR 1.06 per year; 95% CI 1.00-1.12). Sex was not independently associated with hypertension after adjustment. CONCLUSIONS: Hypertension was common among patients with T2DM in primary care and was associated with older age, longer diabetes duration, and established cardiovascular disease. Sex-related differences in clinical profiles were observed but should be interpreted as descriptive. This cross-sectional secondary analysis has limitations, including the lack of blood pressure control data and the potential for residual confounding.

BACKGROUND: Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes (T1DM) and a leading cause of pediatric mortality. Prevention depends on caregivers' ability to recognize early signs and initiate proper sick-day management. However, data on DKA awareness among Iranian parents remains limited. This study aimed to evaluate both subjective self-ratings and objective calculated knowledge regarding DKA among parents of children with T1DM. METHOD: This cross-sectional study was conducted among 217 parents at a pediatric diabetes clinic in Shiraz, Iran. A validated questionnaire (Cronbach's alpha = 0.8), adapted through forward-backward translation, assessed demographics, disease duration, HbA1c, and DKA knowledge. Data were analyzed using descriptive statistics, Kruskal-Wallis tests, and Spearman's correlations (r) to identify predictors of awareness. RESULTS: Most participants were mothers (80.6%), and 38.7% reported DKA as the initial presentation at diagnosis. Subjective knowledge scores (0-10) were 1.86 ± 3.07 for mothers and 0.89 ± 2.16 for fathers (P = 0.06). Mothers demonstrated significantly higher calculated objective awareness than fathers (P = 0.007). Higher objective knowledge significantly correlated with higher education levels (r=0.280, P = 0.01), longer disease duration (P = 0.01), and prior DKA admission (P = 0.02). Awareness showed no significant relationship with the child's most recent HbA1c levels (P = 0.98). CONCLUSION: Parental DKA knowledge is critically inadequate. As DKA mortality is preventable through early detection, targeted educational interventions and accessible resources are urgently needed to empower parents and improve clinical outcomes for children with T1DM.

BACKGROUND: This study aimed to investigate the ability of an ultrasound-based risk stratification model integrating carotid intima thickness (CIT) and carotid-femoral pulse wave velocity (cfPWV) to aid in risk stratification and assessment of atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes mellitus (T2DM), thereby providing an objective basis for identifying high-risk individuals and informing individualized management strategies. METHODS: A total of 105 patients with T2DM were enrolled in this study. According to the 10-year ASCVD risk score, patients were further classified into T2DM patients with low-to-moderate burden of other cardiovascular risk factors and T2DM patients with high burden of other cardiovascular risk factors. CIT was measured using high-resolution ultrasound to assess vascular structure, while cfPWV was evaluated using the automatic measurement of arterial stiffness (AMAS) system to assess vascular function. Logistic regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to identify independent risk factors of high ASCVD risk. Based on these risk factors, individual discriminative models and a nomogram were constructed. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were used to evaluate model performance, and differences among models were assessed using the DeLong test. RESULTS: CIT, cfPWV, and estimated glomerular filtration rate (eGFR) were identified as independent risk factors of high 10-year ASCVD risk in patients with T2DM. The areas under the curve (AUCs) for the CIT model, cfPWV model, eGFR model, combined CIT-cfPWV model, and the nomogram were approximately 0.781, 0.808, 0.797, 0.831, and 0.875, respectively. The constructed nomogram demonstrated excellent discrimination, calibration, and clinical applicability. CONCLUSIONS: CIT and cfPWV show strong potential for identifying T2DM patients at high ASCVD risk as estimated by the China-PAR model. Incorporating these parameters into vascular evaluation may aid in risk stratification and provide a robust basis for individualized clinical intervention strategies. Prospective studies are needed to validate their prognostic value for future ASCVD events.

β-Cell dedifferentiation is a key mechanism of β-cell failure in type 2 diabetes (T2D). To survive metabolic stress, β-cells adopt a progenitor-like state, allowing for potential redifferentiation and T2D remission when conditions improve. Glucolipotoxicity is a known driver of β-cell failure, but the triggers of dedifferentiation remain unclear. Recent research has focused on pancreatic islet innervation, particularly the role of noradrenergic fibers in inhibiting insulin secretion. An increase in noradrenergic fibers has been correlated with β-cell dedifferentiation in humans, suggesting a role in T2D pathogenesis. This review explores the link between β-cell dedifferentiation and pancreatic noradrenergic innervation across murine and human models and examines the possibility of targeting innervation to reverse dedifferentiation, restore insulin secretion, and achieve T2D remission.

Early-life nutritional deprivation from famine may increase lifelong vulnerability to Type 2 Diabetes Mellitus (T2DM). This Systematic Review and Meta-Analysis evaluated studies published over the past three decades to assess and appraise the association between famine exposure across developmental stages and T2DM risk. PubMed, Embase, Web of Science, and the Cochrane Library identified observational studies published between 1995 and 2025. Studies reporting risk estimates or data enabling calculation of risk ratios (RRs) were included, followed by pooled estimates were generated. Methodological quality was assessed using the Newcastle-Ottawa Scale. Subgroup analyses, meta-regression and sensitivity analyses were conducted to explore heterogeneity. Of 6311 identified articles, 40 met the inclusion criteria. Overall, famine exposure was associated with 43 % higher risk of T2DM (95 % CI: 1.30-1.56; I = 96.7 %). The pooled risk increased to 47 % in studies published between 2016 and 2025. Longer famine duration (RR = 1.79) and females (RR = 1.52) showed comparatively higher risk. Higher famine severity and exposures during the fetal stage indicated greater susceptibility. Thus, famine exposure is consistently associated with increased risk of T2DM, particularly with prolonged or severe exposure and among women. Nutritional deprivation during key developmental periods may have lasting metabolic effects.

Mechanotransduction is a process converting mechanical cues into electrochemical signals. Piezo1, a mechanically sensitive cation channel protein, is widely distributed in non-sensory cells of mammals, particularly highly expressed in the endothelial cells (ECs). Piezo1 is implicated in various physiological activities, including the regulation of vascular tone, angiogenesis, and maintenance of the endothelial barrier. Under pathological mechanical forces, Piezo1 is involved in the development of endothelial dysfunction-related diseases, including atherosclerosis (AS), hypertension, heart failure (HF), myocardial infarction (MI), pulmonary arterial hypertension (PAH), acute respiratory distress syndrome (ARDS), and diabetes mellitus (DM). In this review, we focus on the underlying mechanisms of Piezo1 in different endothelial dysfunction-related diseases, highlighting its roles in regulating endothelial function. Moreover, we present some activators and inhibitors targeting Piezo1, and discuss their different effects in distinct contexts. Overall, targeting Piezo1 may open a novel avenue of therapeutic tactic for endothelial dysfunction-related diseases.

BACKGROUND: Atrial fibrillation (AF) commonly complicates myocardial infarction (MI) and is associated with adverse outcomes. However, the prognostic significance of AF timing after MI remains incompletely understood. METHODS: We conducted a retrospective cohort study of 3390 patients with myocardial infarction, stratified by MI subtype (NSTEMI and STEMI). AF was categorized as early (during index hospitalization), late (after discharge), or absent. Clinical, echocardiographic, and angiographic data were collected. Outcomes were assessed using Kaplan-Meier analyses and log-rank testing. The association between AF timing and outcomes was evaluated using multivariable time-dependent Cox proportional hazards models with pairwise comparisons, adjusting for relevant demographic and clinical covariates. Predictors of late AF were evaluated using multivariable logistic regression. RESULTS: Among patients with myocardial infarction, AF developed in 451 patients (13.3%), 114 with STEMI and 337 with NSTEMI, occurring as early AF in 249 and late AF in 202. Kaplan-Meier analyses demonstrated significant in long-term major adverse cardiovascular events (MACE), defined as recurrent myocardial infarction with or without repeat revascularization, stroke, and all-cause mortality, according to AF timing, with late AF associated with the poorest outcomes (p<0.001). In multivariable time-dependent Cox models, late-onset AF was independently associated with an increased risk of MACE (HR: 1.5 [1.0-2.2], p=0.044, HR: 2.4 [1.1-5.3], p=0.032 in NSTEMI and STEMI, respectively). In contrast, early AF was not consistently associated with long-term MACE after adjustment (HR: 0.7 [0.4-1.0], p=0.060, HR: 1.3 [0.8-2.3], p=0.327 in NSTEMI and STEMI, respectively). Pairwise comparisons confirmed higher risk with late AF compared with no AF. In contrast, the late versus early AF comparison did not reach statistical significance in STEMI, likely due to limited event numbers. In multivariable logistic regression, older age and diabetes mellitus were independently associated with the development of late AF. CONCLUSION: AF timing after myocardial infarction is prognostically relevant. Late-onset, but not early, AF was independently associated with adverse outcomes in time-dependent analyses, supporting a temporal classification of AF.

Pancreatic ductal adenocarcinoma (PDAC) is frequently preceded by new-onset diabetes mellitus (NODM), yet differentiating PDAC-associated DM from type 2 diabetes (T2D) remains clinically challenging. We investigated whether plasma proteomic profiling combined with machine learning could discriminate these conditions. Plasma samples from individuals with PDAC (with and without DM), long-standing T2D, and controls were analyzed by MALDI-TOF mass spectrometry. Spectral features were processed through a nested cross-validation framework to prevent data leakage, and model interpretability was explored using SHAP values. In parallel, low-molecular-weight proteins were characterized by GeLC-MS followed by LC-MS/MS and differential abundance analysis. Machine learning models distinguished PDAC-associated DM from T2D with a balanced accuracy of 85%. Proteomic analyses identified distinct signatures in PDAC- associated DM, including downregulation of erythrocyte-related proteins and PPBP, and upregulation of acute-phase reactants such as FGA, CP, and SERPINA3. Treatment-naïve cases displayed increased circulating epithelial and keratin-associated proteins, which were attenuated after therapy, suggesting dynamic tumor-related remodeling. These findings demonstrate that integrating MALDI-TOF profiling with machine learning can capture plasma signatures associated with PDAC-associated DM. Although exploratory, this approach supports further validation in prospective cohorts aimed at improving PDAC risk stratification among individuals with NODM. SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a dismal 5-year survival rate, primarily due to late-stage diagnosis. The frequent occurrence of new-onset diabetes mellitus (NODM) as a paraneoplastic syndrome offers a critical window for early detection. However, the clinical challenge of distinguishing PDAC-associated diabetes (PDAC-DM) from type 2 diabetes mellitus (T2D) has hindered the implementation of effective screening strategies. This study addresses this significant clinical problem by leveraging a multi-faceted proteomics approach. We demonstrate that the integration of MALDI-TOF mass spectrometry peptide profiling with machine learning algorithms can accurately discriminate PDAC-DM from T2D with 85% accuracy. Furthermore, we used LC-MS/MS to identify specific low molecular weight proteins that are differentially regulated between these conditions, providing a molecular basis for the observed discrimination. Our work is significant as it presents a novel, high-throughput pipeline for biomarker discovery that combines the scalability of MALDI-TOF with the analytical power of LC-MS/MS and machine learning. The identified plasma signatures hold strong translational potential to improve risk stratification in patients with new-onset diabetes, ultimately enabling earlier diagnosis of PDAC and improving patient survival prospects. This research directly contributes to the field of clinical proteomics by providing a robust methodological framework and candidate biomarkers for the early detection of one of oncology's most challenging diseases.

BACKGROUND: Numerous carbohydrate quality metrics (CQMs) have been suggested, yet the optimal one(s) associated with the lowest type 2 diabetes (T2D) risk remains unknown. OBJECTIVE: We aimed to systematically compare 23 CQMs with T2D risk, identify the five strongest associations, propose an alternate Carbohydrate Quality Index (aCQI), and compare it with the existing CQI regarding T2D risk and cardiometabolic biomarkers. METHODS: We included participants of three prospective cohort studies (Nurses' Health Study I (1984-2020) and II (1991-2019), and Health Professionals Follow-up Study (1986-2020), free of cancer, diabetes, and cardiovascular disease. Our primary outcome was incident T2D. We examined thirteen plasma biomarkers in relation to CQIs among a subset. RESULTS: During 5,628,955 person-years of follow-up among 213,704 adults, 22,351 cases of incident T2D were ascertained. In multivariable-adjusted models, comparing Q5 to Q1, intakes of cereal fiber (relative risk (RR):0.77 (0.74 - 0.81)), whole-fruit carbohydrates (RR:0.80 (0.76 -0.84)), glycemic index (RR:1.20 (1.14 -1.26)), sugar from sugar-sweetened beverages (RR:1.22 (1.17-1.28)), and whole grain carbohydrates (RR:0.86 (0.82 - 0.91)) had the strongest associations with T2D risk. The aCQI (RR:0.71 (0.68 - 0.75)), comprising these variables, had a larger magnitude of association with T2D risk than the original CQI (RR:0.82 (0.79 - 0.87)), which included total fiber intake, glycemic index, the ratios of whole to total grains and solid to total carbohydrates. The aCQI had significant associations with larger percentage of differences in cardiometabolic biomarker concentrations, such as C-peptide, leptin, and LDL-cholesterol, than the CQI (all P-trend ≤ 0.001). CONCLUSION: The novel aCQI, comprised of carbohydrates from whole fruits, whole grains, sugar-sweetened beverages, cereal fiber, and glycemic index, was more strongly associated with risk of T2D and cardiometabolic biomarkers than its individual components or the existing CQI, necessitating further research.

X-linked inhibitor of apoptosis protein (XIAP) is an antiapoptotic protein which plays canonical functions in the cytoplasm. However, we have previously demonstrated that nuclear XIAP is associated with increased cell growth and drug resistance as well as unfavorable outcomes in breast cancer. Therefore, this work aimed to investigate the non-canonical molecular functions associated with abnormal XIAP nuclear localization in breast cancer. To address this, we have performed both transcriptomic and proteomic large-scale approaches with breast cancer cell line models overexpressing HA-tagged ectopic XIAP (WT, H467A, ΔRING and NLS mutants) in distinct subcellular locations. Nuclear XIAP overexpressing cells (XIAP) have been shown enriched for genes implicated in cellular processes other than apoptosis inhibition, such as proliferation, transport, locomotion, migration, cell motility, and protein phosphorylation. Interestingly, the validation analysis has shown differential expression of genes associated with the Wingless-related integration site (Wnt)/β-catenin pathway, as well as the insulin-like growth factor-binding protein 6 (IGFBP6) tumor suppressor gene. IGFBP6 transcript levels have been found reduced in XIAP-overexpressing cells, as well as invasive breast cancer patients. Notably, IGFBP6 knockdown modulated long-term cell proliferation and doxorubicin sensitivity in cells overexpressing nuclear XIAP, further suggesting that nuclear XIAP might indirectly target the IGFBP6 pathway to promote chemoresistance. Finally, Wnt signaling effectors were identified in nuclear XIAP interactomes, closely linked to activation of β-catenin transcriptional activity in XIAP-overexpressing cells. Our data establishes a non-canonical role for XIAP in the regulation of pathways related to cell growth in the nucleus, with Wnt/IGFBP6 emerging as a potential regulatory node associated with nuclear XIAP effects in breast cancer.

Osteoporosis (OP) is a systemic metabolic bone disorder. The excessive activation of osteoclasts (OCs) leads to a decrease in bone mass and damage to the bone microstructure, which plays a crucial role in OP. β-Hydroxybutyrate (BHB), the main component of ketone bodies, not only serves as an ancillary fuel substituting for glucose but also induces anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone β-hydroxybutyrylation (Kbhb). Recent research has found that BHB has a positive therapeutic effect on OP, but the underlying molecular mechanism remains unclear. In this study, we established osteoporosis (OP) animal models induced by estrogen deficiency and type 2 diabetes using ovariectomized (OVX) and db/db mice, respectively, and administered BHB to OP mice via free drinking in vivo. Our results indicated that BHB increased bone mineral density (BMD), improved bone microstructure, and inhibited the OC formation. Additionally, BHB upregulated the levels of PanKbhb, H3K9bhb, and H3K27bhb modifications in the bone tissue of OP mice. In vitro, we found that BHB or β-hydroxybutyryl-CoA (BHB-CoA) could inhibit RANKL-induced OC differentiation and bone resorption, and upregulate histone Kbhb levels in a concentration-dependent manner. Furthermore, the effects of BHB or BHB-CoA-induced histone Kbhb were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300. In summary, our data reveal that BHB may alleviate bone loss caused by estrogen deficiency and type 2 diabetes through ACSS2/P300-induced histone Kbhb.

Air pollution is currently one of the major environmental problems related to human health, affecting many diseases. In this regard, while studies have established an association between air quality and Type 2 Diabetes Mellitus (T2DM), there is still a need to refine exposure-response functions. Therefore, this study aims to establish the exposure-response function that relates the concentration of two air pollutants (NO and PM) to the hazard ratio associated with acquiring T2DM, based on various cohort studies conducted worldwide. To achieve this, a methodology using nonlinear function adjustments will be employed. This function is then applied to determine the number of T2DM cases attributable to air pollution across Europe for different age groups, using atmospheric concentrations from 1991 to 2020. Results indicate a significant nonlinear relationship between pollutant exposure and T2DM cases, with higher risks observed in areas with elevated levels of NO and PM (specifically, in large European cities and in central Europe, mainly related to traffic and industrial activities). NO relates to 3754000 [3428000 - 3957000; 95% CI] annual T2DM cases, which represent 0.51% [0.46%-0.54%; 95% CI]; while PM, annual cases increase to 5109000 [4036000 - 6581000; 95% CI], corresponding to a 0.69% [0.55%-0.89%; 95% CI] of cases of T2DM attributable to this pollutant. The analysis revealed that, despite lower concentrations, PM shows a higher impact on T2DM incidence compared to NO, especially at lower exposure levels. Findings underscore the need for stringent air quality regulations, particularly in urban and industrial regions, to mitigate air pollution's health impacts.

This retrospective cohort study aimed to compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus metformin for preventing type 2 diabetes mellitus (T2DM), reducing mortality, and improving body mass index (BMI) in antipsychotic-treated patients with overweight /obesity. We used data from the TriNetX Global Collaborative Network. Adults (aged ≥18 years) with overweight or obesity, antipsychotic exposure, and no prior T2DM diagnosis were identified. After propensity score matching, patients initiating GLP-1RA therapy were compared with those initiating metformin. The primary outcome was incident T2DM occurring between 1 and 5 years after treatment initiation. Secondary outcomes included all-cause mortality and BMI change. Among 9939 eligible patients, 3115 matched pairs were included. The incidence of T2DM was significantly lower in the GLP-1RA group compared with the metformin group (1.96% vs 7.26%; hazard ratio [HR]=0.34; 95% CI, 0.26-0.46; p < 0.001). All-cause mortality was also reduced in the GLP-1RA group (0.32% vs 1.96%; HR, 0.25; 95% CI, 0.13-0.49; p < 0.001). Regarding BMI change, patients receiving GLP-1RA experienced greater weight reduction than those receiving metformin. The mean (standard deviation) change in BMI was -2.66 (8.51) kg/m² in the GLP-1 group versus -1.36 (8.63) kg/m² in the metformin group (p < 0.001). In conclusion, in this large real-world cohort of antipsychotic-treated patients with overweight or obesity, GLP-1RA therapy was associated with significantly lower risks of T2DM and mortality, and greater BMI reduction compared with metformin. These findings suggest that GLP-1RAs may offer a more favorable profile against antipsychotic-induced glucose dysregulation.

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic and widespread disease. In patients' pancreas, islet amyloid polypeptide (IAPP) is found as aggregates. As for other disease-related amyloidogenic proteins, oligomeric species of IAPP have been suggested to exhibit cytotoxic activity. Here, we developed an IAPP model, denoted dimIAPP, which assembles into curvilinear oligomers that persist over extended periods of time. DimIAPP is an engineered dimer of a cysteine-free IAPP mutant (C2S, C7S), with the two dimer subunits linked by a flexible (GS) linker on one polypeptide chain. In contrast to IAPP, dimIAPP did not form Thioflavin T-positive amyloid fibrils, but assembled into oligomers (dimIAPP-O) which tended to coalesce into larger clusters. IAPP fibril formation was slowed down by addition of dimIAPP-O, a finding that extends previous studies demonstrating an intrinsic inhibitory activity of off-pathway oligomers on amyloid fibril formation. Exposure of pancreatic RIN-m5f cells to dimIAPP-O and IAPP fibrils differentially activated cellular stress response. We conclude that the dimIAPP model is a useful tool to gain further insights into IAPP aggregation and to characterize the effects of off-pathway oligomers of amyloidogenic proteins.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder that significantly predisposes individuals to delirium and dementia through multifaceted neurobiological pathways. The essence of this neurocognitive decline involves mechanisms such as central insulin resistance, chronic low-grade inflammation, and mitochondrial dysfunction. While metformin remains the cornerstone of T2DM management, its impact on the central nervous system exhibits a "double-edged sword" nature, balancing intrinsic neuroprotective properties against the potential neurotoxicity associated with vitamin B12 deficiency. This review aims to systematically synthesize epidemiological and clinical evidence linking metformin to neurocognitive outcomes, contrasting its efficacy with newer glucose-lowering agents such as GLP-1 receptor agonists and SGLT2 inhibitors. In addition, it sheds light on the reciprocal connectivity between systemic metabolic regulation and direct CNS modulation, specifically elucidating AMPK activation, the autophagy-lysosome axis, and the gut-brain and liver-brain axes. We review these molecular mechanisms to delineate the delicate trade-off between neuroprotection and risk, providing a framework for precision pharmacotherapy and biomarker-guided stratification in high-risk T2DM populations.

OBJECTIVES: Cynandione A (CA), a major bioactive compound isolated from Cynanchum wilfordii Radix, is a crude drug traditionally used in East Asia. We have previously demonstrated that CA induces a beige adipocyte-like phenotype in vitro. This study aimed to investigate the in vivo effects of CA on white adipose tissue (WAT) function. METHODS: C57BL/6 J mice were fed a high-fat diet (HFD) and administered CA (5 or 15 mg/kg, intraperitoneally, once daily) for eight weeks. Body weight, glucose tolerance, insulin sensitivity, and serum parameters were evaluated. Histological analyses of WAT and liver were performed, and gene and protein expression related to beige adipocyte features and mitochondrial biogenesis were assessed in inguinal WAT (iWAT). KEY FINDINGS: CA treatment did not affect body weight, glucose tolerance, insulin sensitivity, or serum parameters. However, adipocyte size was significantly reduced in inguinal and epididymal WAT in mice treated with CA at 15 mg/kg (43.8% reduction, P < .001; 33.1% reduction, P = .021, respectively). Moreover, CA increased the expression of beige adipocyte-specific genes (Tmem26, 2.8-fold, P < .001; Cd137, 3.8-fold, P < .001) and mitochondrial marker proteins (UCP1, 2.1-fold, P = .007; TOM20, 2.2-fold, P < .001; VDAC, 1.6-fold, P = .019) in iWAT. CONCLUSIONS: CA modulates WAT plasticity and improves WAT homeostasis in HFD-fed mice.