Diabetes & Metabolism Journal

Review

Others
Neutrophil-Linked Inflammatory Mechanisms and Biomarkers in Diabetic Microvascular Complications: Junseo Kim, Daeun Jung, Da Hyun Kang, Hyeongseok Kim, Junyoung O. Park, Jun Young Heo, Seong Eun Lee, Hyun Jin Kim, Ju Hee Lee, Yea Eun Kang, Bon Jeong Ku; Diabetes Metab J. 2026;50(3):450-471. Published online April 27, 2026; DOI: https://doi.org/10.4093/dmj.2025.1034

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Abstract PDF PubReader ePub: Diabetic microvascular complications, including nephropathy, retinopathy, and neuropathy, are major causes of morbidity in diabetes. Increasing evidence highlights neutrophils as key contributors to the chronic inflammatory processes underlying these complications. In the diabetic environment, neutrophils exhibit impaired recruitment, defective phagocytosis, dysregulated degranulation, and excessive production of reactive oxygen species and neutrophil extracellular traps (NETs). These dysfunctions not only reduce pathogen clearance but also exacerbate tissue injury through persistent low-grade inflammation. Furthermore, neutrophils interact with other immune cells, such as macrophages, dendritic cells, T cells, and B cells, perpetuating immune imbalance and tissue damage. Various neutrophil-derived cytokines and granular proteins also influence vascular permeability and endothelial dysfunction. In recent years, neutrophil-related biomarkers—such as absolute neutrophil count, neutrophil-to-lymphocyte ratio, platelet-to-neutrophil ratio, and systemic immune-inflammation index—have gained attention as accessible and cost-effective tools for predicting and monitoring diabetic microvascular complications. This review summarizes the multifaceted roles of neutrophils in the pathogenesis of diabetic microvascular disease and highlights emerging clinical applications of neutrophil-based inflammatory biomarkers. A better understanding of neutrophil-driven mechanisms may open new avenues for early diagnosis, therapeutic intervention, and personalized care in diabetic patients.

Original Articles

Complications
Time-Window Stratified Machine-Learning Risk Prediction Model for Diabetic Retinopathy and Cross-Cohort Study: Jingwen Hui, Zheya Han, Yuxi Bai, Yawen Gong, Quanhong Han, Xuehao Cui; Received November 1, 2025 Accepted December 18, 2025 Published online April 15, 2026; DOI: https://doi.org/10.4093/dmj.2025.1098 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Diabetic retinopathy (DR) remains a significant cause of vision loss worldwide. Existing risk models rarely account for when DR develops relative to the onset of diabetes, even though early- and late-onset disease may have different clinical implications. We hypothesized that DR occurring within 6 years of diabetes diagnosis (short-term) represents an early-onset phenotype driven mainly by metabolic dysregulation and microvascular injury, whereas DR developing after 6 years (long-term) reflects late-onset disease shaped by cumulative metabolic burden and aging. This study aimed to develop and validate a time-window- stratified DR risk prediction model.
Methods
Data from two large cohorts (UK Biobank and Tianjin Eye Hospital) were analyzed, including 1,943 patients with diabetes but without DR at baseline. Separate Cox models were built for short-term (≤6 years) and long-term (>6 years) DR incidence. Feature selection used least absolute shrinkage and selection operator (LASSO) and Boruta algorithms, and model performance was assessed by area under the curve (AUC), calibration, and decision curve analyses. Machine-learning models were further developed on pooled data for multiclass classification (no DR, short-term DR, long-term DR) and interpretability using SHapley Additive exPlanations (SHAP) analysis.
Results
Both models identified glycosylated hemoglobin and retinal neurostructural measures (retinal nerve fiber layer thickness and retinal ganglion cell layer thickness) as consistent predictors, indicating that neuroretinal degeneration precedes clinical DR. The short-term model emphasized renal and lipid metabolism markers, whereas the long-term model highlighted age and uric acid. Internal validation and cross-cohort replication showed stable discrimination (AUC 0.79–0.84). The pooled XGBoost model improved accuracy (overall approximately 80%) with transparent interpretability.
Conclusion
Time-window-based modeling revealed distinct early- and late-onset DR risk profiles, thereby enhancing prediction precision. Integrating optical coherence tomography imaging with routine clinical variables offers a practical, interpretable framework for individualized risk assessment and early intervention in DR.

Complications
The Causal Relationship and Association between Biomarkers, Dietary Intake, and Diabetic Retinopathy: Insights from Mendelian Randomization and Cross-Sectional Study: Xuehao Cui, Dejia Wen, Jishan Xiao, Xiaorong Li; Diabetes Metab J. 2025;49(5):1087-1105. Published online March 31, 2025; DOI: https://doi.org/10.4093/dmj.2024.0731

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Background
Diabetic retinopathy (DR) is a major cause of vision loss, linked to hyperglycemia, oxidative stress, and inflammation. Despite advancements in DR treatments, approximately 40% of patients do not respond effectively, underscoring the need for novel, noninvasive biomarkers to predict DR risk and progression. This study investigates causal relationships between specific biomarkers, dietary factors, and DR development using Mendelian randomization (MR) and cross-sectional data.
Methods
We conducted a two-phase analysis combining MR and cross-sectional methods. First, MR analysis examined causal associations between 35 biomarkers, 226 dietary factors, and DR progression using data from the UK Biobank and Genome-Wide Association Study (GWAS) datasets. Second, a cross-sectional study with National Health and Nutrition Examination Survey (NHANES) and a clinical cohort from Tianjin Medical University Eye Hospital validated findings and explored biomarkers’ predictive capabilities through a nomogram-based prediction model.
Results
MR analysis identified eight biomarkers (e.g., glycosylated hemoglobin [HbA1c], high-density lipoprotein cholesterol [HDL-C]) with significant causal links to DR. Inflammatory markers and metabolic factors, such as high glucose and HDL-C levels, were strongly associated with DR risk and progression. Specific dietary factors, like cheese intake, exhibited protective roles, while alcohol intake increased DR risk. Validation within NHANES and Tianjin cohorts supported these causal associations.
Conclusion
This study elucidates causal relationships between biomarkers, dietary habits, and DR progression, emphasizing the potential for personalized dietary interventions to prevent or manage DR. Findings support the use of HDL-C, HbA1c, and dietary factors as biomarkers or therapeutics in DR, though further studies are needed for broader applicability.

Citations

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Zixun Wang, Yimeng Sun, Xiaoling Zhang, Luqiang Wang, Desheng Song, Jingtao Yu, Xiaoxue Hu, Weiping Lin, Ruihua Wei
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Research Status of Diabetic Retinopathy Prediction Models: From Traditional Risk Factors to Artificial Intelligence
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Integrated plasma proteomics and metabolomics reveal immunometabolic pathways and predictive signatures for age-related eye diseases
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Association between weight-adjusted-waist index and retinopathy among American adults: a cross-sectional study and mediation analysis
Junmeng Li, Qianshuo Yin, Jianchen Hao, Ruilin Zhu, Jing Zhang, Yadi Zhang, Xiaopeng Gu, Zihui Wu, Liu Yang
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Zhang Shengnan, Wang Tao, Zhang Yanan, Sun Chao
Nutrition & Metabolism.2025;[Epub] CrossRef
Association between endothelial activation and stress index and diabetic retinopathy in patients with diabetic kidney disease: a cross-sectional study based on NHANES database
Jinping Liu, Di’en Yan, Xiaohui Wang, Yinhua Yao, Ling Wang
BMC Endocrine Disorders.2025;[Epub] CrossRef
Hypertriglyceridemic waist phenotype in relation to diabetes mellitus and cardiovascular diseases in the Indonesian and Korean populations: evidence from two national surveys
Fathimah S. Sigit, Sinyoung Cho, Farid Kurniawan, Hye-Ryeong Jeon, Ratu Ayu Dewi Sartika, Dicky L. Tahapary, Hyuktae Kwon
Diabetology & Metabolic Syndrome.2025;[Epub] CrossRef
Non-linear association between Life’s Essential 8 and diabetic retinopathy: mediating role of depression in US adults with diabetes
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Basic and Translational Research
Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat: Serena Boccella, Andrea Maria Morace, Cristina Giorgio, Francesca Guida, Michela Perrone, Iolanda Manzo, Carmela Belardo, Meghan Jones, Sabatino Maione, Andrea Aramini, Marcello Allegretti, Livio Luongo, Laura Brandolini; Diabetes Metab J. 2025;49(5):990-1005. Published online March 12, 2025; DOI: https://doi.org/10.4093/dmj.2024.0504

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Background
The CXC motif chemokine ligand 8 (CXCL8)-CXC motif chemokine receptor 1/2 (CXCR1/2) axis has been implicated in type 1 diabetes mellitus (T1DM). Its actions on non-immune cells may also contribute to T1DM-associated complications, including painful diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR).
Methods
We assessed the efficacy of early (4–8 weeks) or late (8–12 weeks) daily ladarixin (LDX) for the treatment of streptozotocin (STZ)-induced T1DM and the related complications of DPN or DR in male rats.
Results
Early LDX mitigated STZ-induced dysmetabolism (i.e., blood glucose, insulin), inflammation in dorsal root ganglion/ sciatic nerve (interleukin-1β and tumor necrosis factor-α expression) and mechanical allodynia and thermal hyperalgesia, indicative of DPN. Moreover, vitreous citrullinated histone H3 (CitH3) and plasma GRO/CINC1 (CXCL8) increase were attenuated. Late LDX failed to reverse STZ-induced changes in metabolic parameters (i.e., blood glucose, insulin, C-peptide, pancreatic β-cell number and function). Strikingly, even in the absence of an effect on glycemic control, late LDX mitigated STZ-induced mechanical allodynia and thermal hyperalgesia and vitreous (CXCL8, CitH3) and retinal (CXCL8, CXCR1/2, myeloperoxidase, CitH3) inflammatory/pro-angiogenic (vascular endothelial growth factor, CD34) signs of DR.
Conclusion
These data confirm the efficacy of LDX in STZ-induced T1DM and provide evidence of a protective effect also against DPN and onset of DR which is independent of its effect on β-cell functionality preservation and glycemic control.

Citations

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New pharmacological agents and emerging therapeutic targets for painful diabetic neuropathy
Theodoros Panou, Nikolaos Papanas, Peter Kempler
Frontiers in Endocrinology.2026;[Epub] CrossRef
Beyond inflammation: the multifaceted therapeutic potential of targeting the CXCL8-CXCR1/2 axis in type 1 diabetes
Georgia Fousteri, Meghan Jones, Rubina Novelli, Serena Boccella, Laura Brandolini, Andrea Aramini, Paolo Pozzilli, Marcello Allegretti
Frontiers in Immunology.2025;[Epub] CrossRef
Ladarixin Potential over the Effects of IL-8 and of Serum from Patients with Abdominal Aortic Aneurysm on Human Aortic Cells
Lucia Spartano, Maria Lombardi, Vincenzo Ardita, Roberto Chiesa, Andrea Aramini, Marcello Allegretti, Domenico Baccellieri, Lidia De Filippis, Chiara Foglieni
Cells.2025; 14(21): 1713. CrossRef

Complications
Does 10-Year Atherosclerotic Cardiovascular Disease Risk Predict Incident Diabetic Nephropathy and Retinopathy in Patients with Type 2 Diabetes Mellitus? Results from Two Prospective Cohort Studies in Southern China: Jiaheng Chen, Yu Ting Li, Zimin Niu, Zhanpeng He, Yao Jie Xie, Jose Hernandez, Wenyong Huang, Harry H.X. Wang, on Behalf of the Guangzhou Diabetic Eye Study Group; Diabetes Metab J. 2025;49(2):298-310. Published online February 4, 2025; DOI: https://doi.org/10.4093/dmj.2024.0239

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Background
Diabetic macrovascular and microvascular complications often coexist and may share similar risk factors and pathological pathways. We aimed to investigate whether 10-year atherosclerotic cardiovascular disease (ASCVD) risk, which is commonly assessed in diabetes management, can predict incident diabetic nephropathy (DN) and retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).
Methods
This prospective cohort study enrolled 2,891 patients with clinically diagnosed T2DM who were free of ASCVD, nephropathy, or retinopathy at baseline in the Guangzhou (2017–2022) and Shaoguan (2019–2021) Diabetic Eye Study in southern China. The 10-year ASCVD risk was calculated by the Prediction for ASCVD Risk in China (China-PAR) equations. Multivariable- adjusted Cox proportional hazard models were developed to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). The area under the receiver operating characteristic curve (AUC) was used to evaluate predictive capability.
Results
During follow-up, a total of 171 cases of DN and 532 cases of DR were documented. Each 1% increment in 10-year ASCVD risk was associated with increased risk of DN (pooled HR, 1.122; 95% CI, 1.094 to 1.150) but not DR (pooled HR, 0.996; 95% CI, 0.979 to 1.013). The model demonstrated acceptable performance in predicting new-onset DN (pooled AUC, 0.670; 95% CI, 0.628 to 0.715). These results were consistent across cohorts and subgroups, with the association appearing to be more pronounced in women.
Conclusion
Ten-year ASCVD risk predicts incident DN but not DR in our study population with T2DM. Regular monitoring of ASCVD risk in routine diabetes practice may add to the ability to enhance population-based prevention for both macrovascular and microvascular diseases, particularly among women.

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Investigation of the Potential Association Between Atherosclerotic Cardiovascular Disease Risk Score and Diabetic Retinopathy in Patients with Type 2 Diabetes: A Cross-Sectional Study
Chrysa Agapitou, Theodoros N. Sergentanis, Effie G. Papageorgiou, Panagiotis Theodossiadis, Ignatios Ikonomidis, Vaia Lambadiari, Irini Chatziralli
Biomedicines.2025; 13(3): 633. CrossRef

Complications
To Determine the Risk-Based Screening Interval for Diabetic Retinopathy: Development and Validation of Risk Algorithm from a Retrospective Cohort Study: Jinxiao Lian, Ching So, Sarah Morag McGhee, Thuan-quoc Thach, Cindy Lo Kuen Lam, Colman Siu Cheung Fung, Alfred Siu Kei Kwong, Jonathan Cheuk Hung Chan; Diabetes Metab J. 2025;49(2):286-297. Published online October 31, 2024; DOI: https://doi.org/10.4093/dmj.2024.0142

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Background
The optimal screening interval for diabetic retinopathy (DR) remains controversial. This study aimed to develop a risk algorithm to predict the individual risk of referable sight-threatening diabetic retinopathy (STDR) in a mainly Chinese population and to provide evidence for risk-based screening intervals.
Methods
The retrospective cohort data from 117,418 subjects who received systematic DR screening in Hong Kong between 2010 and 2016 were included to develop and validate the risk algorithm using a parametric survival model. The risk algorithm can be used to predict the individual risk of STDR within a specific time interval, or the time to reach a specific risk margin and thus to allocate a screening interval. The calibration performance was assessed by comparing the cumulative STDR events versus predicted risk over 2 years, and discrimination by using receiver operative characteristics (ROC) curve.
Results
Duration of diabetes, glycosylated hemoglobin, systolic blood pressure, presence of chronic kidney disease, diabetes medication, and age were included in the risk algorithm. The validation of prediction performance showed that there was no significant difference between predicted and observed STDR risks in males (5.6% vs. 5.1%, P=0.724) or females (4.8% vs. 4.6%, P=0.099). The area under the receiver operating characteristic curve was 0.80 (95% confidence interval [CI], 0.78 to 0.81) for males and 0.81 (95% CI, 0.79 to 0.83) for females.
Conclusion
The risk algorithm has good prediction performance for referable STDR. Using a risk-based screening interval allows us to allocate screening visits disproportionally more to those at higher risk, while reducing the frequency of screening of lower risk people.

Citations

Citations to this article as recorded by

Letter to the editor: “Prediction of retinopathy risk: A prospective cohort study in China”
Rachana Mehta, Ranjana Sah
Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2026; 20(4): 103415. CrossRef
A clinically interpretable machine learning model for early detection of diabetic retinopathy in multiple community health centers
Juncheng Tong, Aifa Tang, Lifang Liu, Luyuan Zhang, Hainan Wang, Mengyuan Qu, Bing Liu
Frontiers in Endocrinology.2026;[Epub] CrossRef

Complications
Glycemic Control and Retinal Microvascular Changes in Type 2 Diabetes Mellitus Patients without Clinical Retinopathy: Kangmin Lee, Ga Hye Lee, Seung Eun Lee, Jee Myung Yang, Kunho Bae; Diabetes Metab J. 2024;48(5):983-992. Published online March 13, 2024; DOI: https://doi.org/10.4093/dmj.2023.0149

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Background
To investigate the association of glycemic control and retinal microvascular changes in patients with type 2 diabetes mellitus (T2DM) without diabetic retinopathy (DR).
Methods
This retrospective, observational, cohort study included patients with T2DM without DR. The patients were categorized into intensive control (IC; mean glycosylated hemoglobin [HbA1c] ≤7.0%) and moderate control (MC; mean HbA1c >7.0%) groups. Optical coherence tomography (OCT) and swept-source OCT angiography (OCTA) image parameters were compared between three groups, including healthy controls.
Results
In total, 259 eyes of 259 participants (88 IC, 81 MC, and 90 controls) were included. The foveal avascular zone area was significantly larger in the MC group than IC and control groups (all P<0.05). The IC group had lower vessel density in the superficial retinal layer and deep retinal layer than the controls (all P<0.05). The choriocapillaris (CC) flow deficit (FD) was significantly greater in the MC group than in the IC and control groups (18.2%, 16.7%, and 14.2%, respectively; all P<0.01). In multivariate regression analysis, CC-FD was associated with the mean HbA1c level (P=0.008). There were no significant differences in OCT parameters among the groups.
Conclusion
OCTA revealed that early CC impairment is associated with HbA1c levels; the CC changes precede clinically apparent DR. The OCTA parameters differed among the groups according to the degree of glycemic control. Our results suggest that microvascular changes precede DR and are closely related to glycemic control.

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Quantitative evaluation of the topographical maps of three-dimensional choroidal vascularity index in gestational diabetes mellitus: a cross-sectional observational study
Ligang Jiang, Yimei Ji, Xin Jiang, Yune Zhao
BMC Pregnancy and Childbirth.2026;[Epub] CrossRef
Impact of Vascular Risk Factors on Longitudinal Changes in Diabetic Macular Edema After Intravitreal Therapy
Carmen Alba-Linero, José Coín Ruiz, Marta Mérida Luque, Javier Espíldora-Hernández, Mario Gutiérrez Bedmar
Diabetology.2026; 7(4): 65. CrossRef
Correlation of Glycemic Risk Index with Retinal Structure and Blood Flow in Patients without Diabetic Retinopathy
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Advances in Clinical Medicine.2026; 16(04): 4184. CrossRef
Intermittent Fasting and Risk of Diabetic Retinopathy: Retrospective Data from the National Health and Nutrition Examination Survey
Sejeong Lee, Youngjoon Kim, Min Heui Yu, Yong-ho Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Soo-Hyun Park, Sungha Park, Min Kim, Christopher Seungkyu Lee, Eun Young Choi, Minyoung Lee
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Periodontal Inflammatory Burden and Multi-Organ Microvascular Impairment in Type 2 Diabetes: A Cross-Sectional Observational Study
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Flow and ischemic changes in retina and choroid across diabetic retinopathy spectrum: a SS-OCTA study
Qianhui Yang, Kelvin Y. C. Teo, Yueheng Hong, Bingyao Tan, Leopold Schmetterer, Chui Ming Gemmy Cheung, Tien Yin Wong, Gavin Tan Siew Wei
Eye.2025; 39(8): 1631. CrossRef
Postprandial C-Peptide to Glucose Ratio as a Promising Systemic Marker of Diabetic Retinopathy in Type 2 Diabetes
Zhaoxia Zheng, Nianen Liu, Yue Zhang, Xiaoya Gu, Hui Li, Xiaobing Yu
Translational Vision Science & Technology.2025; 14(7): 27. CrossRef
The Correlation Between Macular Vessel Density and Its Clinical Parameters in Diabetes Mellitus Type 2
Nadia Dewi, Muhammad Arfan, Herisa Rahmasari, Mutiara Putri, Rulli Rosandi
Clinical Ophthalmology.2025; Volume 19: 3113. CrossRef
Comment on: “Risk factors and incidence of macular edema in eyes with retinal vein occlusion after uneventful cataract surgery: The MEVO study”
Xianmei Zhang, Jing Chen
Indian Journal of Ophthalmology.2025; 73(11): 1698. CrossRef
Prevalence and determinants of comorbidities among patients with type 2 diabetes mellitus in Nepal: a cross-sectional study
Nitendra Kumar Chaurasia, Md Mothashin, Md Golam Hossain
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Drug/Regimen
Risk of Diabetic Retinopathy between Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists: Tzu-Yi Lin, Eugene Yu-Chuan Kang, Shih-Chieh Shao, Edward Chia-Cheng Lai, Sunir J. Garg, Kuan-Jen Chen, Je-Ho Kang, Wei-Chi Wu, Chi-Chun Lai, Yih-Shiou Hwang; Diabetes Metab J. 2023;47(3):394-404. Published online March 6, 2023; DOI: https://doi.org/10.4093/dmj.2022.0221

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Background
To compare risk of diabetic retinopathy (DR) between patients taking sodium-glucose cotransporter-2 inhibitors (SGLT2is) and those taking glucagon-like peptide-1 receptor agonists (GLP1-RAs) in routine care.
Methods
This retrospective cohort study emulating a target trial included patient data from the multi-institutional Chang Gung Research Database in Taiwan. Totally, 33,021 patients with type 2 diabetes mellitus using SGLT2is and GLP1-RAs between 2016 and 2019 were identified. 3,249 patients were excluded due to missing demographics, age <40 years, prior use of any study drug, a diagnosis of retinal disorders, a history of receiving vitreoretinal procedure, no baseline glycosylated hemoglobin, or no follow-up data. Baseline characteristics were balanced using inverse probability of treatment weighting with propensity scores. DR diagnoses and vitreoretinal interventions served as the primary outcomes. Occurrence of proliferative DR and DR receiving vitreoretinal interventions were regarded as vision-threatening DR.
Results
There were 21,491 SGLT2i and 1,887 GLP1-RA users included for the analysis. Patients receiving SGLT2is and GLP-1 RAs exhibited comparable rate of any DR (subdistribution hazard ratio [SHR], 0.90; 95% confidence interval [CI], 0.79 to 1.03), whereas the rate of proliferative DR (SHR, 0.53; 95% CI, 0.42 to 0.68) was significantly lower in the SGLT2i group. Also, SGLT2i users showed significantly reduced risk of composite surgical outcome (SHR, 0.58; 95% CI, 0.48 to 0.70).
Conclusion
Compared to those taking GLP1-RAs, patients receiving SGLT2is had a lower risk of proliferative DR and vitreoretinal interventions, although the rate of any DR was comparable between the SGLT2i and GLP1-RA groups. Thus, SGLT2is may be associated with a lower risk of vision-threatening DR but not DR development.

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Karen M. Wai, Kapil Mishra, Euna Koo, Cassie Ann Ludwig, Ravi Parikh, Prithvi Mruthyunjaya, Ehsan Rahimy
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Complications
Fatty Acid-Binding Protein 4 in Patients with and without Diabetic Retinopathy: Ping Huang, Xiaoqin Zhao, Yi Sun, Xinlei Wang, Rong Ouyang, Yanqiu Jiang, Xiaoquan Zhang, Renyue Hu, Zhuqi Tang, Yunjuan Gu; Diabetes Metab J. 2022;46(4):640-649. Published online April 28, 2022; DOI: https://doi.org/10.4093/dmj.2021.0195

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Background
Fatty acid-binding protein 4 (FABP4) has been demonstrated to be a predictor of early diabetic nephropathy. However, little is known about the relationship between FABP4 and diabetic retinopathy (DR). This study explored the value of FABP4 as a biomarker of DR in patients with type 2 diabetes mellitus (T2DM).
Methods
A total of 238 subjects were enrolled, including 20 healthy controls and 218 T2DM patients. Serum FABP4 levels were measured using a sandwich enzyme-linked immunosorbent assay. The grade of DR was determined using fundus fluorescence angiography. Based on the international classification of DR, all T2DM patients were classified into the following three subgroups: non-DR group, non-proliferative diabetic retinopathy (NPDR) group, and proliferative diabetic retinopathy (PDR) group. Multivariate logistic regression analyses were employed to assess the correlation between FABP4 levels and DR severity.
Results
FABP4 correlated positively with DR severity (r=0.225, P=0.001). Receiver operating characteristic curve analysis was used to assess the diagnostic potential of FABP4 in identifying DR, with an area under the curve of 0.624 (37% sensitivity, 83.6% specificity) and an optimum cut-off value of 76.4 μg/L. Multivariate logistic regression model including FABP4 as a categorized binary variable using the cut-off value of 76.4 μg/L showed that the concentration of FABP4 above the cut-off value increased the risk of NPDR (odds ratio [OR], 3.231; 95% confidence interval [CI], 1.574 to 6.632; P=0.001) and PDR (OR, 3.689; 95% CI, 1.306 to 10.424; P=0.014).
Conclusion
FABP4 may be used as a serum biomarker for the diagnosis of DR.

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GMSCs‐Derived Exosome ZHX2 Improves Diabetes Nephropathy by Blocking AGEs/RAGE/NLRP3 Pathway to Inhibit Podocyte Pyroptosis and Inflammatory Response
Shaobo Wang, Xue Cai, Chanyan Weng, Miaozhu Su, Qunfeng Yang, Bo Chen, Jincheng Zeng
The FASEB Journal.2026;[Epub] CrossRef
Increased fatty acid-binding protein 4 levels are associated with the risk of developing retinopathy in type 2 diabetes mellitus patients
Yan Liu, Kaihui Ma, Aiying Zhang, Yun Cui, Hui Zhao, Xinhua Li, Ke Zhao
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Proteome atlas for mechanistic discovery and risk prediction of diabetic retinopathy
Shaopeng Yang, Zhuoyao Xin, Ruilin Xiong, Ziyu Zhu, Huangdong Li, Yanping Chen, Zhenghao Zhong, Lanqi Du, Lisa Zhuoting Zhu, Xianwen Shang, Wenyong Huang, Lei Zhang, Shida Chen, Chang He, Shaoying Tan, Mingguang He, Nathan Congdon, Jost B. Jonas, Yih-Chun
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Circulating AFABP, FGF21, and PEDF Levels as Prognostic Biomarkers of Sight-threatening Diabetic Retinopathy
Chi-Ho Lee, David Tak-Wai Lui, Chloe Yu-Yan Cheung, Carol Ho-Yi Fong, Michele Mae-Ann Yuen, Yu-Cho Woo, Wing-Sun Chow, Ian Yat-Hin Wong, Aimin Xu, Karen Siu-Ling Lam
The Journal of Clinical Endocrinology & Metabolism.2023; 108(9): e799. CrossRef
A Prediction Model for Sight-Threatening Diabetic Retinopathy Based on Plasma Adipokines among Patients with Mild Diabetic Retinopathy
Yaxin An, Bin Cao, Kun Li, Yongsong Xu, Wenying Zhao, Dong Zhao, Jing Ke, Takayuki Masaki
Journal of Diabetes Research.2023; 2023: 1. CrossRef

Complications
Prevalence of Diabetic Retinopathy in Undiagnosed Diabetic Patients: A Nationwide Population-Based Study: Han Na Jang, Min Kyong Moon, Bo Kyung Koo; Diabetes Metab J. 2022;46(4):620-629. Published online February 23, 2022; DOI: https://doi.org/10.4093/dmj.2021.0099

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Background
We investigated the prevalence of diabetic retinopathy (DR) in patients with undiagnosed diabetes through a nationwide survey, compared to those with known diabetes.
Methods
Among the participants of the Korean National Health and Nutrition Examination Surveys (KNHANES) from 2017 to 2018, individuals aged ≥40 years with diabetes and fundus exam results were enrolled. Sampling weights were applied to represent the entire Korean population. Newly detected diabetes patients through KNHANES were classified under “undiagnosed diabetes.”
Results
Among a total of 9,108 participants aged ≥40 years, 951 were selected for analysis. Of them, 31.3% (standard error, ±2.0%) were classified under “undiagnosed diabetes.” The prevalence of DR in patients with known and undiagnosed diabetes was 24.5%±2.0% and 10.7%±2.2%, respectively (P<0.001). The DR prevalence increased with rising glycosylated hemoglobin (HbA1c) levels in patients with known and undiagnosed diabetes (P for trend=0.001 in both). Among those with undiagnosed diabetes, the prevalence of DR was 6.9%±2.1%, 8.0%±3.4%, 5.6%±5.7%, 16.7%±9.4%, and 42.6%±14.8% for HbA1c levels of <7.0%, 7.0%–7.9%, 8.0%–8.9%, 9.0%–9.9%, and ≥10.0% respectively. There was no difference in the prevalence of hypertension, dyslipidemia, hypertriglyceridemia, or obesity according to the presence or absence of DR.
Conclusion
About one-third of patients with diabetes were unaware of their diabetes, and 10% of them have already developed DR. Considering increasing the prevalence of DR according to HbA1c level was found in patients with undiagnosed diabetes like those with known diabetes, screening and early detection of diabetes and DR are important.

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Manling Lin, Guihua Zhang, Hanfu Wu, Yongqun Xiong, Xiaoling Xiao, Lixia Sun, Chuhua Zhang
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Miao Wang, Yufei Xiang, Waiman Tong, Lijian Jin, Yue Chen, Longlong He, Hang Zhou, Dan Xu, Tianfan Cheng, Qin Zhou
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Retinal OCT-Derived Texture Features as Potential Biomarkers for Early Diagnosis and Progression of Diabetic Retinopathy
Sara Oliveira, Pedro Guimarães, Elisa Julião Campos, Rosa Fernandes, João Martins, Miguel Castelo-Branco, Pedro Serranho, Paulo Matafome, Rui Bernardes, António Francisco Ambrósio
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Frequency and Pattern of Retinopathy in Newly Diagnosed Type 2 Diabetic Patients
Faisal Mehmood, Syed Abdullah Mazhar, Nesr Farooq, Muhammad Awais Afzal
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Retinal Biomarkers in Diabetic Retinopathy: From Early Detection to Personalized Treatment
Georgios Chondrozoumakis, Eleftherios Chatzimichail, Oussama Habra, Efstathios Vounotrypidis, Nikolaos Papanas, Zisis Gatzioufas, Georgios D. Panos
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Type 1 Diabetes
Association between Metabolic Syndrome and Microvascular Complications in Chinese Adults with Type 1 Diabetes Mellitus: Qianwen Huang, Daizhi Yang, Hongrong Deng, Hua Liang, Xueying Zheng, Jinhua Yan, Wen Xu, Xiangwen Liu, Bin Yao, Sihui Luo, Jianping Weng; Diabetes Metab J. 2022;46(1):93-103. Published online August 31, 2021; DOI: https://doi.org/10.4093/dmj.2020.0240

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Background
Both type 1 diabetes mellitus (T1DM) and metabolic syndrome (MetS) are associated with an elevated risk of morbidity and mortality yet with increasing heterogeneity. This study primarily aimed to evaluate the prevalence of MetS among adult patients with T1DM in China and investigate its associated risk factors, and relationship with microvascular complications.
Methods
We included adult patients who had been enrolled in the Guangdong T1DM Translational Medicine Study conducted from June 2010 to June 2015. MetS was defined according to the updated National Cholesterol Education Program criterion. Logistic regression models were used to estimate the odds ratio (OR) for the association between MetS and the risk of diabetic kidney disease (DKD) and diabetic retinopathy (DR).
Results
Among the 569 eligible patients enrolled, the prevalence of MetS was 15.1%. While female gender, longer diabetes duration, higher body mass index, and glycosylated hemoglobin A1c (HbA1c) were risk factors associated with MetS (OR, 2.86, 1.04, 1.14, and 1.23, respectively), received nutrition therapy education was a protective factor (OR, 0.46). After adjustment for gender, age, diabetes duration, HbA1c, socioeconomic and lifestyle variables, MetS status was associated with an increased risk of DKD and DR (OR, 2.14 and 3.72, respectively; both P<0.05).
Conclusion
Although the prevalence of MetS in adult patients with T1DM in China was relatively low, patients with MetS were more likely to have DKD and DR. A comprehensive management including lifestyle modification might reduce their risk of microvascular complications in adults with T1DM.

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Brief Report

Complications
Diabetic Retinopathy and Related Clinical Practice for People with Diabetes in Korea: A 10-Year Trend Analysis: Yoo-Ri Chung, Kyoung Hwa Ha, Kihwang Lee, Dae Jung Kim; Diabetes Metab J. 2020;44(6):928-932. Published online July 10, 2020; DOI: https://doi.org/10.4093/dmj.2020.0096

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We performed a retrospective cohort study including people diagnosed with diabetes from 2006 to 2015 according to the Korean National Health Insurance Service-National Sample Cohort database, to analyze the changes in the prevalence, screening rate, and treatment patterns for diabetic retinopathy (DR) over 10 years. The proportion of people who underwent fundus screening for DR steadily increased over the past decade. The prevalence of DR increased from 13.4% in 2006 to 15.9% in 2015, while that of proliferative DR steadily decreased from 1.29% in 2006 to 1.16% in 2015. The proportion of patients undergoing retinal photocoagulation constantly decreased. The prevalence of DR increased over the past decade, while its severity seemed to have improved, with a decreased rate of proliferative DR and retinal photocoagulation. A higher proportion of patients underwent ophthalmic screening using fundus examination, but still less than 30% of patients with diabetes underwent comprehensive examination in 2015.

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Original Article

Complications
Dipeptidyl Peptidase-4 Inhibitors versus Other Antidiabetic Drugs Added to Metformin Monotherapy in Diabetic Retinopathy Progression: A Real World-Based Cohort Study: Yoo-Ri Chung, Kyoung Hwa Ha, Hyeon Chang Kim, Sang Jun Park, Kihwang Lee, Dae Jung Kim; Diabetes Metab J. 2019;43(5):640-648. Published online February 20, 2019; DOI: https://doi.org/10.4093/dmj.2018.0137

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Background

To investigate the effects of dipeptidyl peptidase-4 inhibitor (DPP4i) as add-on medications to metformin on progression of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus, compared with sulfonylurea (SU) or thiazolidinedione (TZD).

Methods

We identified 4,447 patients with DPP4i, 6,136 with SU, and 617 with TZD in addition to metformin therapy from the database of Korean National Health Insurance Service between January 2013 and December 2015. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) for DR progression. The progression of DR was defined by the procedure code of panretinal photocoagulation, intravitreal injection or vitrectomy; or the addition of diagnostic code of vitreous hemorrhage, retinal detachment, or neovascular glaucoma.

Results

The age and sex-adjusted HR of DR progression was 0.74 for DPP4i add-on group compared with SU add-on group (95% confidence interval [CI], 0.62 to 0.89). This lower risk of DR progression remained significant after additional adjustments for comorbidities, duration of metformin therapy, intravitreal injections and calendar index year (HR, 0.80; 95% CI, 0.66 to 0.97).

Conclusion

This population-based cohort study showed that the use of DPP4i as add-on therapy to metformin did not increase the risk of DR progression compared to SU.

Citations

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Letter: Dipeptidyl Peptidase-4 Inhibitors versus Other Antidiabetic Drugs Added to Metformin Monotherapy in Diabetic Retinopathy Progression: A Real World-Based Cohort Study (Diabetes Metab J 2019;43:640–8)
Jun Sung Moon
Diabetes & Metabolism Journal.2019; 43(6): 911. CrossRef
Response: Dipeptidyl Peptidase-4 Inhibitors versus Other Antidiabetic Drugs Added to Metformin Monotherapy in Diabetic Retinopathy Progression: A Real World-Based Cohort Study (Diabetes Metab J 2019;43:640–8)
Yoo-Ri Chung, Kyoung Hwa Ha, Kihwang Lee, Dae Jung Kim
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Review

Complications
Pathophysiology of Diabetic Retinopathy: The Old and the New: Sentaro Kusuhara, Yoko Fukushima, Shuntaro Ogura, Naomi Inoue, Akiyoshi Uemura; Diabetes Metab J. 2018;42(5):364-376. Published online October 22, 2018; DOI: https://doi.org/10.4093/dmj.2018.0182

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Abstract PDF PubReader ePub

Vision loss in diabetic retinopathy (DR) is ascribed primarily to retinal vascular abnormalities—including hyperpermeability, hypoperfusion, and neoangiogenesis—that eventually lead to anatomical and functional alterations in retinal neurons and glial cells. Recent advances in retinal imaging systems using optical coherence tomography technologies and pharmacological treatments using anti-vascular endothelial growth factor drugs and corticosteroids have revolutionized the clinical management of DR. However, the cellular and molecular mechanisms underlying the pathophysiology of DR are not fully determined, largely because hyperglycemic animal models only reproduce limited aspects of subclinical and early DR. Conversely, non-diabetic mouse models that represent the hallmark vascular disorders in DR, such as pericyte deficiency and retinal ischemia, have provided clues toward an understanding of the sequential events that are responsible for vision-impairing conditions. In this review, we summarize the clinical manifestations and treatment modalities of DR, discuss current and emerging concepts with regard to the pathophysiology of DR, and introduce perspectives on the development of new drugs, emphasizing the breakdown of the blood-retina barrier and retinal neovascularization.

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Evidence Supporting Autotaxin as a Potential New Drug Treatment Target in Patients With Advanced Diabetic Retinopathy
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Ocular pharmacological and biochemical profiles of 6-thioguanine: a drug repurposing study
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RG7774 (Vicasinabin), an orally bioavailable cannabinoid receptor 2 (CB2R) agonist, decreases retinal vascular permeability, leukocyte adhesion, and ocular inflammation in animal models
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Health Utility Values Among Patients With Diabetic Retinopathy, Wet Age-Related Macular Degeneration, and Cataract in Thailand: A Multicenter Survey Using Time Trade-Off, EQ-5D-5L, and Health Utility Index 3
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Treatment of Acute and Long-COVID, Diabetes, Myocardial Infarction, and Alzheimer’s Disease: The Potential Role of a Novel Nano-Compound—The Transdermal Glutathione–Cyclodextrin Complex
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Methylglyoxal: A Key Factor for Diabetic Retinopathy and Its Effects on Retinal Damage
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Prevalence and its associated factors of diabetic retinopathy among type 1 and type 2 diabetic patients at public hospitals in Eastern Ethiopia, 2023: a hospital-based comparative cross-sectional study
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Evaluating deep learning models for classifying OCT images with limited data and noisy labels
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Real-World Outcomes After Switch From Aflibercept to Faricimab in Eyes With Diabetic Macular Edema
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Comparison of retrobulbar circulation in type 2 diabetics and non-diabetics using color Doppler imaging
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Indian Journal of Clinical and Experimental Ophthalmology.2024; 10(4): 655. CrossRef
Diabetic Retinopathy Requiring Vitrectomy: Epidemiology and Pathology
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Pharmacological mechanism and clinical study of Qiming granules in treating diabetic retinopathy based on network pharmacology and literature review
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Journal of Ethnopharmacology.2023; 302: 115861. CrossRef
Vitreous humor proteome: unraveling the molecular mechanisms underlying proliferative and neovascular vitreoretinal diseases
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Protective Effects of Human Pericyte-like Adipose-Derived Mesenchymal Stem Cells on Human Retinal Endothelial Cells in an In Vitro Model of Diabetic Retinopathy: Evidence for Autologous Cell Therapy
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Proteomics profiling of vitreous humor reveals complement and coagulation components, adhesion factors, and neurodegeneration markers as discriminatory biomarkers of vitreoretinal eye diseases
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Downregulation of plasma microRNA-29c-3p expression may be a new risk factor for diabetic retinopathy
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L-type calcium channel blocker increases VEGF concentrations in retinal cells and human serum
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Efficacy and safety of curcumin in diabetic retinopathy: A protocol for systematic review and meta-analysis
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Highly water-soluble diacetyl chrysin ameliorates diabetes-associated renal fibrosis and retinal microvascular abnormality in db/db mice
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Preventive and management approach of triptonide, a diterpenoid compound against streptozotocin-induced diabetic retinopathy in Wistar rat model
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New Insights on Dietary Polyphenols for the Management of Oxidative Stress and Neuroinflammation in Diabetic Retinopathy
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Evaluation of Social Platform-Based Continuity of Care in Improving Cognitive and Prognostic Effects of Young Patients with Diabetic Retinopathy
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The rs1800469 T/T and rs1800470 C/C genotypes of the TGFB1 gene confer protection against diabetic retinopathy in a Southern Brazilian population
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Evaluation of Self-Care in Patients with Diabetic Retinopathy
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Diabetes mellitus and its influence on the incidence and process of diabetic retinopathy
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Dysregulation of the NLRP3 Inflammasome in Diabetic Retinopathy and Potential Therapeutic Targets
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Adult-induced genetic ablation distinguishes PDGFB roles in blood-brain barrier maintenance and development
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Investigation on the Q-markers of Bushen Huoxue Prescriptions for DR treatment based on chemometric methods and spectrum-effect relationship
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Corneal Confocal Microscopy in Type 1 Diabetes Mellitus: A Six-Year Longitudinal Study
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Long-Term Oral Administration of Salidroside Alleviates Diabetic Retinopathy in db/db Mice
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Chorioretinal Hypoxia Detection Using Lipid-Polymer Hybrid Organic Room-Temperature Phosphorescent Nanoparticles
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LncRNA FLG-AS1 Mitigates Diabetic Retinopathy by Regulating Retinal Epithelial Cell Inflammation, Oxidative Stress, and Apoptosis via miR-380-3p/SOCS6 Axis
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Correlation between the progression of diabetic retinopathy and inflammasome biomarkers in vitreous and serum – a systematic review
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The relationship between the neutrophil-to-lymphocyte ratio and diabetic retinopathy in adults from the United States: results from the National Health and nutrition examination survey
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Th22 cells induce Müller cell activation via the Act1/TRAF6 pathway in diabetic retinopathy
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Prevalence and Factors Associated with Diabetic Retinopathy among Adult Diabetes Patients in Southeast Ethiopia: A Hospital-Based Cross-Sectional Study
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Diabetic Retinopathy: Are lncRNAs New Molecular Players and Targets?
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Diosgenin protects retinal pigment epithelial cells from inflammatory damage and oxidative stress induced by high glucose by activating AMPK/Nrf2/HO‐1 pathway
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Selective Activation of the Wnt-Signaling Pathway as a Novel Therapy for the Treatment of Diabetic Retinopathy and Other Retinal Vascular Diseases
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Development and validation of a predictive risk model based on retinal geometry for an early assessment of diabetic retinopathy
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VEGF Gene Polymorphism Among Diabetes Mellitus and Diabetic Retinopathy
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Th22 Cells Induce Müller Cells Activation Via the Act1/Traf6 Pathway in Diabetic Retinopathy
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Pathogenesis of diabetic macular edema: the role of pro-inflammatory and vascular factors. Aliterature review
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INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine).2022; 18(3): 180. CrossRef
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Qushmua E. Alzahrani, Richard B. Gillis, Stephen E. Harding, Luciano Henrique Pinto, Monica Gulati, Bhupinder Kapoor, Pooja Rani, Sachin Kumar Singh, Gary G. Adams
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Transient receptor potential vanilloid 4 channel deletion regulates pathological but not developmental retinal angiogenesis
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Involvement of miR‐126 rs4636297 and miR‐146a rs2910164 polymorphisms in the susceptibility for diabetic retinopathy: a case–control study in a type 1 diabetes population
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Factors based on optical coherence tomography correlated with vision impairment in diabetic patients
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Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss
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Changes in Gene Expression Profiling and Phenotype in Aged Multidrug Resistance Protein 4-Deficient Mouse Retinas
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MicroRNA-431-5p encapsulated in serum extracellular vesicles as a biomarker for proliferative diabetic retinopathy
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EndMT Regulation by Small RNAs in Diabetes-Associated Fibrotic Conditions: Potential Link With Oxidative Stress
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Nimbolide ameliorates the streptozotocin-induced diabetic retinopathy in rats through the inhibition of TLR4/NF-κB signaling pathway
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Basic regulatory effects and clinical value of metalloproteinase-14 and extracellular matrix metalloproteinase inducer in diabetic retinopathy
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Inflammatory resolution and vascular barrier restoration after retinal ischemia reperfusion injury
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Diferenças de mensuração de acuidade visual e velocidade de leitura para perto entre pacientes com retinopatia diabética. Repercussão entre conceitos de deficiência visual parcial e cegueira legal
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Luteolin, an aryl hydrocarbon receptor antagonist, alleviates diabetic retinopathy by regulating the NLRP/NOX4 signalling pathway: Experimental and molecular docking study
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Short Communication

Complications
The Prevalence and Risk Factors for Diabetic Retinopathy in Shiraz, Southern Iran: Haleh Ghaem, Nima Daneshi, Shirin Riahi, Mostafa Dianatinasab; Diabetes Metab J. 2018;42(6):538-543. Published online August 9, 2018; DOI: https://doi.org/10.4093/dmj.2018.0047

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Globally, diabetic retinopathy (DR) is one of the leading causes of blindness, that diminishes quality of life. This study aimed to describe the prevalence of DR, and its associated risk factors. This cross-sectional study was carried out among 478 diabetic patients in a referral center in Fars province, Iran. The mean±standard deviation age of the participants was 56.64±12.45 years old and DR prevalence was 32.8%. In multivariable analysis, lower education levels (adjusted odds ratio [aOR], 0.43; 95% confidence interval [CI], 0.24 to 0.76), being overweight (aOR, 1.70; 95% CI, 1.02 to 2.83) or obese (aOR, 1.88; 95% CI, 1.09 to 3.26), diabetes duration of 10 to 20 years (aOR, 2.35; 95% CI, 1.48 to 3.73) and over 20 years (aOR, 5.63; 95% CI, 2.97 to 10.68), receiving insulin (aOR, 1.99; 95% CI, 1.27 to 3.10), and having chronic diseases (aOR, 1.71; 95% CI, 1.02 to 2.85) were significantly associated with DR. In conclusion, longer diabetes duration and obesity or having chronic diseases are strongly associated with DR suggesting that control of these risk factors may reduce both the prevalence and impact of retinopathy in Iran.

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Prevalence and Risk Factors of Non-proliferative Diabetic Retinopathy in Individuals with Type 2 Diabetes Mellitus Taking Oral Antidiabetic Medications
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Original Article

Complications
The Association between Pancreatic Steatosis and Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients: Jee Sun Jeong, Mee Kyung Kim, Kyung Do Han, Oak Kee Hong, Ki-Hyun Baek, Ki-Ho Song, Dong Jin Chung, Jung-Min Lee, Hyuk-Sang Kwon; Diabetes Metab J. 2018;42(5):425-432. Published online August 9, 2018; DOI: https://doi.org/10.4093/dmj.2017.0107

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Background

Whether pancreatic steatosis has a local or systemic effect, like ectopic fat of other major organs, remains unknown. Data on the influence of pancreatic steatosis on microvascular complication are rare. Therefore, we investigated the relationship between pancreatic steatosis and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).

Methods

The attenuation of three pancreatic regions (head, body, and tail) and the spleen (S) in 186 patients with T2DM was measured using non-enhanced computed tomography imaging. We used three parameters for the assessment of pancreatic steatosis (‘P’ mean: mean attenuation of three pancreatic regions; P–S: difference between ‘P’ mean and ‘S’; P/S: the ‘P’ mean to ‘S’ ratio). The presence of DR was assessed by an expert ophthalmologist using dilated fundoscopy.

Results

The average P mean was 29.02 Hounsfield units (HU), P–S was −18.20 HU, and P/S was 0.61. The three pancreatic steatosis parameters were significantly associated with the prevalence of DR in non-obese T2DM patients. In the non-obese group, the odds ratios of P mean, P–S, and P/S for the prevalence of DR, after adjustment for age, sex, and glycosylated hemoglobin level, were 2.449 (P=0.07), 2.639 (P=0.04), and 2.043 (P=0.02), respectively.

Conclusion

In this study, pancreatic steatosis was significantly associated with DR in non-obese patients with T2DM. Further studies are necessary to clarify the causal relationship between pancreatic steatosis and the development of DR.

Citations

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Saeed Ahmad, Hyun Hee Sul, Pojsakorn Danpanichkul, Matheus Souza
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Qiang Yang, Xueting Liu, Tianyi Zhang, Xu Zhao, Xiaohe Xiao
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Yingxin Zhang, Yutong Liu, Maxim S. Petrov
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Review

Clinical Diabetes & Therapeutics
Past and Current Status of Adult Type 2 Diabetes Mellitus Management in Korea: A National Health Insurance Service Database Analysis: Seung-Hyun Ko, Kyungdo Han, Yong-ho Lee, Junghyun Noh, Cheol-Young Park, Dae-Jung Kim, Chang Hee Jung, Ki-Up Lee, Kyung-Soo Ko; Diabetes Metab J. 2018;42(2):93-100. Published online April 19, 2018; DOI: https://doi.org/10.4093/dmj.2018.42.2.93

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Korea's National Healthcare Program, the National Health Insurance Service (NHIS), a government-affiliated agency under the Korean Ministry of Health and Welfare, covers the entire Korean population. The NHIS supervises all medical services in Korea and establishes a systematic National Health Information database (DB). A health information DB system including all of the claims, medications, death information, and health check-ups, both in the general population and in patients with various diseases, is not common worldwide. On June 9, 2014, the NHIS signed a memorandum of understanding with the Korean Diabetes Association (KDA) to provide limited open access to its DB. By October 31, 2017, seven papers had been published through this collaborative research project. These studies were conducted to investigate the past and current status of type 2 diabetes mellitus and its complications and management in Korea. This review is a brief summary of the collaborative projects between the KDA and the NHIS over the last 3 years. According to the analysis, the national health check-up DB or claim DB were used, and the age category or study period were differentially applied.

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Original Articles

Complications
Features of Long-Standing Korean Type 2 Diabetes Mellitus Patients with Diabetic Retinopathy: A Study Based on Standardized Clinical Data: Sejeong Park, Sang Youl Rhee, Su Jin Jeong, Kiyoung Kim, Suk Chon, Seung-Young Yu, Jeong-Taek Woo; Diabetes Metab J. 2017;41(5):393-404. Published online September 5, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.5.393

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Abstract PDF PubReader ePub

Background

This is part of a prospective study carried out as a national project to secure standardized public resources for type 2 diabetes mellitus (T2DM) patients in Korea. We compared various characteristics of long-standing T2DM patients with diabetic retinopathy (DR) and macular edema (ME).

Methods

From September 2014 to July 2015, T2DM patients with disease duration of at least 15 years were recruited at a single university hospital. Clinical data and samples were collected according to the common data elements and standards of procedure developed by the Korean Diabetes Association Research Council. Each participant was assessed by ophthalmologists for DR and ME.

Results

Among 220 registered patients, 183 completed the ophthalmologic assessment. DR was associated with longer disease duration (odds ratio [OR], 1.071; 95% confidence interval [CI], 1.001 to 1.147 for non-proliferative diabetic retinopathy [NPDR]) (OR, 1.142; 95% CI, 1.051 to 1.242 for proliferative diabetic retinopathy [PDR]) and the use of long-acting insulin (OR, 4.559; 95% CI, 1.672 to 12.427 for NPDR) (OR, 4.783; 95% CI, 1.581 to 14.474 for PDR), but a lower prevalence of a family history of cancer (OR, 0.310; 95% CI, 0.119 to 0.809 for NPDR) (OR, 0.206; 95% CI, 0.063 to 0.673 for PDR). ME was associated with higher glycosylated hemoglobin levels (OR, 1.380; 95% CI, 1.032 to 1.845) and the use of rapid-acting insulin (OR, 5.211; 95% CI, 1.445 to 18.794).

Conclusion

Various clinical features were associated with DR and ME. Additional epidemiological and biorepository-based studies using this cohort are being conducted to deepen our understanding of diabetic complications in Korea.

Citations

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Complications
Clinical Course and Risk Factors of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus in Korea: Jae-Seung Yun, Tae-Seok Lim, Seon-Ah Cha, Yu-Bae Ahn, Ki-Ho Song, Jin A Choi, Jinwoo Kwon, Donghyun Jee, Yang Kyung Cho, Yong-Moon Park, Seung-Hyun Ko; Diabetes Metab J. 2016;40(6):482-493. Published online October 5, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.6.482

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Background

We investigated clinical course and risk factors for diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).

Methods

A total of 759 patients with T2DM without DR were included from January 2001 to December 2004. Retinopathy evaluation was performed at least annually by ophthalmologists. The severity of the DR was classified into five categories according to the International Clinical Diabetic Retinopathy Severity Scales.

Results

Of the 759 patients, 523 patients (68.9%) completed the follow-up evaluation. During the follow-up period, 235 patients (44.9%) developed DR, and 32 patients (13.6%) progressed to severe nonproliferative DR (NPDR) or proliferative DR (PDR). The mean duration of diabetes at the first diagnosis of mild NPDR, moderate NPDR, and severe NPDR or PDR were 14.8, 16.7, and 17.3 years, respectively. After adjusting multiple confounding factors, the significant risk factors for the incidence of DR risk in patients with T2DM were old age, longer duration of diabetes, higher mean glycosylated hemoglobin (HbA1c), and albuminuria. Even in the patients who had been diagnosed with diabetes for longer than 10 years at baseline, a decrease in HbA1c led to a significant reduction in the risk of developing DR (hazard ratio, 0.73 per 1% HbA1c decrement; 95% confidence interval, 0.58 to 0.91; P=0.005).

Conclusion

This prospective cohort study demonstrates that glycemic control, diabetes duration, age, and albuminuria are important risk factors for the development of DR. More aggressive retinal screening for T2DM patients diagnosed with DR should be required in order to not miss rapid progression of DR.

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Review

Complications
The Effect of Bariatric Surgery on Diabetic Retinopathy: Good, Bad, or Both?: Dora M. Gorman, Carel W. le Roux, Neil G. Docherty; Diabetes Metab J. 2016;40(5):354-364. Published online September 27, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.5.354

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Abstract PDF PubReader ePub

Bariatric surgery, initially intended as a weight-loss procedure, is superior to standard lifestyle intervention and pharmacological therapy for type 2 diabetes in obese individuals. Intensive medical management of hyperglycemia is associated with improved microvascular outcomes. Whether or not the reduction in hyperglycemia observed after bariatric surgery translates to improved microvascular outcomes is yet to be determined. There is substantial heterogeneity in the data relating to the impact of bariatric surgery on diabetic retinopathy (DR), the most common microvascular complication of diabetes. This review aims to collate the recent data on retinal outcomes after bariatric surgery. This comprehensive evaluation revealed that the majority of DR cases remain stable after surgery. However, risk of progression of pre-existing DR and the development of new DR is not eliminated by surgery. Instances of regression of DR are also noted. Potential risk factors for deterioration include severity of DR at the time of surgery and the magnitude of glycated hemoglobin reduction. Concerns also exist over the detrimental effects of postprandial hypoglycemia after surgery. In vivo studies evaluating the chronology of DR development and the impact of bariatric surgery could provide clarity on the situation. For now, however, the effect of bariatric surgery on DR remains inconclusive.

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Original Articles

Complications
Risk Factors for the Development and Progression of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Advanced Diabetic Retinopathy: Kyung-Jin Yun, Hye Ji Kim, Mee Kyoung Kim, Hyuk-Sang Kwon, Ki-Hyun Baek, Young Jung Roh, Ki-Ho Song; Diabetes Metab J. 2016;40(6):473-481. Published online September 20, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.6.473

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Background

Some patients with type 2 diabetes mellitus (T2DM) do not develop diabetic kidney disease (DKD) despite the presence of advanced diabetic retinopathy (DR). We aimed to investigate the presence of DKD and its risk factors in patients with T2DM and advanced DR.

Methods

We conducted a cross-sectional study in 317 patients with T2DM and advanced DR. The phenotypes of DKD were divided into three groups according to the urine albumin/creatinine ratio (uACR, mg/g) and estimated glomerular filtration rate (eGFR, mL/min/1.73 m²): no DKD (uACR <30 and eGFR ≥60), non-severe DKD (uACR ≥30 or eGFR <60), and severe DKD (uACR ≥30 and eGFR <60). Mean systolic and diastolic blood pressure, mean glycosylated hemoglobin (HbA1c) level, and HbA1c variability (standard deviation [SD] of serial HbA1c values or HbA1c-SD) were calculated for the preceding 2 years.

Results

The prevalence of no DKD, non-severe DKD, and severe DKD was 37.2% (n=118), 37.0% (n=117), and 25.8% (n=82), respectively. HbA1c-SD and the triglyceride/high density lipoprotein cholesterol (TG/HDL-C) ratio correlated positively with uACR and negatively with eGFR. Multiple linear regression analyses showed that the HbA1c-SD and TG/HDL-C ratio were significantly related with eGFR. Multiple logistic regression analyses after adjusting for several risk factors showed that HbA1c-SD and the TG/HDL-C ratio were significant risk factors for severe DKD.

Conclusion

The prevalence of DKD was about 60% in patients with T2DM and advanced DR. HbA1c variability and TG/HDL-C ratio may affect the development and progression of DKD in these patients.

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Intravitreal Ranibizumab for Subfoveal Choroidal Neovascularization from Age-Related Macular Degeneration with Combined Severe Diabetic Retinopathy: So Young Han, Jeong Hun Bae, Jaeryung Oh, Hyeong Gon Yu, Su Jeong Song; Diabetes Metab J. 2015;39(1):46-50. Published online February 16, 2015; DOI: https://doi.org/10.4093/dmj.2015.39.1.46

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Background

To evaluate the efficacy of intravitreal ranibizumab for subfoveal choroidal neovascularization (CNV) from age-related macular degeneration (AMD) with combined severe diabetic retinopathy (DR).

Methods

This retrospective, interventional case series included eleven patients (mean age, 70.09 years; range, 54 to 83 years) with at least severe non-proliferative DR and subfoveal CNV secondary to AMD. Each subject was treated with intravitreal injections of 0.5 mg ranibizumab. The primary outcomes included change in best-corrected visual acuity and central subfield thickness (CST) on optical coherence tomography (OCT).

Results

The mean follow-up time was 16.7±14 months (range, 6 to 31 months). Mean visual acuity improved from 1.21±0.80 logarithm of the minimum angle of resolution (logMAR) to 1.0±0.6 logMAR (P=0.107), 0.95±0.62 logMAR (P=0.044), 1.10±0.68 logMAR (P=0.296), and 1.13±0.66 logMAR (P=0.838) at 1, 3, 6, and 12 months after injection, respectively. Eight patients (72.7%) gained or maintained vision (mean 0.32 logMAR), whereas three patients (27.3%) lost more than one line of vision (mean 0.51 logMAR). The mean OCT CST was 343.9±134.6 µm at baseline, and the mean CST at 1, 3, 6, 12 months after the injection was 367.8±172.1 (P=0.864), 346.2±246.2 (P=0.857), 342±194.1 (P=0.551), and 294.2±108.3 µm (P=0.621), respectively.

Conclusion

Intravitreal ranibizumab injection can be considered to be a therapy for the stabilization of subfoveal CNV secondary to AMD with combined severe DR. However, these patients might exhibit limited visual improvement after treatment.

Citations

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Comparative study of widefield swept-source optical coherence tomography angiography in eyes with concomitant age-related macular degeneration and diabetic retinopathy
Matthew Finn, Grace Baldwin, Itika Garg, Hannah E Wescott, Thomas Koch, Filippos Vingopoulos, Rebecca Zeng, Hanna Choi, Diane Sayah, Deeba Husain, Nimesh A Patel, Leo A Kim, Joan W Miller, David M Wu, Demetrios G Vavvas, John B Miller
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Outcomes of intravitreal anti-VEGF therapy in eyes with both neovascular age-related macular degeneration and diabetic retinopathy
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Reviews

The Optimal Cutoff Value of Glycated Hemoglobin for Detection of Diabetic Retinopathy: Jung Min Kim, Dong-Jun Kim; Diabetes Metab J. 2015;39(1):16-26. Published online February 16, 2015; DOI: https://doi.org/10.4093/dmj.2015.39.1.16

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With standardization of measurement of glycated hemoglobin (A1C), the International Expert Committee Report in 2009 and the American Diabetes Association in 2010 recommended incorporating A1C ≥6.5% into the previous diagnostic criteria using fasting plasma glucose and/or 2-hour plasma glucose. Whereas the association of A1C with cardiovascular diseases and other diabetic microvascular complications was linear without evidence of a distinct threshold, several studies suggested a threshold value for A1C in diabetic retinopathy (DR). In studies about the optimal cutoff value for A1C in DR, the A1C values range from 5.2% to 7.8%. There are several possible reasons why these values for DR differ so widely (differences in the definition and/or methods for DR, variation in statistical methods, differences in study population, differences in exclusion criteria, and difference in methods for measuring A1C). With these wide variations in the study method, drawing a conclusive cutoff value for A1C in DR is impossible. In published studies, the cutoff values for moderate or severe DR were higher than those for any or mild DR (6.4% to 7.0% vs. 5.5% to 6.5%).

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Current Concepts in Diabetic Retinopathy: Su Jeong Song, Tien Yin Wong; Diabetes Metab J. 2014;38(6):416-425. Published online December 15, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.6.416

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For the past several decades, tremendous efforts have been made to decrease the complications of diabetes, including diabetic retinopathy. New diagnostic modalities like ultrawide field fundus fluorescein angiography and spectral domain optical coherence tomography has allowed more accurate diagnosis of early diabetic retinopathy and diabetic macular edema. Antivascular endothelial growth factors are now extensively used to treat diabetic retinopathy and macular edema with promising results. There remains uncertainty over the long term effects and the socioeconomic costs of these agents.

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Interrelationships between the Retinal Neuroglia and Vasculature in Diabetes: Timothy S. Kern; Diabetes Metab J. 2014;38(3):163-170. Published online June 17, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.3.163

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For years, diabetic retinopathy has been defined based on vascular lesions, and neural abnormalities were not regarded as important. This review summarizes evidence that the neural retina has important effects on the retinal vasculature under normal conditions, and the interaction between the retinal neuroglial cells and vascular function is altered in diabetes. Importantly, new evidence raises a possibility that abnormalities within retinal neuroglial cells (notably photoreceptors) might actually be causing or initiating the vascular disease in diabetic retinopathy.

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Original Article

Diabetic Retinopathy and Endothelial Dysfunction in Patients with Type 2 Diabetes Mellitus: Jae-Seung Yun, Seung-Hyun Ko, Ji-Hoon Kim, Kun-Woong Moon, Yong-Moon Park, Ki-Dong Yoo, Yu-Bae Ahn; Diabetes Metab J. 2013;37(4):262-269. Published online August 14, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.4.262

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Background

We investigated the relationship between endothelial dysfunction and diabetic retinopathy (DR) in patients with type 2 diabetes.

Methods

We used a cross-sectional design to examine 167 patients with type 2 diabetes mellitus. All patients underwent biochemical and ophthalmological examination. We assessed endothelial dysfunction by a flow-mediated vasodilation method of the brachial artery. Changes in vasodilation (flow-mediated vasodilatation, %FMD) were expressed as percent change over baseline values.

Results

The mean±standard deviation of patient age was 54.1±8.6 years. The %FMD was significantly lower in patients with DR than without DR. The prevalence of retinopathy decreased across increasing tertiles of %FMD. After adjusting for patients' age, sex, diabetes duration, use of insulin, use of antihypertensive, antiplatelet, and lipid lowering medications, systolic blood pressure, fasting plasma glucose, 2-hour plasma glucose, glycated hemoglobin, and urinary albumin excretion, participants with a reduced %FMD were more likely to have DR (odds ratio, 11.819; 95% confidence interval, 2.201 to 63.461; P=0.004, comparing the lowest and highest tertiles of %FMD).

Conclusion

Endothelial dysfunction was associated with DR, which was most apparent when the endothelial dysfunction was severe. Our study provides insights into the possible mechanism of the influence of endothelial dysfunction on the development of DR.

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Review

Identification of Novel Drug Targets for the Treatment of Diabetic Retinopathy: Akiyoshi Uemura; Diabetes Metab J. 2013;37(4):217-224. Published online August 14, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.4.217

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Vision loss in diabetic retinopathy (DR) is attributable to retinal vascular disorders that result in macular edema and neoangiogenesis. In addition to laser photocoagulation therapy, intraocular injections of antivascular endothelial growth factor drugs have contributed to the treatment of these disease conditions. Nonetheless, the clinical feasibility of intraocular drug administration has raised an increasing demand to develop alternative drugs that can fundamentally ameliorate the retinal vascular dysfunctions in DR. For this purpose, experimental animal models that reproduce human DR would be of clinical benefit. Despite the unavailability of DR models in rats or mice, pharmacological and genetic manipulations without hyperglycemia have successfully recapitulated retinal edema and neoangiogenesis in postnatal mouse retinas, thereby enabling the understanding of the pathophysiology underlying DR. This article highlights the utility of experimental mouse models of retinal vascular abnormalities and discusses cellular and molecular mechanisms responsible for the onset and progression of DR. These approaches will lead to the identification of novel drug targets for the restoration of vascular integrity and regeneration of functional capillaries in DR.

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Original Articles

Prevalence of Chronic Complications in Korean Patients with Type 2 Diabetes Mellitus Based on the Korean National Diabetes Program: Sang Youl Rhee, Suk Chon, Mi Kwang Kwon, Ie Byung Park, Kyu Jeung Ahn, In Ju Kim, Sung-Hoon Kim, Hyoung Woo Lee, Kyung Soo Koh, Doo Man Kim, Sei Hyun Baik, Kwan Woo Lee, Moon Suk Nam, Yong Soo Park, Jeong-taek Woo, Young Seol Kim; Diabetes Metab J. 2011;35(5):504-512. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.504

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Background

The Korean National Diabetes Program (KNDP) cohort study is performing an ongoing large-scale prospective multicenter investigation to discover the pathogenesis of type 2 diabetes in Korean patients. This study was performed to examine the prevalence of chronic complications in patients with type 2 diabetes among those registered in the KNDP cohort within the past 4 years.

Methods

This study was performed between June 2006 and September 2009 at 13 university hospitals and included 4,265 KNDP cohort participants. Among the participants, the crude prevalence of microvascular and macrovascular diseases of those checked for diabetes-related complications was determined, and the adjusted standard prevalence and standardization of the general population prevalence ratio (SPR) was estimated based on the 2005 Korean National Health and Nutrition Examination Survey (KNHANES) population demographics.

Results

Among the KNDP registrants, 43.2% had hypertension, 34.8% had dyslipidemia, 10.8% had macrovascular disease, and 16.7% had microvascular disease. The SPR of the KNDP registrants was significantly higher than that of the KNHANES subjects after adjusting for demographics in the KNHANES 2005 population. However, with the exception of cardiovascular disease in females, the standardized prevalence for the most complicated items in the survey was significantly higher than that in the KNHANES subjects.

Conclusion

The prevalence of macrovascular disease and peripheral vascular disease were significantly higher in Korean patients with type 2 diabetes than in the normal population. However, no significant difference was noted in the prevalence of cardiovascular disease in females.

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Vascular Endothelial Growth Factor (VEGF) and Advanced Glycation End Products (AGEs) Overexpression in the Retina and Serum and Lens Opacities of Streptozotocin-induced Diabetic Rats.: Young Sook Kim, Eun Jin Sohn, Chan Sik Kim, Yun Mi Lee, Dong Ho Jung, Nan Hee Kim, Hyun Young Lee, Jung Yeon Kim, Jin Sook Kim; Korean Diabetes J. 2008;32(1):44-52. Published online February 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.1.44

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Abstract PDF

BACKGROUND
Vascular Endothelial Growth Factor (VEGF) and Advanced Glycation End products (AGEs) have been implicated in the development of diabetic retinopathy. In this study, we examined the expression of VEGF and AGEs in the retina and serum, apoptosis in the retina, and lens opacities in streptozotocin (STZ)-induced diabetic rats. METHODS: The localization of VEGF and AGEs in the retina of STZ-induced diabetic rats was determined by immunohistochemical analysis, and apoptotic cell death was assessed using the TUNEL assay. In the serum, STZ-induced diabetic rats were assayed for VEGF and AGEs by ELISA. Lenses were also isolated to detect the opacity. RESULTS: Expression of VEGF and accumulation of AGEs were significantly increased in the retinal ganglion cell layers (GCL) and nuclear cell layers (NCL) of STZ-induced diabetic rats compared to normal control rats. In addition to cellular expression, serum VEGF and AGEs levels were also increased significantly in STZ-diabetic rats compared to normal rats (both P < 0.001) and there was a significant correlation between the serum VEGF and AGEs levels (r = 0.504). The lens opaque density of STZ-induced diabetic rats were significantly higher than in normal rats (P < 0.001). CONCLUSIONS: AGEs could be involved in the development of diabetic retinopathy through the induction of VEGF. One could possibly correlate this lens opaque formation with elevation of AGE induced VEGF level. Thus, this study should be considered as a basic research for studying pathology of the retina and lens in diabetic experimental models.

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Activity dependent neuroprotective protein mediates the protective effects against VEGF-induced corneal barrier disruption in diabetes
Grazia Maugeri, Agata Grazia D’Amico, Nicoletta Palmeri, Elisabetta Pricoco, Claudio Bucolo, Velia D’Agata
Peptides.2026; 197: 171488. CrossRef
Growth factor and hypoxia-inducible factor alpha content in the retina of male Wistar rats in experimental diabetic retinopathy and the effect of cellular protein kinase blockade
K. O. Usenko, Olena Strubchevska, S. O. Rykov, M. S. Babenko, Kateryna Strubchevska, Oleksandra Kozyk, S. V. Ziablitsev, Marko Kozyk
Frontiers in Endocrinology.2025;[Epub] CrossRef

Prevalence of Diabetic Retinopathy in Diabetics Who are Positive for GAD Autoantibody.: Seon Joong Moon, Chan Hee Lee, Jun Sung Moon, Hee Jung Moon, Ji Eun Lee, Kyung Ah Chun, Ji Sung Yoon, Ihn Ho Cho, Kyu Chang Won, Hyoung Woo Lee; Korean Diabetes J. 2007;31(5):429-434. Published online September 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.5.429

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Abstract PDF

BACKGROUND
Diabetic retinopathy is a leading cause of adult blindness. Some patients show early development and progression of diabetic retinopathy despite of apparently good glycemic control. This is suggesting the involvement of other contributing factors. Recent studies have shown that retinopathy and GAD autoantibody (GADA) show an inverse relationship immunologically. This study is designed to investigate the clinical manifestation of diabetes who are positive for GADA and the relationship between GADA and diabetic retinopathy. METHODS: Type 1 diabetic patients & LADA patients who had visited Yeungnam university Medical Center from 1988 to 2005 were involved. We reviewed the pathologic and laboratory records of these patients and investigated the development of diabetic microvascular complications. RESULTS: Compared with patients who had GADA negative diabetes, patients with GADA positive diabetes had lower prevalence of diabetic retinopathy (GADA negative subject: 25.8% vs. GADA positive subject: 9.6%, P < 0.05). CONCLUSION: We confirmed that diabetic retinopathy and GADA showed an inverse relationship. It seems quite probable that GADA may contribute to the prevention of retinopathy. Further research should be needed concerning the effect of GADA on diabetic retinopathy.

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Chronic Complications in Adult Diabetic Patients with and without GAD Antibody
Jin Ook Chung, Dong Hyeok Cho, Dong Jin Chung, Min Young Chung
Korean Diabetes Journal.2009; 33(2): 124. CrossRef

VEGF-Angiopoietin-Tie2 System in Diabetic Retinopathy.: Nan Hee Kim, Hee Young Kim, Ji A Seo, Kye Won Lee, Sin Gon Kim, Kyung Mook Choi, Sei Hyun Baik, Yoon Shin Park, Inho Jo, Dong Seop Choi; Korean Diabetes J. 2005;29(2):122-132. Published online March 1, 2005

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Abstract PDF: BACKGROUND
Ischemia-induced neovascularization can cause the loss of vision in retinal disorders such as diabetic retinopathy. Recent studies have shown that the angiopoietin-Tie2 system is a major regulator of vascular integrity and it is involved in pathologic angiogenesis. However, its role in the pathophysiology of diabetic retinopathy is not yet known. We examined the regulation of the VEGF-angiopoietin-Tie2 system in both in vitro and in vivo studies to discover their possible role in diabetic retinopathy. METHODS: We investigated the effects of a well-known angiogenic stimulus, hypoxia(2% O2 concentration) and vascular endothelial growth factor(VEGF, 10 ng/mL) on the expression of the angiopoietin-Tie2 mRNA in bovine retinal pericytes(BRP) and bovine aortic endothelial cells(BAEC). We also examined the expressions of VEGF-angiopoietin-Tie2 mRNA in retinas of type 2 diabetic OLETF(Otsuka-Long-Evans-Tokushima-Fatty) rats at 30 and 50 weeks. We also investigated the effect of angiotensin II receptor type 1(AT1) antagonist on the VEGFangiopoietin-Tie2 expression. RESULTS: Hypoxia and VEGF treatment significantly increased angiopoietin-1(Ang1) mRNA expression in the BRPs. In contrast, the angiopoietin-2(Ang2) mRNA expression was unaltered in the BRPs treated with hypoxia and VEGF. Significant up-regulation of Tie2 mRNA expression was found and this lasted up to 12 h. However, using BAECs, we found that only the Ang2 expression responded to these two angiogenic stimuli. In OLETF rats, the Ang-Tie2 expression patterns were similar with those of the BAECs. Ang2 and VEGF mRNA were increased at 30 and 50 weeks for the OLETF rats, whereas the Ang1 expression was not changed. The up-regulation of Ang2 and VEGF was decreased with the losartan treatment, an AT1 receptor antagonist. Tie2 mRNA expression was increased only at 50 weeks and it did not show any decrement by the losartan treatment. CONCLUSION: Our data suggest that hypoxia and VEGF treatment differentially regulate the angiopoietin-Tie2 system in the two vascular cells. Ang2 and VEGF expressions were predominantly increased in type 2 diabetic rats, and the unopposed action of Ang2 with VEGF might be involved in the development of diabetic retinopathy. The renin-angiotensin system may be a potential mechanism for the up-regulated VEGF-Ang2 system

The Risk Factors of Diabetic Retinopathy in NIDDM Patients.: Won Tae Seo, Seung O Song, Sy Young Kim, Yoon Sang Choi, Hye Ran Jang, Sang Jong Lee; Korean Diabetes J. 1999;23(2):162-171. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Diabetic retinopathy, which is one of the microvascular complications, has been shown to be related to visual disturbance and blindness. In this report we examined the risk factors for diabetic retinopathy in NIDDM patients and investigate the relationship between the prevalence of diabetic retinopathy and other risk factors. METHODS: Clinical characteristics and laboratory findings such as HbAlc, fasting plasma glucose, hemoglobin, BUN, creatinine and lipid profile and treatment modality were evaluated and their relation with diabetic retinopathv were analyzed. Fundoscopic examinations of the retina were performed using direct/indirect opthalmoscopy and fundus photograph. The grade of retinopathy was judged from the results of opthalmological examinations and were elassified into non-proliferative retinopathy and proliferative retinopathy. RESULTS: A total of 163 patients with NIDDM (M/F=59:104) were evaluated. Of these patients, 80 of them developed diabetic retinopathy. 71 patients were detected to have non-proliferatie and 9 patients to have proliferative retinopathy. The presence of proteinuria, the long diabetic duration, hypertension, anemia, the high plasma glucose levels, the high level of HbA1c, old age were all associated with the development of diabetic retinopathy. I-lowever, sex, body mass index, type of therapy, lipid profile, C-peptide levels, insulin levels had little impact on the development of retinopathy. CONCLUSIONS: The presence of proteinuria, the long diabetic duration, hypertension, anemia, high plasma glucose levels, high HbA., and old age are important risk factors for the development of rc;tinopathy in patients with NIDDM.

High Serum Lipoprotein ( a ) Levels in Korean Type 2 Diabetic Patients with Proliferative Diabetic retinopathy.: Hyung Joo Park, Chul Hee Kim, Yun Ey Chung, Sang Wook Kim, Jin Yub Kim, Eun Sook Kim, Sung Kwan Hong, Ki Up Lee; Korean Diabetes J. 1998;22(3):338-343. Published online January 1, 2001

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Abstract PDF: BACKGROUND
To examine the possible association between serum lipoprotein(a) (Lp(a)) concentration and proliferative diabetic retinopathy(PDR) in Korean patients with type 2 diabetes mellitus. METHODS: A total of 412 Korean outpatients with type 2 diabetes were examined. Diabetic retinopathy was determined by fundoscopic examination by an ophthalmologist and/or by fluorecein angiography. Semm Lp(a) levels were measured by one step sandwich ELISA method. RESULTS: The patient with PDR had higher serum Lp(a) levels than those with no retinopathy or non-proliferative diabetic retinopathy(NPDR). Multiple logistic regression analysis showed that serum Lp(a) level and the presence of diabetic nephropathy were independent variables having a statistically significant association with PDR. CONCLUSION: Korean type 2 diabetic patients with PDR had higher serum Lp(a) levels compared with those with no retinopathy or NPDR. Although these results suggested that Lp(a) might play a role in the occlusion of retinal capillaries leading to PDR, further prospective studies are required to prove causal relationship.

Changes of Glomerular Filtration Rate and Urinary Albumin Excretion Rate in NIDDM patients with Microalbuminuria.: Hyo Jung Kim, Jung Min Koh, Eun Sug Shin, Yun Ey Chung, Young Il Kim, Chul Hee Kim, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee; Korean Diabetes J. 1997;21(4):414-424. Published online January 1, 2001

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Abstract PDF: BACKGROUND
We previously suggested that micro-albuminuria in the presence of retinopathy may represent a state of real incipient diabetic nephropathy with declining glomerular filtration rate(GFR), while the meaning of microalbuminuria in the absence of retinopathy may be more heterogeneous. This study was performed to further test this hypothesis. METHODS: We prospectively followed up the changes in GFR and urinary albumin excretinn rate (UAE) in microalbuminuric NIDDM patients with or without diabetic retinopathy for 3.1 years. RESULTS: 1) Among 45 patients who completed the followup, 27 had retinopathy from the baseline(group A), while 18 patients did not have retinopathy throughout the study(group B). 2) UAE at baseline was not statistically different between the group A and group B. During follow-up, VAE remained stable in the group B patients(40.0 [20.5 ~ 158.0) to 60.0[20.2 ~ 231.0] ug/min, NS). On the other hand, UAE significantly increased in the group A patients(47.9[20.0~186.0] to 140.0[24.5~2862.0] ug/min, P <0.001). 3) Thirty percent of the group A patients(8/27) progressed to overt proteinuria, while 11%(2/18) of the group B patients developed overt proteinuria(NS). 4) GFR significantly decreased both in the group A (113.0+21.2 to 89.1+24.0 mL/min/1.73 m, P < 0,001) and in the group B patients(134.1+27.2 to 121.5+27.3 mL/min/1.73 m, P<0.01). However, the magnitude of change in GFR was significantly higher in the group A than in the group B patients(7.7+7.6 vs 3.9+4.2 mL/min/1.73 m /year, P <0.05), 5) Multiple logistic regression analysis revealed that the presence of retinopathy was a independent risk factor for faster decline in GFR. CONCLUSION: It appears that clinical course is different in NIDDM patients with microalbuminuria, according to the presence or absence of diabetic retinopathy. Microalbuminuria in the presence of retinopathy predicts aggravation of albuminuria and decline in GFR. In contrast, the renal function in microalbuminuric NIDDM patients in the absence of retinopathy may remain stable for years.

Relationship between Cardiovascular Autonomic Neuropathy and Diabetic Retinopathy in Patients with Non-Insulin Dependent Diabetes Mellitus.: Jae Chun Lee, Sang Yob Nam, Ji Sung Yoon, Jin Chul Park, Kyu Chang Won, Ihn Ho Cho, Hyoung Woo Lee, Hyun Woo Lee; Korean Diabetes J. 1997;21(1):82-90. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The presence of cardiovascular autonomic neuropathy may play a permissive role in the development and progression of diabetic retinopathy. But, there is little information regarding the degree of association between the progression of diabetic retinopathy and cardiovascular autonomic neuropathy in patients with non-insulin dependent diabetes mellitus. Thus, this study defined the relationship between the progression of diabetic retinopathy and cardiovascular autonomic neuropathy in patients with non-insulin dependent diabetes mellitus. METHODS: Seventy-nine patients with non-insulin dependent diabetes mellitus were separated into 2 groups based on the presence of cardiovascular autonomic neuropathy. Age, body mass index, duration of illness, plasma creatinine, BUN, fasting plasma glueose, glycated hemoglobin, lipid profile and 24hr urine total protein were not statistically different among the two groups. According to indirect ophthalmoscopy, patients were also classified as having proliferative, non-proliferative or no retinopathy. RESULTS: The results showed a striking relntionship between cardiovascular autonomic neuropathy and proliferative diabetic retinopathy(p<0.01). Corrected QT interval was more prolonged in non-insulin dependent diabetes mellitus patients with cnrdiovascular autonomic neuropathy than patients without cardiovascular autonomic neuropathy(p<0.05). In non-insulin dependent diabetes mellitus patients with cardiovascular autonomic neuropathy, there was no relationship between the prolongation of corrected QT interval and proliferative diabetic retinopathy, and there was no significant relationship between each of 5 components of cardiovascular autonomic neuropathy test and proliferative diiabetic retinopathy. CONCLUSION: These results suggest that the presence of cardiovascular autonomic neuropathy is strongly associated with proliferative retinopathy in patients with non-insulin dependent diabetes mellitus. But, long-term prospective studies on large cohorts of patients must be done to evaluate if cardiovascular autonomic neuropathy would be a risk factor or a risk indicator of an etiologic process underlying the development of proliferative retinopathy.

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