Diabetes Res Clin Pract
· 2026 May · PMID 41794135
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Oxidative stress (OS) is increasingly recognised as a central mechanistic component of type 2 diabetes (T2D), linking chronic hyperglycaemia, insulin resistance, mitochondrial dysfunction, inflammation, and the developme...Oxidative stress (OS) is increasingly recognised as a central mechanistic component of type 2 diabetes (T2D), linking chronic hyperglycaemia, insulin resistance, mitochondrial dysfunction, inflammation, and the development of vascular complications. Experimental and human data support a contributory role of reactive oxygen species in β-cell dysfunction, impaired insulin signalling, endothelial injury, and progressive tissue damage. This narrative review synthesises clinically relevant oxidative pathways and critically evaluates major biomarker classes, including lipid peroxidation products, protein and DNA oxidation markers, redox couples, antioxidant enzymes, and redox-sensitive regulatory networks. Particular emphasis is placed on analytical robustness, biological variability, methodological heterogeneity, and translational maturity. Despite extensive associative evidence, no oxidative stress biomarker currently demonstrates consistently replicated incremental prognostic value beyond established cardiometabolic risk models sufficient for routine clinical implementation. Most available data derive from cross-sectional or intermediate translational studies, with limited prospective outcome validation. Although glucose-lowering therapies and lifestyle interventions may reduce oxidative biomarker levels, modulation of these markers has not been established as a validated mediator of clinical benefit. At present, oxidative biomarkers remain primarily mechanistic and research tools, and meaningful clinical integration will require assay harmonisation and rigorous longitudinal demonstration of added predictive or therapeutic value.
Al-Sofiani ME, Alharthi SK, Alsuhaibani M
… +10 more, Alhashem A, Almurashi A, Almigbal TH, Alamoudi RM, Zarif H, Alzaman N, Almehthel M, Mohammed S, Kalyani RR, Klonoff DC
Diabetes Res Clin Pract
· 2026 May · PMID 41780645
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INTRODUCTION: Most people with type 1 diabetes (PWT1D) typically avoid fasting during Ramadan because of dysglycemia risks. We compared efficacy, safety profiles, and fear of hypoglycemia (FOH) during Ramadan fasting in...INTRODUCTION: Most people with type 1 diabetes (PWT1D) typically avoid fasting during Ramadan because of dysglycemia risks. We compared efficacy, safety profiles, and fear of hypoglycemia (FOH) during Ramadan fasting in users of four insulin delivery modalities. METHODS: We compared four treatment groups: automated insulin delivery (AID) (n = 114), sensor augmented pump with predictive-low-glucose suspend (SAP-PLGS) (n = 4), sensor-unintegrated pump (SUP) (n = 24), and multiple daily injections (MDI) + continuous glucose monitoring (CGM) (n = 136). RESULTS: Pre/during-Ramadan mean percent time in range for the AID, SAP-PLGS, SUP, and MDI-CGM groups was 73.2/73.4, 62/65.5, 57.8/54.6, and 52.1/47.4. The pre/during-Ramadan Glycemia Risk Index for the AID, SAP-PLGS, SUP, and MDI-CGM groups was 30/29, 43/35, 52/55, and 60/64. The proportion of PWT1D achieving a "double target of fasting" (broken fasting ≤ 2 days of Ramadan because of diabetes and TIR > 70%) for the AID, SAP-PLGS, SUP, and MDI-CGM groups was 46.5%, 25%, 12.5%, and 7.35%. AID system users, versus MDI + CGM users, were 22 times likelier to achieve the double target after adjusting for age, sex, employment/insurance status, educational level, and diabetes duration. While the overall FOH score did not significantly differ across the four groups (p > 0.05), AID users had the lowest score and MDI had the highest score (1.23 and 1.63, respectively, p < 0.01) on the survey's behavior subscale. CONCLUSION: Use of AID during Ramadan fasting was associated with fasting the most days of Ramadan, best glycemic control, and the least frequent hypoglycemia avoidance behaviors. The International Diabetes Federation/Diabetes and Ramadan International Alliance risk calculator should consider a lower risk score for AID technology when used by PWT1D.
Basilicata MG, Scisciola L, Pesapane A
… +15 more, Fontanella RA, Balzano N, Maddalena Palazzo AM, Joshi R, Zia A, Tortorella G, Ulfat Z, Arshad M, Aquino G, Sommella E, Malavolta M, Giuliani A, Campiglia P, Barbieri M, Paolisso G
Diabetes Res Clin Pract
· 2026 May · PMID 41780644
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AIMS: This review aims to evaluate the hypothesis that Volatilomics-the comprehensive analysis of volatile organic compounds (VOCs) from breath, skin, urine, and other biological matrices-can serve as a non-invasive tool...AIMS: This review aims to evaluate the hypothesis that Volatilomics-the comprehensive analysis of volatile organic compounds (VOCs) from breath, skin, urine, and other biological matrices-can serve as a non-invasive tool to characterize metabolic alterations associated with aging and diabetes mellitus in older adults, supporting precision geriatric medicine. METHODS: We conducted a narrative review of experimental and clinical studies investigating VOC signatures in aging individuals with diabetes. The analysis focused on associations between VOC profiles and key biological mechanisms, including oxidative stress, lipid peroxidation, mitochondrial dysfunction, inflammaging, and host-microbiome interactions. We also examined analytical technologies and methodologies, such as advanced mass spectrometry platforms, sensor-based devices, and artificial intelligence-driven pattern recognition approaches. RESULTS: The reviewed evidence suggests that diabetes is associated with distinctive VOC patterns; however, direct evidence specifically derived from geriatric cohorts remains limited. These VOC patterns are associated with glycemic imbalance and age-related metabolic dysfunction and show potential utility for early detection, clinical phenotyping, and individualized monitoring, particularly in frail or multimorbid patients. Technological advances are facilitating translation toward portable and home-based applications. CONCLUSIONS: Volatilomics represents a promising, non-invasive approach to improve diabetes management in aging populations. Despite its potential, challenges remain, including methodological heterogeneity, limited reproducibility, confounding effects of comorbidities and polypharmacy, and the lack of large longitudinal geriatric cohorts.
Diabetes Res Clin Pract
· 2026 May · PMID 41771442
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Diabetes-related cognitive dysfunction (DCI) is a common central nervous system complication of diabetes mellitus; however, its pathogenesis remains poorly understood despite its significant clinical impact. The glymphat...Diabetes-related cognitive dysfunction (DCI) is a common central nervous system complication of diabetes mellitus; however, its pathogenesis remains poorly understood despite its significant clinical impact. The glymphatic system (GS), a waste clearance pathway in the brain, has been implicated in various central nervous system disorders. This review aims to systematically elaborate on the central role of the glymphatic system in DCI. We first summarize neuroimaging evidence of glymphatic system dysfunction in diabetes, including a reduced DTI-ALPS index and enlarged perivascular spaces. Furthermore, we examine its mechanisms, including dysregulated AQP4, impaired perivascular space function, and compromised drivers like arterial pulsation and sleep. Finally, we discuss the potential of glymphatic-targeted therapies, from lifestyle adjustments to pharmacological agents, for ameliorating DCI. This review emphasizes that glymphatic system dysfunction is a key link connecting diabetic metabolic disturbances to cognitive decline, offering a novel perspective and direction for research in this field.
Li M, Sharma K, Chon JE
… +4 more, Yehia NA, Retnakaran R, Harris SB, Hanley AJ
Diabetes Res Clin Pract
· 2026 May · PMID 41763558
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We aimed to systematically review literature investigating the impact of COVID-19 on insulin resistance and beta-cell dysfunction in humans. Ovid MEDLINE and Embase were searched for studies published between December 20...We aimed to systematically review literature investigating the impact of COVID-19 on insulin resistance and beta-cell dysfunction in humans. Ovid MEDLINE and Embase were searched for studies published between December 2019 and May 2024. Observational studies examining adults with no history of type 2 diabetes comparing the development of insulin resistance and beta-cell dysfunction between COVID-19 exposed groups vs. controls were included. Risk of bias was assessed using adapted Newcastle-Ottawa and Joanna Briggs Institute scales. Among 6901 studies screened, 10 met the inclusion criteria. Across these studies, 37 individual measures of insulin resistance and beta-cell dysfunction were reported. Insulin resistance worsened significantly in 16 of 25 (64.0%) comparisons, whereas beta-cell dysfunction worsened significantly in 7 of 12 (58.3%) measures among COVID-19 patients when compared to controls. Five studies were considered low risk of bias. COVID-19 was associated with worsened insulin resistance and beta-cell dysfunction, suggesting infection may be a metabolic stressor that overwhelms gluco-regulatory mechanisms. Results, especially those for beta-cell function, should be interpreted cautiously given methodological limitations in the utilized measures. These findings highlight the pathophysiological aspects of type-2 diabetes impacted by COVID-19 infection and support the development of targeted monitoring and therapeutic strategies.
Liu S, Chen J, Du J
… +4 more, Song J, Kang Y, Zhang D, Feng S
Diabetes Res Clin Pract
· 2026 May · PMID 41747772
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AIMS: To investigate the association between metformin use and osteoarthritis (OA) risk or total knee replacement (TKR) need in type 2 diabetes (T2DM) patients, addressing limited real-world evidence on metformin's poten...AIMS: To investigate the association between metformin use and osteoarthritis (OA) risk or total knee replacement (TKR) need in type 2 diabetes (T2DM) patients, addressing limited real-world evidence on metformin's potential joint-protective effects. METHODS: This retrospective cohort study analyzed electronic health records (January 2015-December 2021) from a large healthcare database. We identified 244,562 metformin users and 117,529 non-users with T2DM. Multivariable-adjusted Cox proportional hazards models evaluated OA development and TKR risk, with propensity score matching and competing risk models minimizing confounding. RESULTS: Among 362,091 patients, 28,724 incident OA cases and 1,593 TKR procedures occurred. Metformin users showed significantly reduced OA risk versus non-users (adjusted HR 0.95, 95% CI 0.92-0.96, p < 0.001). No significant TKR risk difference was observed (adjusted HR 1.05, 95% CI 0.94-1.18, p = 0.352). Results remained robust through sensitivity analyses including propensity score matching and competing risk regression. CONCLUSION: In this large real-world T2DM cohort, metformin use associated with modestly reduced OA incidence but unchanged TKR risk. These findings support preclinical and clinical evidence for metformin's potential protective role against OA development.
Murakoshi M, Kamei N, Tanaka M
… +6 more, Sato T, Furuhashi M, Kubota M, Sanuki M, Suzuki Y, Gohda T
Diabetes Res Clin Pract
· 2026 May · PMID 41747771
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AIMS: To evaluate the independent prognostic value of B-type natriuretic peptide (BNP) for chronic kidney disease (CKD) progression in comparison with urinary albumin-to-creatinine ratio (UACR), protein-to-creatinine rat...AIMS: To evaluate the independent prognostic value of B-type natriuretic peptide (BNP) for chronic kidney disease (CKD) progression in comparison with urinary albumin-to-creatinine ratio (UACR), protein-to-creatinine ratio (UPCR), and dipstick proteinuria, and assess its incremental value when added with UACR. METHODS: We analyzed 636 adults with diabetes followed for median 5.4 years. The primary endpoint was a ≥30% estimated glomerular filtration rate (eGFR) decline. Discrimination was assessed using time-dependent area under the curve (AUC), comparing the incremental value of BNP and urinary markers added to a clinical base model. RESULTS: During follow-up, 74 participants reached the endpoint. Baseline median BNP and UACR were 14.5 pg/mL and 21 mg/g, respectively. BNP showed prognostic performance (AUC) comparable to UACR, UPCR, and dipstick proteinuria. BNP was independently associated with CKD progression after adjustment for UACR and covariates (p = 0.002). Spline analyses demonstrated a graded risk even within the normal BNP range (≤18.4 pg/mL), paralleling the UACR risk gradient. Combined BNP and UACR elevations identified those at highest risk. CONCLUSIONS: BNP is independently associated with kidney function decline, enabling graded risk stratification even within normal ranges. As a cardiac-derived marker of cardiorenal vulnerability, BNP complements urinary measures in identifying high-risk individuals with diabetes.
BACKGROUND: The role of elevated remnant cholesterol (RC) across different glycemic status categories remains unclear. METHODS: We used data from the China Health and Retirement Longitudinal Study (CHARLS), including 9,1...BACKGROUND: The role of elevated remnant cholesterol (RC) across different glycemic status categories remains unclear. METHODS: We used data from the China Health and Retirement Longitudinal Study (CHARLS), including 9,182 participants aged ≥ 45 years without prior stroke. Baseline RC was categorized into quartiles. Incident self-reported stroke over 7 years was the primary outcome. Associations between RC and stroke were assessed using Kaplan-Meier curves, Cox proportional hazards models, and restricted cubic spline (RCS) analyses, with stratification by glucose metabolism status and by the clinical low-density lipoprotein cholesterol (LDL-C) threshold of 130 mg/dL. RESULTS: During follow-up, 867 participants (9.44%) developed stroke. Stroke risk increased across RC quartiles in the overall cohort and among those with prediabetes (Pre-DM) and diabetes mellitus (DM), but not in individuals with normal glucose regulation (NGR). In fully adjusted models for the overall cohort, compared with the lowest RC quartile, hazard ratios (95% CIs) were 1.228 (0.980-1.537), 1.390 (1.116-1.730), and 1.419 (1.138-1.769) for quartiles 2-4, respectively. In analyses stratified by LDL-C, associations were stronger when LDL-C was <130 mg/dL, and were significant in Pre-DM and DM but not in NGR. CONCLUSIONS: In individuals with Pre-DM and DM, higher RC independently predicts incident stroke, especially when LDL-C is <130 mg/dL, supporting RC as a potential target after LDL-C goals are achieved.
AIMS: To evaluate the effect of the Accu-Chek® SmartGuide Predict app Night Low Predict (NLP) feature use on nocturnal hypoglycemia in people with diabetes in a real-world setting. METHODS: This retrospective analysis us...AIMS: To evaluate the effect of the Accu-Chek® SmartGuide Predict app Night Low Predict (NLP) feature use on nocturnal hypoglycemia in people with diabetes in a real-world setting. METHODS: This retrospective analysis used deidentified, aggregated data from Predict app users. Outcomes included hypoglycemic events of any severity (glucose < 70 mg/dL), level 2 (L2) events (glucose < 54 mg/dL), hyperglycemic events (glucose > 180 mg/dL), time below 70 mg/dL (TB70), time below 54 mg/dL (TB54), and time above 180 mg/dL (TAR). Users without nocturnal hypoglycemic events were excluded. Nights when predictions were received were compared with nights when predictions were not generated. RESULTS: Data from 249 people (aged 20-84 years) showed NLP use was associated with 20.0 % lower odds of hypoglycemic events of any severity occurring in a given night and 31.2 % lower odds of any TB70 occurring. Data from 159 people showed NLP use was associated with 31.0 % lower odds of L2 events occurring and 39.2 % lower odds of any TB54 occurring. Hyperglycemic events and TAR were not affected by NLP use. CONCLUSION: NLP use is associated with lower odds of nocturnal hypoglycemia in people with diabetes without raising odds of hyperglycemia, offering valuable self-management support.
AIM: This study assessed the cost-effectiveness of oral semaglutide versus subcutaneous dulaglutide for type 2 diabetes mellitus (T2DM) from the perspective of the Taiwanese healthcare payer, considering the self-paid st...AIM: This study assessed the cost-effectiveness of oral semaglutide versus subcutaneous dulaglutide for type 2 diabetes mellitus (T2DM) from the perspective of the Taiwanese healthcare payer, considering the self-paid status of oral semaglutide and the reimbursed but injectable route of dulaglutide under the National Health Insurance (NHI). METHODS: A Markov decision-analytic model simulated clinical and economic outcomes over a 10-year horizon. Transition probabilities, utilities, and treatment costs were derived from clinical trials, national databases, and expert consensus. Costs and health outcomes were discounted at 3% annually. The willingness-to-pay (WTP) threshold was set at US$33,983, reflecting per capita gross domestic product in Taiwan. Probabilistic and one-way sensitivity analyses evaluated model robustness. RESULTS: Oral semaglutide was dominant, yielding an incremental gain of 0.33 quality-adjusted life years (QALYs) and reducing costs by US$1,137 compared with dulaglutide, with an incremental cost-utility ratio of -US$3,478.66/QALYs. Sensitivity analyses confirmed the robustness, with a 96.5% probability of cost-effectiveness across all WTP thresholds. Cost differences were most sensitive to drug price, particularly in patients without cardiovascular disease. CONCLUSION: Oral semaglutide demonstrated higher clinical effectiveness and strong economic favorability relative to dulaglutide, supporting its potential inclusion in Taiwan NHI formulary to optimize the allocation of healthcare resources in T2DM.
AIMS: The intervention of prediabetes, with lifestyle modification as its first-line therapy, is an emerging method to prevent diabetes and cardiovascular complications. This study investigated the association of Life's...AIMS: The intervention of prediabetes, with lifestyle modification as its first-line therapy, is an emerging method to prevent diabetes and cardiovascular complications. This study investigated the association of Life's Essential 8 (LE8) with cardiovascular outcomes and mortality among individuals with prediabetes, and the mediating role of inflammation in these relationships. METHODS: The main analyses included 33,745 participants with prediabetes from the UK Biobank cohort study. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Mediation analyses were conducted to examine underlying pathways. RESULTS: After multivariable adjustment, a higher LE8 score was significantly associated with lower risks of CVD incidence (HR 0.49; 95% CI 0.45, 0.53), CVD mortality (HR 0.46; 95% CI 0.35, 0.61), and all-cause mortality (HR 0.54; 95% CI 0.48, 0.60). Inflammatory biomarkers, particularly neutrophil count (mediating 9.65% of the LE8-CVD association and 17.20% of the LE8-mortality association), significantly mediated these associations. Moreover, in the genetic susceptibility analysis, LE8 adherence was associated with lower cardiovascular risk across all PRS groups (p for interaction > 0.05). CONCLUSIONS: Achieving optimal LE8 metrics is significantly associated with reduced cardiovascular risk and mortality in people with prediabetes, and systemic inflammation partially explains these associations.
AIMS: We investigated longitudinal, bidirectional associations between objectively measured moderate to vigorous physical activity (MVPA), health-related quality of life (HRQoL), and emotional well-being (EWB) in individ...AIMS: We investigated longitudinal, bidirectional associations between objectively measured moderate to vigorous physical activity (MVPA), health-related quality of life (HRQoL), and emotional well-being (EWB) in individuals recently diagnosed with type 2 diabetes mellitus. METHODS: Participants were 972 adults. MVPA was assessed using accelerometry, HRQoL using the SF-12 (physical [PCS], mental [MCS]), and EWB using the WHO-5. A three-wave cross-lagged panel model tested associations, adjusting for age and sex. RESULTS: Baseline PCS predicted MVPA at 24 months (β = 0.124, p < 0.001), and PCS at 24 months predicted MVPA at 48 months (β = 0.146, p < 0.001). Baseline MCS predicted MVPA at 24 months (β = 0.116, p = 0.001), but not 48 months (β = -0.016, p = 0.653). Baseline EWB predicted MVPA at 24 months (β = 0.080, p = 0.023), but not 48 months (β = 0.068, p = 0.058). Baseline MVPA did not predict PCS at 24 months (β = 0.038, p = 0.184), but MVPA at 24 months predicted PCS at 48 months (β = 0.065, p = 0.024). MVPA did not predict MCS or EWB. CONCLUSIONS: HRQoL and EWB predicted subsequent MVPA, whereas MVPA showed limited and inconsistent effects on later HRQoL or EWB.
OBJECTIVE: No epidemiological studies have yet explored the relationship between TZD use and epilepsy incidence within a population context. This study aimed to evaluate the association between TZD use and risk of epilep...OBJECTIVE: No epidemiological studies have yet explored the relationship between TZD use and epilepsy incidence within a population context. This study aimed to evaluate the association between TZD use and risk of epilepsy in a Chinese population by using a target trial emulation framework with active-comparator new-user (ACNU) design. METHODS: We emulated a target trial comparing the risk of epilepsy between use of TZDs and alpha glucosidase inhibitors (AGIs) in patients with type 2 diabetes mellitus (T2DM). Participants aged between 18 and 100 years, who were new users of TZDs or AGIs were included. The primary outcome was incident epilepsy identified by using ICD-10 codes. A Cox model with inverse probability of treatment weighting (IPTW) was used to estimate the hazard ratio (HR) and confidence interval (CI). Various subgroup analyses and sensitivity analyses were conducted. RESULTS: The final cohort included 22,128 new users of TZDs and 79,166 new users of AGIs. The mean age was 60.3 (SD, 12.8) years and 47.2% of participants were female. The incidence of epilepsy was 140.1 per 100,000 person-years in users of TZDs and 208.2 per 100,000 person-years for AGIs users, respectively. After adjusting for potential confounders using stabilized IPTW, use of TZDs was associated with a 23% (HR 0.77; 95% CI, 0.64-0.93) decrease in incidence of epilepsy. This association was consistent in various subgroup analyses and sensitivity analyses. CONCLUSION: Our results indicated that use of TZDs was associated with reduced risk of epilepsy in the study population. More studies are needed to confirm and replicate the study results in other settings and populations..
AIMS: Notch signaling may regulate adipogenesis. The objective of the present study was to analyze the role of the Notch pathway in the development of insulin resistance and metabolic complications of obesity. We analyze...AIMS: Notch signaling may regulate adipogenesis. The objective of the present study was to analyze the role of the Notch pathway in the development of insulin resistance and metabolic complications of obesity. We analyzed subcutaneous (SAT) and visceral adipose tissue (VAT) expression of Notch genes in relation to insulin sensitivity, obesity, and metabolic syndrome (MS). METHODS: Study group 1 comprised 48 individuals with normal-weight, 28 with overweight and 12 with obesity. Group 2 comprised 27 participants with overweight/obesity examined before and after weight loss. Group 3 comprised 8 individuals without obesity, 23 with obesity without MS, 29 with obesity with MS. SAT biopsy was performed in group 1 and 2. In group 3, SAT and VAT were collected during surgery. RESULTS: In group 1, SAT DLL1, NOTCH2, NOTCH4, and HEY1 were lower in individuals with obesity compared to normal-weight individuals. In group 2, weight loss increased DLL1, JAG1, NOTCH2, NOTCH4, and HES1. In group 3, both groups with obesity had lower SAT and VAT JAG1, NOTCH2, NOTCH4, and HEY1. Positive correlations between Notch genes and adipogenic genes were observed in all study groups. CONCLUSIONS: Notch signaling pathway may be associated with healthy adipose tissue through regulation of adipogenesis in humans.
BACKGROUND: There is emerging evidence that gestational diabetes mellitus (GDM) increases the risk of multi-system long-term complications such as cancer and autoimmune disease, however this evidence is scarce and confli...BACKGROUND: There is emerging evidence that gestational diabetes mellitus (GDM) increases the risk of multi-system long-term complications such as cancer and autoimmune disease, however this evidence is scarce and conflicting. Therefore, we aim to explore the long-term health implications of GDM. METHODS: We performed analyses using TriNetX in women ≥ 18 years who had a birth. Four cohorts were generated with a reference and GDM arm, and PSM 1:1 for factors including age, BMI, and cohort-specific risk factors. The cohort sizes were metabolic n = 72,014, cancer n = 88,131, autoimmune n = 96,110, and gynaecological n = 94,945. RESULTS: GDM increased the risk of 5-year incident clinical outcomes: metabolic: T2D (HR 18.42, p < 0.0001), hypertriglyceridemia (HR 2.47, p < 0.0001), obesity (HR 1.89, p < 0.0001), and sleep apnoea (HR 1.83, p < 0.0001); cancer: thyroid cancer (HR 1.34, p = 0.036); autoimmune: type 1 diabetes (HR 12.32, p < 0.001), Grave's disease (HR 1.57, p=<0.0001), and psoriasis (HR 1.25, p = 0.007); and gynaecological PCOS (HR 1.97, p < 0.0001), uterine fibroids (HR 1.29, p < 0.0001), and endometriosis (HR 1.16, p = 0.018). At 10 years, there was a significantly increased risk of the composite 13 adiposity-related cancers (HR 1.18, p = 0.008). CONCLUSION: Women with GDM are at risk of a myriad of long-term adverse health outcomes meriting targeted early intervention and long-term post-partum monitoring.
Diabetic neuropathy (DN), a major microvascular complication of diabetes mellitus, results from a complex interplay among oxidative stress, inflammation, and persistent epigenetic modifications. Hyperglycemia-induced mit...Diabetic neuropathy (DN), a major microvascular complication of diabetes mellitus, results from a complex interplay among oxidative stress, inflammation, and persistent epigenetic modifications. Hyperglycemia-induced mitochondrial dysfunction increases reactive oxygen species (ROS), which activate redox-sensitive inflammatory cascades, including NF-κB, JAK/STAT, and the NLRP3 inflammasome. These pathways amplify cytokine release and neuronal sensitisation, while reciprocal feedback between ROS and inflammation mediated by Nrf2 suppression further perpetuates nerve damage. Damage-associated molecular patterns (DAMPs), including HMGB1, S100A8/A9, mitochondrial DNA, and extracellular ATP, act as key amplifiers of neuroinflammation. By engaging receptors such as RAGE, Toll-like receptors (TLRs), and NOD-like receptors (NLRs), particularly NLRP3, these DAMPs trigger glial activation and nociceptive signalling, contributing to axonal degeneration and pain hypersensitivity in DN. Epigenetic dysregulation, including DNA methylation drift, histone modification imbalance, and aberrant non-coding RNA expression, constitutes a critical mechanism underlying metabolic memory, wherein prior hyperglycemic exposure leaves lasting molecular imprints. Persistent histone acetylation (H3K9ac), altered methylation (H3K4me1/Set7, H3K9me3/SUV39H1), and stable 5-methylcytosine patterns sustain inflammatory and oxidative pathways, even after glucose normalisation. Therapeutically, DNMT and HDAC inhibitors, miRNA modulators, and agents targeting RAGE/TLR4/NLRP3 pathways show promise in reversing these molecular imprints. Antioxidants and anti-inflammatory compounds with epigenetic effects further represent potential disease-modifying strategies. Future research must focus on longitudinal human studies, nerve-specific epigenomics, and multi-omics integration to enable personalised, mechanism-based therapy for DN. Understanding the interdependence of ROS, DAMPs, and epigenetic memory is key to breaking the cycle of chronic neuroinflammation and neuronal injury.
AIMS: We aimed to investigate the association between liver fibrosis scores (LFS) and major adverse cardiovascular events (MACE) in patients with myocardial infarction and non-obstructive coronary arteries (MINOCA), part...AIMS: We aimed to investigate the association between liver fibrosis scores (LFS) and major adverse cardiovascular events (MACE) in patients with myocardial infarction and non-obstructive coronary arteries (MINOCA), particularly in those with and without diabetes (DM) or prediabetes (pre-DM). METHODS: Consecutive MINOCA patients were enrolled, and LFS were assessed using the fibrosis-4 index (FIB-4) and nonalcoholic fatty liver disease fibrosis score (NFS). High LFS were defined as FIB-4 ≥ 2.67 or NFS ≥ 0.676. Kaplan-Meier, restricted cubic spline (RCS) analysis, and Cox regression were used to assess MACE risk. RESULTS: Among 406 MINOCA patients (mean age 63.7 years; 211 men), 271 had DM/pre-DM. Of these, 38.9% had high FIB-4, and 28.3% had high NFS. Over 32 months, high LFS predicted higher MACE rates (log-rank p < 0.05), particularly in patients with DM or pre-DM. RCS analysis showed a linear association between FIB-4 and MACE and a nonlinear association for NFS. Fully adjusted Cox models revealed that FIB-4 ≥ 2.67 or NFS ≥ 0.676 were independently associated with an increased risk of MACE in DM/pre-DM patients, but not in non-DM/pre-DM. CONCLUSION: Elevated LFS predicts a higher risk of MACE in MINOCA, especially in patients with DM/pre-DM, and may aid in risk stratification.
OBJECTIVE: Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, cardiac energy balance, vascular inflammation and cell differentiation. We examined whether a PPARα gene variant (rs6008845, C/T...OBJECTIVE: Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, cardiac energy balance, vascular inflammation and cell differentiation. We examined whether a PPARα gene variant (rs6008845, C/T) is associated with risk of chronic complications and death, and with benefit of fenofibrate (a PPARα agonist) in adults with type 2 diabetes. METHODS: The variant was genotyped in 8,159 participants in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. During a median 5-year follow-up, 2,931 (35.9%) developed chronic complications, including 2,004 (24.6%) microvascular and 1,359 (16.7%) macrovascular events. RESULTS: The association with microvascular complications was non-linear, with the highest risk among T/T homozygotes (hazard ratio (HR) 1.15 (95% CI 1.01-1.31), p = 0.041 vs. C/C homozygotes). Each T allele was associated with higher risk of any vascular complication (HR 1.06 (1.00-1.12), p = 0.029), non-CVD-related mortality (HR 1.18 (1.01-1.36), p = 0.032), and cancer-related mortality (HR 1.19 (1.01-1.41), p = 0.041). A significant genotype-by-dyslipidemia interaction was observed for cancer-related mortality under the atherogenic dyslipidemia definition. Fenofibrate reduced microvascular, macrovascular, and composite vascular events (HR 0.79-0.87, all p < 0.02) with no evidence of treatment-by-genotype interaction. CONCLUSIONS: PPARα rs6008845 T allele was associated with a higher risk of microvascular complications and cancer death. Fenofibrate showed consistent vascular protection irrespective of PPARα genotype.
AIMS: Type 1 diabetes (T1D) exhibits sex differences in genetic risk, yet most genetic studies treat sex as a covariate rather than a modifier of risk. We hypothesized that sex-stratified genome-wide association studies...AIMS: Type 1 diabetes (T1D) exhibits sex differences in genetic risk, yet most genetic studies treat sex as a covariate rather than a modifier of risk. We hypothesized that sex-stratified genome-wide association studies (GWAS) would uncover sex-specific genetic architecture and improve risk prediction. METHODS: We performed GWAS in 6,599 T1D cases (3,483 males, 3,109 females, 7 undetermined) and 12,350 controls (6,665 males, 5,658 females, 27 undetermined) of European ancestry, testing additive models and sex-stratified analyses. For mechanistic insights, we performed scRNA-seq of PBMCs from nine matched male-female pediatric pairs. Finally, we tested male-, female-, and standard polygenic risk scores (PRS) in an independent cohort (471 T1D cases, 2,300 controls). RESULTS: Sex-stratified analyses identified 215 genome wide significant SNPs (P < 5x10) with heterogeneity: 119 male-specific and 94 female-specific. Integration of scRNA-seq data revealed 41 sex-specific T1D genes with cell type-specific differential expression. In the independent cohort, sex-specific PRS outperformed the combined PRS: in males, AUC = 0.668 versus 0.623 (p < 2.2x10); in females, AUC = 0.719 versus 0.635 (p < 2.2x10). CONCLUSIONS: Sex-stratified GWAS reveal novel T1D risk loci influenced by sex. Incorporating sex-specific effect sizes into PRS enhances risk discrimination, underscoring the value of sex-aware genetic analyses for precise prediction of T1D.