Clinical observations and mechanistic insights of traditional Chinese medicine in the management of diabetic retinopathy.

CONTEXT: Diabetic retinopathy (DR) is one of the leading causes of vision impairment and blindness among diabetic patients globally. Despite advancements in conventional treatments, the quest for more holistic approaches and fewer side effects persists. Traditional Chinese medicine (TCM) has been used for centuries in managing various diseases, including diabetes and its complications. OBJECTIVE: This review evaluated the efficacy and underlying mechanisms of TCM in the management of DR, providing information on its potential integration with conventional treatment methods. METHODS: A comprehensive literature review was conducted using PubMed, Web of Science, and the China National Knowledge Infrastructure (CNKI) with the search terms 'traditional Chinese medicine', 'diabetic retinopathy', 'clinical efficacies' and their combinations. Studies published before 2023 without language restriction were included, focusing on clinical trials and observational studies that assessed the effectiveness of TCM in DR treatment. RESULTS: The review synthesized evidence of empirical traditional Chinese formulas, traditional Chinese patent medicines, and isolated phytochemicals on DR treatment. The key mechanisms identified included the reduction of oxidative stress, inflammation, and neovascularization, as well as the improvement in neurovascular functionality and integrity of the retinal blood barrier. CONCLUSIONS: TCM shows promising potential to manage DR. More large-scale, randomized controlled trials are recommended to validate these findings and facilitate the integration of TCM into mainstream DR treatment protocols.

Development and External Validation of Machine Learning Models for Diabetic Microvascular Complications: Cross-Sectional Study With Metabolites.

BACKGROUND: Diabetic kidney disease (DKD) and diabetic retinopathy (DR) are major diabetic microvascular complications, contributing significantly to morbidity, disability, and mortality worldwide. The kidney and the eye, having similar microvascular structures and physiological and pathogenic features, may experience similar metabolic changes in diabetes. OBJECTIVE: This study aimed to use machine learning (ML) methods integrated with metabolic data to identify biomarkers associated with DKD and DR in a multiethnic Asian population with diabetes, as well as to improve the performance of DKD and DR detection models beyond traditional risk factors. METHODS: We used ML algorithms (logistic regression [LR] with Least Absolute Shrinkage and Selection Operator and gradient-boosting decision tree) to analyze 2772 adults with diabetes from the Singapore Epidemiology of Eye Diseases study, a population-based cross-sectional study conducted in Singapore (2004-2011). From 220 circulating metabolites and 19 risk factors, we selected the most important variables associated with DKD (defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2) and DR (defined as an Early Treatment Diabetic Retinopathy Study severity level ≥20). DKD and DR detection models were developed based on the variable selection results and externally validated on a sample of 5843 participants with diabetes from the UK biobank (2007-2010). Machine-learned model performance (area under the receiver operating characteristic curve [AUC] with 95% CI, sensitivity, and specificity) was compared to that of traditional LR adjusted for age, sex, diabetes duration, hemoglobin A1c, systolic blood pressure, and BMI. RESULTS: Singapore Epidemiology of Eye Diseases participants had a median age of 61.7 (IQR 53.5-69.4) years, with 49.1% (1361/2772) being women, 20.2% (555/2753) having DKD, and 25.4% (685/2693) having DR. UK biobank participants had a median age of 61.0 (IQR 55.0-65.0) years, with 35.8% (2090/5843) being women, 6.7% (374/5570) having DKD, and 6.1% (355/5843) having DR. The ML algorithms identified diabetes duration, insulin usage, age, and tyrosine as the most important factors of both DKD and DR. DKD was additionally associated with cardiovascular disease history, antihypertensive medication use, and 3 metabolites (lactate, citrate, and cholesterol esters to total lipids ratio in intermediate-density lipoprotein), while DR was additionally associated with hemoglobin A1c, blood glucose, pulse pressure, and alanine. Machine-learned models for DKD and DR detection outperformed traditional LR models in both internal (AUC 0.838 vs 0.743 for DKD and 0.790 vs 0.764 for DR) and external validation (AUC 0.791 vs 0.691 for DKD and 0.778 vs 0.760 for DR). CONCLUSIONS: This study highlighted diabetes duration, insulin usage, age, and circulating tyrosine as important factors in detecting DKD and DR. The integration of ML with biomedical big data enables biomarker discovery and improves disease detection beyond traditional risk factors.

Diabetic Retinopathy and Chronic Kidney Disease: Associations and Comorbidities in a Large Diabetic Population - The Tongren Health Care Study.

INTRODUCTION: The aim of the study was to investigate associations between diabetic retinopathy (DR) and chronic kidney disease (CKD) in patients with type 2 diabetes (TD2). METHODS: The participants of the cross-sectional, community-based Tongren Health Care Study underwent a detailed medical and ophthalmological examination. We defined TD2 by a fasting plasma glucose concentration of ≥7.0 mmol/L or a medical history. CKD was classified as either reduced estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 mm2 or presence of albuminuria. DR was assessed using color fundus photographs. RESULTS: Out of 62,217 participants of the Tongren Health Care Study, 5,103 (8.2%) patients had TD2. The prevalence of DR was 12.8% (95% CI, 11.8%, 13.7%), CKD was 13.3% (95% CI, 12.4%, 14.3%), and the subtypes of CKD including reduced eGFR and albuminuria was 4.6% (95% CI, 4.2%, 5.1%) and 10.1% (95% CI, 9.3%, 10.9%), respectively. DR was detectable in 21.0% of the patients with CKD, while CKD was present in 20.9% of the DR patients. Higher DR prevalence was associated with higher prevalence of albuminuria and reduced eGFR (both p < 0.05). Factors independently associated with the presence of CKD instead of DR were older age (p < 0.001, OR = 1.05), a higher body mass index (p < 0.001, OR = 1.14), a higher serum concentration of triglycerides (p < 0.001, OR = 1.26), and a lower blood glucose (p < 0.001, OR = 0.93). Having hypertension was additionally associated with the presence of reduced eGFR as compared with DR (p = 0.005, OR = 4.47). CONCLUSIONS: TD2 patients of older age and with higher body mass index, hypertension, and dyslipidemia had a higher probability of being affected by CKD rather than DR, while those with a higher blood glucose level were more prone to DR than CKD.

Relationship between cortisol and diabetic microvascular complications: a retrospective study.

OBJECTIVE: We aimed to investigate whether serum cortisol associate with diabetic microvascular compliments in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: The subjects were recruited from hospitalized patients with T2DM from 2019 to 2021. The odds ratios (OR) and corresponding 95% confidence intervals (CI) in relation to cortisol quartiles were obtained by multiple logistic regression analysis. RESULTS: (1) Cortisol level was positively correlated with the severity of microalbuminuria. The OR (95% CI) of microalbuminuria and macroalbuminuria in the last quartile were 3.396 (2.030, 5.682) and 8.407 (3.726, 18.971) compared with the first quartile (p < 0.001). (2) Cortisol level was positively correlated with the severity of diabetic retinopathy (DR). The OR (95% CI) of non-proliferative diabetic retinopathy group (NPDR) and proliferative diabetic retinopathy group (PDR) in the last quartile were 2.007 (1.401, 2.875) and 7.122 (2.525, 20.090) compared with the first quartile. (3) Elevated cortisol level was associated with diabetic peripheral neuropathy. The OR (95% CI) of diabetic peripheral neuropathy (DPN) in the last quartile was 1.956 (1.371, 2.792) and that in the third quartile was 1.854 (1.319, 2.608). CONCLUSIONS: High serum cortisol levels were significantly associated with diabetic microvascular compliments in inpatients. Its causality remains to be further studied. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR2100051749.

The association of alanine aminotransferase and diabetic microvascular complications: A Mendelian randomization study.

Aims: Alanine aminotransferase (ALT) is positively related to diabetes risk in observational studies, whereas Mendelian randomization supports a linear causal association. In contrast, the relationship between ALT and diabetic nephropathy, and diabetic retinopathy is counter-intuitive in observational studies. Furthermore, no MR study has examined their causal association. The study aimed to investigate whether genetically determined ALT has a causal effect on diabetic nephropathy and diabetic retinopathy. Methods: Genetic instruments associated with ALT (P < 5×10-8) were obtained from a recent genome-wide association study (GWAS) that included 437,267 individuals of European ancestry. Summary data of diabetic microvascular complications were derived from the FinnGen study (3,283 cases and 181,704 controls for diabetic nephropathy, and 14,584 cases and 176,010 controls for diabetic retinopathy, both were of European ancestry). Effect estimation and pleiotropy testing were performed using inverse variance weighted (IVW), MR-Egger regression, weighted median, and mode-based estimator methods. We additionally performed sensitivity analysis excluding proxy single nucleotide polymorphisms (SNPs) or lowering the GWAS significance threshold (P < 5×10-7) to test the robustness of the results. Results: Based on IVW, a 2-fold increase in genetically determined ALT level was positively associated with diabetic nephropathy (odd ratio, [95% confidence interval], 1.73 [1.26-2.37], P = 0.001) and diabetic retinopathy (1.29 [1.08-1.54], P = 0.005), but a null causal association in three pleiotropy robust methods, namely, MR-Egger, weighted median and mode-based estimator. We obtained similar results in the sensitivity analysis of excluding proxy SNPs or lowering the GWAS significance threshold. Conclusions: With caution, we concluded that ALT plays no linear causal role in developing both diabetic nephropathy and diabetic retinopathy. Further investigations are required to test the hypothesis of a non-linear causal association.

Specific alterations of gut microbiota in diabetic microvascular complications: A systematic review and meta-analysis.

Background: The role of gut microbiota in diabetes mellitus (DM) and its complications has been widely accepted. However, the alternation of gut microbiota in diabetic microvascular complications (DC) remains to be determined. Methods: Publications (till August 20th, 2022) on gut microbiota in patients with DC were retrieved from PubMed, Web of Science, Embase and Cochrane. Review Manager 5.3 was performed to estimate the standardized mean difference (SMD) and 95% confidence interval (CI) and calculate alpha diversity indices and the relative abundance of gut microbiota between patients in DC v.s. DM and DC v.s. healthy controls (HC). Results: We included 13 studies assessing 329 patients with DC, 232 DM patients without DC, and 241 HC. Compared to DM, patients with DC shared a significantly lower Simpson index (SMD = -0.59, 95% CI [-0.82, -0.36], p < 0.00001), but a higher ACE index (SMD = 0.42, 95% CI[0.11, 0.74], p = 0.009). Compared to HC, DC patients held a lower ACE index (SMD = -0.61, 95% CI[-1.20, -0.02], p = 0.04). The relative abundances of phylum Proteobacteria (SMD = 0.03, 95% CI[0.01, 0.04], p = 0.003, v.s. HC) and genus Klebsiella (SMD = 0.00, 95% CI[0.00, 0.00], p < 0.00001, v.s. HC) were enriched, accompanying with depleted abundances of phylum Firmicutes (SMD = -0.06, 95% CI[-0.11, -0.01], p = 0.02, v.s. HC), genera Bifidobacterium (SMD = -0.01, 95% CI[-0.02,-0.01], p < 0.0001, v.s. DM), Faecalibacterium (SMD = -0.01, 95% CI[-0.02, -0.00], p = 0.009, v.s. DM; SMD = -0.02, 95% CI[-0.02, -0.01], p < 0.00001, v.s. HC) and Lactobacillus (SMD = 0.00, 95% CI[-0.00, -0.00], p < 0.00001, v.s. HC) in DC. Conclusions: Gut microbiota perturbations with the depletion of alpha diversity and certain short-chain fatty acids (SCFAs)-producing bacteria were associated with the pathology of DC. Therefore, gut microbiota might serve as a promising approach for the diagnosis and treatment of DC. Further investigations are required to study the mechanisms by which gut dysbiosis acts on the onset and progression of DC.

Sodium Glucose Cotransporter-2 Inhibitor Protects Against Diabetic Neuropathy and Nephropathy in Modestly Controlled Type 2 Diabetes: Follow-Up Study.

Aims: This three-year follow-up study aimed to elucidate whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) have any protection against diabetic neuropathy and nephropathy in patients with type 2 diabetes via reducing variability in glycemia and extraglycemic factors or their averages. Methods: Two type 2 diabetic cohorts of 40 and 73 patients treated with or without SGLT2i along with 60 control subjects were recruited. Two diabetic cohorts matched for HbA1c levels and oral hypoglycemic agents other than SGLT2is underwent glycemic control with or without SGLT2is more than two years. The urinary albumin to creatinine ratio (ACR), estimated glomerular filtration rate (eGFR) every 3 months and neuropathy outcome measures and mean Z-score of 8 neurophysiological tests were determined at the baseline and endpoint. Glycemic variability, evaluated by the coefficient of variation of monthly measured HbA1c levels and casual postprandial plasma glucose (CPPG), and coefficient of variation and average of extraglycemic parameters in diabetic cohorts were determined. Results: The glycemic variability and variability of some extraglycemic factors in SGLT2i cohort were smaller than those in non-SGLT2i cohort. However, only smaller coefficient of variation of HbA1c improved some neuropathy outcome measures, and ameliorated eGFR decline. SGLT2i improved the Z-score of neurophysiological tests. The optimized changes in the blood pressure, HDL-cholesterol and uric acid by SGLT2i led to neurological and renal protection. SGLT2i decreased the prevalence of nephropathy significantly and the prevalence of neuropathy insignificantly. Conclusion: Over 3 years period, SGLT2i significantly improved some neuropathy outcome measures, mean Z-score of 8 neurophysiological tests, and attenuated nephropathy in modestly controlled type 2 diabetes by reducing glycemic variability and mean nonglycemic factors of diabetic microvascular complication.

Clinical Significance of Non-invasive Skin Autofluorescence Measurement in Patients with Diabetes: A Systematic Review and Meta-analysis.

BACKGROUND: Advanced glycation end products (AGE), one of the main factors causing diabetic end-organ damage, accumulate in long half-life proteins, such as skin and cartilage collagen. AGE measurement may offer additional evidence to predict diabetic vascular complications. Skin autofluorescence (SAF) is suggested as a non-invasive, quick, and reliable method to measure tissue AGE level. The aim of this study was to review and evaluate evidence on the clinical validation of SAF measurement in diabetes mellitus (DM) patients. METHODS: In this systematic review and meta-analysis, we searched "PubMed" (MEDLINE) and "Cochrane" databases from their inception to 10 August 2021 for observational studies concerning SAF measurement in diabetic patients. The following key terms were used in advanced searching: "Diabetes", "Diabetes Mellitus"," DM", "Glycation ", "Advanced Glycation End product", "AGE", "skin autofluorescence", "SAF". Published studies that included DM patients and estimated their AGE using SAF were considered eligible for meta-analysis. Articles that were editorials, study proposals, congress posters, or case reports and were not on human subjects were excluded. We used a random-effect models for meta-analyzing the clinical validation of SAF in DM with particular emphasis on chronic diabetes complications. FINDINGS: We identified 881 records and twenty-nine records fulfilled our eligibility criteria and were included in the systematic review and meta-analysis. A statistically significant correlation was found between SAF and diabetes last HbA1c 0.21(0.13,0.28) in studies with substantial heterogeneity (I2=77.99%, p<0.05). Nevertheless, a significant positive association between SAF level and diabetic retinopathy (DR) [(OR= 1.05, 95% CI=1.03,1.08), (I2=63.78%, p<0.05)], diabetic peripheral neuropathy (DPN) [(OR= 1.11, 95%CI= 1.06,1.16), (I2=79.17%, p<0.05)], diabetic nephropathy (DNP) [(OR= 1.08, 95%CI: 1.05,1.11), (I 2 =65.36%, p<0.05)] and diabetic macrovascular events (D-MVE) [(OR=1.08, 95%CI=1.05,1.11) (I2=67.32, p<0.05)] were found. INTERPRETATION: Our study confirmed the significance of SAF measurement as a non-invasive surrogate marker of DM micro and macrovascular complications. Skin AGE estimation may be a useful factor for the prediction and early detection of irreversible DM complications. More studies with larger populations and longer follow-up periods are required.

Clinical Features and Microvascular Complications Risk Factors of Early-onset Type 2 Diabetes Mellitus.

The aim of this research was to study the clinical features and microvascular complications risk factors of early-onset type 2 diabetes mellitus (T2DM). We analyzed the clinical data from 1421 T2DM inpatients at Wuhan Union Hospital. Subjects were divided into early-onset T2DM group (diagnostic age <40 years) and late-onset T2DM group (diagnostic age >40 years). All subjects underwent a standardized assessment of microvascular complications. Data were compared with independent-samples t test or Chi-square test. Multiple logistic regression was used to determine the risk factors of microvascular complications. Patients with early-onset T2DM were more inclined to have a lower systolic blood pressure (SBP), a longer duration of diabetes and higher levels of body mass index (BMI), uric acid (UA), fasting plasma glucose (FPG), total cholesterol (TC)- triglyceride (TG) and glycosylated hemoglobin (HbA1c) than those with late-onset T2DM (P<0.05). The prevalence of diabetic retinopathy (DR) was significantly higher and that of diabetic peripheral neuropathy (DPN) was significantly lower in early-onset group than in late-onset group (P<0.05). For DN, UA was an independent risk factor in early-onset T2DM. SBP and TG were independent risk factors in late-onset T2DM. For DR, duration of diabetes and SBP were independent risk factors in early-onset T2DM. Duration of diabetes, SBP and HbA1c were independent risk factors in late-onset T2DM. This study demonstrated that the clinical characteristics of early-onset T2DM were metabolic disorders, including glucose metabolism, lipid metabolism and amino acid metabolism. Early-onset T2DM was more likely to be associated with DR. The potential pathogenesis of early and late-onset T2DM might be different. The management of metabolic risk factors especially HbA1c, SBP, TG and UA is advised to be performed in the early stage of diabetes.

Associations between erythropoietin polymorphisms and risk of diabetic microvascular complications.

We conducted a meta-analysis to evaluate the relationship between erythropoietin (EPO) polymorphisms and diabetic microvascular complications. We searched the PubMed, Embase, Cochrane library, Web of Science, Wanfang, and Chinese National Knowledge Infrastructure databases for appropriate studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations. Ultimately, eight studies consisting of 2,861 cases and 2,136 controls were identified and included in our meta-analysis. Results with our genotype model indicated an association between rs1617640 polymorphisms and diabetic microvascular complications (TT vs. GG: OR = 1.544, 95% CI = 1.089-2.189, P = 0.015). No clear associations between the rs1617640 and rs507392 polymorphisms and diabetic retinopathy were observed. By contrast, rs551238 polymorphisms were associated with increased diabetic retinopathy risk (allele model: OR = 0.774, 95% CI = 0.658-0.911, P = 0.002; genotype model: AC vs. CC: OR = 0.598, 95% CI = 0.402-0.890, P = 0.011; dominant model: OR = 0.561, 95% CI = 0.385-0.817, P = 0.003; recessive model: OR = 0.791, 95% CI = 0.643-0.973, P = 0.026). These results indicate that EPO polymorphisms are a risk factor for diabetic microvascular complications.

Synthesis and structure activity relationships of glycine amide derivatives as novel Vascular Adhesion Protein-1 inhibitors.

Vascular Adhesion Protein-1 (VAP-1) is a promising therapeutic target for the treatment of several inflammatory-related diseases including diabetic microvascular complication. We identified glycine amide derivative 3 as a novel structure with moderate VAP-1 inhibitory activity. Structure-activity relationship studies of glycine amide derivatives revealed that the tertiary amide moiety is important for stability in rat blood and that the position of substituents on the left phenyl ring plays an important role in VAP-1 inhibitory activity. We also found that low TPSA values and weak basicity are both important for high PAMPA values for glycine amide derivatives. These findings led to the identification of a series of orally active compounds with enhanced VAP-1 inhibitory activity. Of these compounds, 4g exhibited the most potent ex vivo efficacy, with plasma VAP-1 inhibitory activity of 60% after oral administration at 1mg/kg.

Relationship between serum homocysteine and oxidative stress in patients with Diabetic Microangiopathy / 中国综合临床

Objective To investigate the changes of serum homocysteine and it s relationship with oxidative stress and diabetic microangiopathy.Methods Eighty health participants were recruited as control 100 type 2 diabetis patients without diabetic microangiopathy were recruited as DM group,100 type 2 diabetis patients with diabetic nephropathy were recruited as DN group,and 100 type 2 diabetis patients with diabetic retinopathy were recruited as DR group.Their serum levels of homocysteine,malonaldehyde(MDA),superoxide dismutase (SOD)and glutathione(GSH)were measured.Results The homocysteine was(98.86 ± 21.46),(198.95 ±19.35),(138.65 ± 15.25)ng/L in the DM,DN and DR group respectively,which were signigicantly higher than that of(62.48 ± 15.36)ng/L in the control group(F =7.95,P ＜ 0.01).MDA was(17.49 ± 1.64),(22.47 ± 1.86)and(22.47 ± 1.86)mmol/L,which was significantly higher than that of(11.86 ± 0.48)mmol/L in the control group(F =6.89,P ＜0.01).The homocysteine and MDA in the DN and DR group were both significantly higher than those in the DM group(P ＜ 0.01).The SOD and GSH was(107.80 ± 15.62)mg/L and(179.26 ± 25.8)mg/L in the DM group,(79.86 ± 14.63)mg/L and(143.36 ± 21.75)mg/L in the DN group,(89.34 ± 12.75)mg/L and(156.96 ± 19.35)mg/L in the DR group,which were significantly higher than those of(128.32 ± 19.21)mg/L and(237.38 ± 27.31)mg/L in the control group(F =7.89 and 8.76 respectively,P＜0.01).The SOD and GSH in the DN and DR group were both significantly lower than those in the DM group(P ＜ 0.01),and the DN group was significantly lower than the DR group(P ＜ 0.01)Serum homocysteine was positively correlated with MDA(r =0.79,P ＜ 0.05),and negtively correlated with SOD and GSH(r =-0.71 and-0.78,P ＜0.01).Conclusion Diabetic microangiopathy patients have higher serum homocysteine level and severe oxidative stress.Oxidative stress were related to higher serum homocysteine level.The higher serum homocysteine level and oxidative stress might play an important role in development of diabetic Microangiopathy