Oxidative stress contributes to diabetic microvascular complications (DMCs). This study investigated the association between lifestyle-associated oxidative stress and the risk of DMCs in patients with type 2 diabetes (T2D). Our prospective study analysed data from 5635 individuals with T2D who were free of DMCs at baseline in the UK Biobank cohort. The lifestyle-associated oxidative balance score (OBS) was computed from 20 dietary and lifestyle factors, with a higher OBS indicating a more favourable antioxidant status. Cox proportional hazards and mediation analyses were employed to examine the association between the OBS and the risk of DMCs. Over a median follow-up period of 11.5 years, 1508 DMC patients were identified, including 873 patients with diabetic kidney disease (DKD), 317 patients with neuropathy, and 646 patients with retinopathy. Higher OBS quartiles were associated with lower risks of composite DMCs (HR: 0.72; 95% CI: 0.60-0.87) and DKD (HR: 0.50; 95% CI: 0.39-0.64). A one-unit increase in the OBS was associated with a 1.9% reduction in the hazard of composite DMCs and a 4.3% reduction in the hazard of DKD. Seven biomarkers, including HbA1c and cystatin C, mediated these associations. A higher lifestyle-associated OBS is associated with a reduced risk of DMCs in patients with T2D, underscoring the potential benefits of maintaining oxidative balance in diabetes management.

Integrated biomarker analysis in type 2 diabetes: soluble CD36, glycine, homocysteine, miR-375, and miR-126

To comprehensively assess the cost-utility of icodec, the first once-weekly basal insulin, at 700 and 1050 U formulations compared with once-daily basal insulin analogues in Chinese adults with type 2 diabetes within reimbursement context. A long-term cost-utility analysis was performed using ONWARDS 5 data from the perspective of the Chinese healthcare system. Icodec (700 and 1050 U) was compared with once-daily insulin glargine U100, glargine U300, and degludec over a 40-year time horizon, applying a 5% annual discount rate. Outcomes included diabetes-related complications, costs, and quality-adjusted life-years (QALYs). Sensitivity and scenario analyses were conducted to evaluate robustness and individual comparator results. Compared with once-daily basal insulin analogues, icodec was associated with reduced cardiovascular mortality (RR = 0.97) and lower cumulative incidence of microvascular and macrovascular complications. Icodec yielded an additional 0.261 QALYs and increased life expectancy by 0.031 years, while reducing total costs by $2544.93 (700 U) and $2,916.92 (1050 U). Cost savings were primarily driven by fewer hypoglycemia events. Probabilistic sensitivity analysis showed 100% cost-effectiveness at below 0.4 times China's GDP per capita. Across all scenario analyses, icodec was projected to be cost-saving or cost-effective over a lifetime horizon compared with once-daily basal insulin comparators. Once-weekly icodec represents a cost-effective and clinically beneficial alternative to once-daily basal insulin analogues for Chinese adults with type 2 diabetes within the current reimbursement framework.

The evidence remains contradictory regarding the optimal glycaemic targets needed to address the long-term effects of hyperglycaemia in people with diabetes mellitus (T2DM). We examined the association between HbA1c levels and the risk of individual microvascular complications among people with T2DM. We used the Clinical Practice Research Datalink (CPRD) GOLD database for a prospective cohort study, following patients ≥18years old from diagnosis of T2DM between January 2007 and December 2017. Neuropathy included foot ulcers, peripheral arterial disease, gangrene, and amputation. Nephropathy was classified by chronic kidney disease stages, and retinopathy included blindness and macular oedema. The risk of each complication in five HbA1c intervals [1.0%] intervals compared to 48.0-57.9mmol/mol (6.5-7.5%) was assessed using a multivariate time-varying Cox regression adjusted by various patients' characteristics. Subgroup analyses were performed according to age, hypertension, and the use of antihypertensive medications. Our study included 172,869 patients (mean age 62.6years and, 54.6% women). The risks were the highest in HbA1c levels >81.0mmol/mol (>9.6%) (HR 1.27, 95%CI 1.17-1.39 for nephropathy; 1.55, 1.27-1.47 for neuropathy; 1.66, 1.41-1.96 for retinopathy). The lowest risks observed in levels 48.0-57.9mmol/mol (6.5-7.5%) for nephropathy and in levels <48.0mmol/mol (<6.5%) for neuropathy (0.98, 0.88-1.09) and for retinopathy (0.89, 0.79-0.99). In the subgroup analysis, higher HbA1c levels were associated with an increased risk of nephropathy, particularly in individuals over 60, those with hypertension, and those using antihypertensive medications. For neuropathy, being over 60 was associated with an increased risk across all HbA1c levels. In retinopathy, hypertension and the use of antihypertensive medications were associated with lower risk across all HbA1c levels, while individuals under 60 were associated with higher risks at elevated HbA1c levels compared to those over 60. The risk of retinopathy and neuropathy was lowest in individuals with HbA1c levels within the non-diabetic range <48.0mmol/mol (<6.5%) and increased progressively with higher HbA1c levels. In contrast, the lowest risk of nephropathy was observed in individuals with HbA1c levels between 48.0 and 57.9mmol/mol (6.5-7.5%). These findings underscore the importance of a personalized approach to diabetes management that considers multiple risk factors and incorporates novel therapeutic strategies beyond glucose control.

Microvascular disease beyond diabetes: a metabolic continuum with implications for early detection and diabetes care.

OPU-NET-DADENA: Optimized deep learning ensemble with u-net segmentation for early detection of diabetic retinopathy.

Yitangkang decoction in the treatment of glomerular filtration barrier damage through AMPKα1/ZDHHC8/SLC7A11/GPX4 and TGF-β/Smad signaling pathways: A multi-omics analysis.

Background: Type 2 diabetes mellitus (T2DM) in India presents across all BMI categories. Unlike the predominantly obese Western diabetic phenotype, Indian patients include a sizeable lean and normal-weight subset with distinct clinical and metabolic characteristics. This study compares clinical features, biochemical profiles, and treatment responses across BMI-stratified T2DM groups. Objectives: To compare clinical features, glycaemic parameters, lipid profiles, complications, and treatment outcomes across lean, normal-weight, and overweight/obese T2DM patients. Methods: A retrospective-prospective observational study of 90 T2DM patients: Group A – Lean (BMI &lt;18.5, n=20), Group B – Normal weight (BMI 18.5–24.9, n=40), Group C – Overweight/Obese (BMI ≥25, n=30). Study period: 9 months at MMCHRI, Kanchipuram. Data analysed using SPSS 23.0. Results: Lean patients had higher HbA1c (10.2 ± 1.2%), FBS (270.5 ± 50.8 mg/dL), and PPBS (385.2 ± 52.4 mg/dL), with 85% in poor glycaemic control. Neuropathy (45%) and infections (55%) were highest in lean patients. Insulin requirement was highest in lean patients (60%). Macrovascular complications (hypertension 5%, cardiac 10%, dyslipidaemia 20%) were lowest in the lean group. Obese patients had significantly higher macrovascular burden: hypertension 53.3%, cardiac complications 43.3%, dyslipidaemia 70%. Conclusion: Lean T2DM in Indians is a distinct entity characterised by severe hyperglycaemia, microvascular and infective complications, and early insulin requirement. Obese T2DM patients carry greater macrovascular risk. BMIstratified clinical management is essential.

ABSTRACT Background Diabetic kidney disease (DKD) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Nonalcoholic fatty liver disease (NAFLD) frequently coexists with T2DM and may increase metabolic and renal vulnerability. The uric acid-to-high-density lipoprotein cholesterol ratio (UHR) is a composite metabolic marker, but its association with DKD in T2DM with NAFLD remains unclear. Research design and methods We analyzed 797 adults with T2DM and CAP-defined NAFLD from NHANES 2017–2018 and 202 hospitalized adults with ultrasound-confirmed NAFLD. Kidney outcome was defined as eGFR <60 mL/min/1.73 m² in NHANES and as eGFR <60 mL/min/1.73 m² and/or albuminuria/proteinuria in the hospital cohort. Multivariable logistic regression and restricted cubic spline models were used. Results Higher UHR was independently associated with higher odds of kidney outcome in NHANES (OR=1.31, 95% CI: 1.19–1.46, p<0.001) and in the hospital cohort (OR=1.30, 95% CI: 1.13–1.50, p<0.001). Highest vs lowest quartile showed higher odds (NHANES: OR=7.93; hospital cohort: OR=4.03). RCS suggested an approximately linear association. Conclusions Higher UHR was associated with higher odds of DKD in T2DM with NAFLD. Findings should be interpreted cautiously and confirmed in prospective studies.

Chronic hyperglycemia induces microvascular complications in patients with type 2 diabetes (T2D), particularly diabetic retinopathy, nephropathy, and neuropathy. We revisited to examine such vascular damage in the pancreas in 3D. Using thick pancreatic tissue slices, we analyzed volumetric intraislet and peri-islet exocrine capillary density (vICD and vECD), as well as interface capillary counts along the islet periphery to quantify vascular integration between the islets and surrounding acinar cells. Contrary to the previous reports, vICD was not homogeneous, but highly heterogeneous across the five species studied (human, monkey, pig, ferret and mouse), especially in smaller islets (15%-80%). vICD became less variable with increasing islet size converging at approximately 20%. With this foundation of islet vascularization, pancreatic tissues from non-diabetic (ND) and T2D subjects consisting of eight age- and sex-matched pairs (age range of 35-65 years with various duration: 0-15 years) were examined. Strikingly, no significant differences in microvasculature were found, where mean vICD (~30%) and mean vECD (~15%) were nearly equivalent between the groups. Capillary integration with respect to islet size was comparable. It suggests that integrated pancreatic blood flow with robust crosstalk between the endocrine and exocrine pancreas may facilitate microvascular preservation in T2D via local distribution of insulin.

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus, leading to chronic kidney disease and end-stage renal failure. Current therapies only slow progression but do not reverse renal damage. The present study was designed to evaluate the renoprotective potential of dapagliflozin (SGLT2 inhibitor) and valproic acid (HDAC inhibitor with antioxidative and anti-inflammatory activity), individually and in combination, in streptozotocin (STZ)-induced diabetic nephropathy in Wistar rats. Experimental diabetes was induced by a single intraperitoneal injection of STZ (50 mg/kg). Animals were divided into six groups: normal control, diabetic control, standard drug-treated, dapagliflozin-treated, valproic acid-treated, and combination-treated groups. Treatments were continued for 8 weeks. Parameters assessed included fasting blood glucose, body weight, renal function markers (serum creatinine, urea, uric acid, BUN), oxidative stress markers (SOD, CAT, GSH, MDA), inflammatory cytokines, and histopathological examination of renal tissue. Results showed significant renal impairment in diabetic control rats, with elevated serum creatinine, urea, BUN, and marked histopathological changes. Dapagliflozin and valproic acid treatment significantly improved renal parameters, attenuated oxidative stress, and preserved histological architecture. Combination therapy demonstrated greater renoprotective efficacy compared to monotherapy. The study concludes that dapagliflozin and valproic acid possess complementary renoprotective actions, suggesting potential for combination therapy in diabetic nephropathy management. Keywords: Diabetic nephropathy, dapagliflozin, valproic acid, Wistar rats, oxidative stress, renoprotection.

Diabetic Retinopathy (DR) is one of the most severe microvascular complications of diabetes mellitus and a leading cause of preventable blindness worldwide. Early diagnosis and timely treatment are critical, as DR often progresses asymptomatically until irreversible retinal damage occurs. Conventional diagnosis relies on manual examination of retinal fundus images by ophthalmologists, which is time-consuming, costly, and subject to inter-observer variability. Recent advancements in computer-aided diagnosis have demonstrated that machine learning, particularly deep learning, can significantly enhance the accuracy and efficiency of DR detection. Convolutional Neural Networks (CNNs) have emerged as the most effective approach for automated analysis of fundus images due to their capability to learn hierarchical and discriminative features directly from raw data. This review presents a comprehensive analysis of recent deep learning–based methods for diabetic retinopathy detection, classification, and severity grading. Key aspects such as preprocessing techniques, network architectures, publicly available datasets, and evaluation metrics are discussed. Furthermore, existing challenges including dataset imbalance, lack of interpretability, and limited clinical deployment are highlighted. The review also identifies emerging trends and future research directions aimed at developing robust, explainable, and scalable DR screening systems suitable for real-world clinical applications.

In type 1 diabetes (T1D), preservation of β-cell function is correlated with improved long-term clinical outcomes, such as better glycemic control, fewer microvascular complications, and lower hypoglycemia risk. However, current interventions thus far are unable to stop the destruction of β-cells after clinical onset of T1D. Disease-modifying therapies must follow a long, complex regulatory path requiring clinical end points for full regulatory approval. To facilitate the development of new therapies, regulatory bodies should reinstate C-peptide, the most reliable and feasible measure of endogenous insulin secretion, as an end point for full, unconditional approval. T1D organizations and networks have accepted C-peptide as a primary efficacy end point for years, as did the U.S. Food and Drug Administration (FDA) from 2008 to 2023, followed by its failure to appear on the Surrogate Endpoint Table by the FDA, for unclear reasons. A C-peptide–based policy would substantially decrease the time for disease-modifying therapies to become available and increase investment in them, improving clinical outcomes and easing burden in those living with T1D.

Expanded field swept-source OCT angiography biomarkers associated with microvascular complications of diabetes mellitus.

To assess the association of accelerometer-measured sleep regularity with macrovascular and microvascular complications among individuals with type 2 diabetes mellitus (T2DM). A total of 3,862 participants with T2DM at baseline participated. The sleep regularity metrics measured by wrist-worn accelerometers include sleep regularity index (SRI) and standard deviation (SD) of sleep duration. Incident macrovascular complications including coronary heart disease (CHD) and stroke, microvascular complications including diabetic neuropathy, diabetic kidney disease, and diabetic retinopathy were recorded. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for macrovascular and microvascular complications. During a median follow-up of 7.2 years, 410 composite macrovascular and 615 composite microvascular events occurred. Compared to regular sleepers (the highest tertile of SRI), irregular sleepers were at higher risk of composite macrovascular complications (HR, 1.29; 95% CI, 1.01 to 1.66) and stroke (HR, 1.97; 95% CI, 1.08 to 3.58). Compared to regular sleepers (the lowest tertile of sleep duration SD), irregular sleepers were at higher risk of composite macrovascular complications (HR, 1.44; 95% CI, 1.12 to 1.84), CHD (HR, 1.40; 95% CI, 1.07 to 1.82), and stroke (HR, 2.07; 95% CI, 1.13 to 3.81). For microvascular complications, no significant association of sleep regularity metrics was found (all P>0.05). However, the dose-response analysis suggested a potential nonlinear association between SRI and diabetic neuropathy, with lower SRI consistently associated with higher risk of diabetic neuropathy (HR, 1.92; 95% CI, 1.28 to 2.88; 5th percentile vs. 50th percentile). An irregular sleep pattern across days is clinically relevant for increasing the risk of macrovascular complications and diabetic neuropathy among individuals with T2DM.

Pulmonary hemorrhage is a rare but life-threatening microvascular complication of antiphospholipid syndrome (APS). Despite aggressive immunosuppressive therapy, its prognosis remains guarded because of high rates of non-response to treatment and relapse, leading to increased mortality. We report the case of a 24-year-old Chinese woman with primary APS who developed recurrent diffuse pulmonary hemorrhage (DAH), in addition to superior vena cava thrombosis and myocardial infarction with normal coronary arteries. Her pulmonary hemorrhage was refractory to high-dose glucocorticoid therapy and anticoagulation but stabilized after escalation of treatment with a combination of rituximab and cyclophosphamide. In this report, the current evidence on the pathophysiology, treatment, and challenges of APS-associated DAH is reviewed and discussed.

Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes. It can be identified by thickening of the glomerular basement membrane, reduced glomerular filtration rate, and persistent proteinuria. Macrophages play a key role in the pathogenesis of DKD, and their phenotype (M1 and M2) is finely regulated by metabolic reprogramming. M1 macrophages exacerbate inflammatory damage and fibrosis in renal tissue by secreting pro-inflammatory mediators and reactive oxygen species (ROS). M2 macrophages (further subdivided into M2a, M2b, M2c and M2d subtypes) primarily exert anti-inflammatory and tissue-repairing effects. Of these, the M2a and M2c subtypes are particularly crucial for anti-inflammatory repair. This study aimed to systematically review the mechanisms by which glucose, lipid, amino acid, and mitochondrial function-related metabolism influence macrophage polarization. It further explored therapeutic strategies to mitigate renal inflammation and fibrosis by regulating macrophage polarization through targeted metabolic pathways, including inhibiting glycolysis, promoting fatty acid oxidation, modulating amino acid metabolism, and enhancing mitochondrial biogenesis and oxidative phosphorylation (OXPHOS). Several natural compounds and synthetic drugs exhibit the potential to induce M2 polarization and suppress M1 polarization through metabolic reprogramming, thereby offering new directions for optimizing therapeutic strategies for DKD.

Diabetic nephropathy, as one of the most serious microvascular complications of diabetes, has an extremely complex pathogenesis. Currently, there are still no effective treatment methods available in clinical practice that can effectively prevent its pathological progression. In recent years, it has been discovered that the microcirculation system facilitates the exchange of substances between blood and tissues, profoundly influencing the homeostasis of the internal environment within the body. Abnormalities in renal microcirculation are closely related to the occurrence and development of diabetic nephropathy. Given the significant importance of improving renal microcirculation disorders in delaying the progression of diabetic nephropathy, by exploring the pathological association between microcirculation disorders and diabetic nephropathy, this paper elaborates on the "key node" role of microvascular lesions in the course of diabetic nephropathy, and conducts an analysis of the signaling pathways. It explains the interactions among cellular signal transduction, growth transformation factors, and oxidative stress pathways in microvascular lesions, providing a more comprehensive theoretical basis and research direction for the treatment strategy of diabetic nephropathy targeting improving renal microcirculation disorders.

BACKGROUND Type 2 diabetes mellitus (T2DM) represents a major global public health challenge, with projections indicating that the number of affected individuals could reach 853 million by 2050. While microvascular and macrovascular complications in diabetic patients are well-documented, there is a growing focus on skeletal involvement, particularly diabetic osteoporosis. Traditionally, the increased fracture risk in T2DM has been attributed to mechanisms like the accumulation of advanced glycation end products and oxidative stress. However, emerging evidence suggests that T2DM patients may experience compensatory skeletal adaptations, such as increases in bone density, which complicate the relationship between T2DM and fracture risk. This study utilizes an umbrella meta-analysis to systematically assess the association between T2DM and fracture risk, aiming to clarify existing controversies in the literature. AIM To thoroughly evaluate the association between T2DM and fracture risks at various anatomical sites, including overall fractures, hip fractures, and non-vertebral fractures. The goal is to provide an evidence-based foundation for developing individualized fracture management strategies in clinical practice. METHODS Conducted in accordance with PRISMA guidelines, this umbrella meta-analysis involved a systematic literature search across the PubMed, Web of Science, and EMBASE databases up to October 1, 2025. The search aimed to identify meta-analyses that evaluated the association between T2DM and fracture risk. Inclusion criteria were limited to studies involving T2DM patients, with fracture risk as the outcome measure, expressed as relative risk (RR) and 95% confidence intervals (CIs). The methodological quality of the studies was assessed using the AMSTAR 2 tool. Statistical analyses employed either fixed-effects or random-effects models based on I 2 heterogeneity statistics, and sensitivity analyses were performed to confirm the robustness of the findings. RESULTS A total of 16 studies were included in the analysis. The findings revealed a significant association between T2DM and an increased risk of total fractures (RR = 1.23, 95%CI: 1.17-1.28), with low heterogeneity observed (I 2 = 44.8%). Site-specific analyses showed heterogeneous associations: Increased risks were identified for non-vertebral fractures (RR = 1.22, 95%CI: 1.18-1.27), ankle fractures (RR = 1.43, 95%CI: 1.21-1.64), and upper arm fractures (RR = 1.43, 95%CI: 1.21-1.64). Conversely, the risk of hip fractures was significantly reduced (RR = 0.80, 95%CI: 0.72-0.89), although this result exhibited considerable heterogeneity (I 2 = 94.9%). No significant associations were found for vertebral or humeral fractures. Sensitivity analyses confirmed the robustness of the hip fracture outcome after excluding outliers. A forest plot for total fractures visually illustrated a consistent trend toward increased risk. Furthermore, funnel plot analysis indicated mild publication bias, which did not compromise the primary conclusions. The observed heterogeneity in the hip fracture analysis was mainly due to specific study deviations. CONCLUSION T2DM shows a heterogeneous association with fracture risk, highlighting the need for the development of site-specific clinical strategies. The reduced risk of hip fractures may indicate compensatory skeletal adaptation, while the increased risk at other sites is linked to diabetic complications like neuropathy. Future research should focus on large-scale cohort studies, inclusive of ethnic diversity, and the optimization of risk prediction tools to improve fracture prevention and management in T2DM patients.

BACKGROUND Diabetic nephropathy (DN) is a major microvascular complication of diabetes, and progressive renal fibrosis is the central feature that drives long-term kidney function decline. Epigenetic regulation is increasingly recognized in metabolic diseases, but the contribution of the histone acetyltransferase EP300 to diabetic renal fibrosis remains unclear. Nephrocystin-4 (NPHP4 ), a cilia-related gene, has been implicated in tubular injury and fibrotic changes, yet its regulation and role in DN have not been defined. AIM To determine whether EP300 promotes renal fibrosis in DN by activating NPHP4 through H3K27 acetylation and to evaluate the functional consequences of targeting this pathway in cell and animal models. METHODS Transcriptomic analysis of human diabetic kidney samples was performed using RNA sequencing, with EP300 expression patterns validated by real-time quantitative polymerase chain reaction (RT-qPCR). Chromatin immunoprecipitation-RT-qPCR was used to assess EP300 binding and histone H3 lysine 27 acetylation (H3K27ac) levels at the NPHP4 promoter. In vitro studies were conducted in HK-2 cells cultured under high-glucose conditions (30 mmol/L) with EP300 or NPHP4 knockdown, followed by functional assays including cell viability measured by the Cell Counting Kit-8 assay, apoptosis assessed by TUNEL staining, and fibrotic marker expression analyzed by western blotting for alpha-smooth muscle actin and fibronectin. In vivo experiments involved diabetic mice treated with the EP300 inhibitor C646, AAV-mediated NPHP4 silencing, or combination therapy. Renal function was subsequently evaluated by measuring serum creatinine, blood urea nitrogen, and 24-hour proteinuria, along with histological assessment of fibrosis using Masson staining and immunostaining. RESULTS Our results revealed that EP300 was significantly upregulated in the kidneys of DN patients, and it transcriptionally activated NPHP4 by enriching H3K27ac at its promoter, as demonstrated by chromatin immunoprecipitation-RT-qPCR. In high glucose-stimulated HK-2 cells, knockdown of either EP300 or NPHP4 effectively attenuated fibrosis marker expression (alpha-smooth muscle actin and fibronectin) and restored the balance between apoptosis and proliferation. In a DN mouse model, pharmacological inhibition of EP300 (C646) or AAV-mediated knockdown of NPHP4 substantially improved renal function (reduced serum creatinine, blood urea nitrogen, and proteinuria) and attenuated renal fibrosis, with combination therapy showing the most pronounced benefits. Immunohistochemical and immunofluorescence analyses further validated that the EP300–NPHP4 axis critically regulates renal fibrotic progression. CONCLUSION In conclusion, our study identifies the EP300/H3K27ac/NPHP4 axis as a novel epigenetic pathway driving renal fibrosis in DN. These findings provide mechanistic insight into the diabetic renal fibrotic process and highlight the therapeutic potential of targeting EP300 or NPHP4 in the treatment of DN.