Advances in the Research of Diabetic Retinopathy

Editorial

25 October 2022

Editorial: Advances in the research of diabetic retinopathy

Subrata Chakrabarti

Michele Lanza

and

Khalid Siddiqui

1,693 views

3 citations

Editors

Michele Lanza

University of Campania Luigi Vanvitelli

Khalid Siddiqui

Faculty of Medicine, Kuwait University

Subrata Chakrabarti

Western University

Impact

Exosomes are synthesized in various cells. Under physiological or pathological conditions, their carriers may change and participate in the formation of the collective pathological state. They may activate TGF-β, the signaling pathway that mediates the hemodynamics of individuals with PDR. By blocking TGF-β, the activation of the signaling pathway promotes cell proliferation and reduces apoptosis and the inflammatory response. Exosomes (such as miR-141-3p) may also inhibit retinal neovascularization by preventing the activation of the p38/MAPK signaling pathway. Exosomes can also be detected by the PI3K/Akt signaling pathway, which can induce vascular endothelial cell proliferation while preventing cell apoptosis, as well as cell proliferation and migration of the retinal pigment epithelium cell. The stimulation of the signaling system may also aid in the reduction of HG-induced cell proliferation, migration, and angiogenesis. In diabetic rats, the activity of the NF-κB signaling pathway rose dramatically, and inhibiting the NF-κB signaling pathway can reduce inflammation, apoptosis, and oxidative stress.

Review

09 August 2022

Research progress on exosomes/microRNAs in the treatment of diabetic retinopathy

Si-ru Niu

, 2 more and

Yu Hong

Diabetic retinopathy (DR) is the leakage and obstruction of retinal microvessels caused by chronic progressive diabetes that leads to a series of fundus lesions. If not treated or controlled, it will affect vision and even cause blindness. DR is caused by a variety of factors, and its pathogenesis is complex. Pericyte-related diseases are considered to be an important factor for DR in many pathogeneses, which can lead to DR development through direct or indirect mechanisms, but the specific mechanism remains unclear. Exosomes are small vesicles of 40–100 nm. Most cells can produce exosomes. They mediate intercellular communication by transporting microRNAs (miRNAs), proteins, mRNAs, DNA, or lipids to target cells. In humans, intermittent hypoxia has been reported to alter circulating excretory carriers, increase endothelial cell permeability, and promote dysfunction in vivo. Therefore, we believe that the changes in circulating exocrine secretion caused by hypoxia in DR may be involved in its progress. This article examines the possible roles of miRNAs, proteins, and DNA in DR occurrence and development and discusses their possible mechanisms and therapy. This may help to provide basic proof for the use of exocrine hormones to cure DR.

7,166 views

21 citations

Original Research

18 July 2022

The Association Between Diabetic Retinopathy and the Prevalence of Age-Related Macular Degeneration—The Kailuan Eye Study

Zhang Yongpeng

, 22 more and

Wei Wenbin

Background: Disability has become a global population health challenge. Due to difficulties in self-care or independent living, patients with disability mainly live in community-based care centers or institutions for long-term care. Nonetheless, these settings often lack basic medical resources, such as ultrasonography. Thus, remote ultrasonic robot technology for clinical applications across wide regions is imperative. To date, few experiences of remote diagnostic systems in rural care centers have been reported.

Objective: To assess the feasibility of a fifth-generation cellular technology (5G)-based robot-assisted remote ultrasound system in a care center for disabled patients in rural China.

Methods: Patients underwent remote robot-assisted and bedside ultrasound examinations of the liver, gallbladder, spleen, and kidneys. We compared the diagnostic consistency and differences between the two modalities and evaluated the examination duration, image quality, and safety.

Results: Forty-nine patients were included (21 men; mean age: 61.0 ± 19.0 [range: 19–91] years). Thirty-nine and ten had positive and negative results, respectively; 67 lesions were detected. Comparing the methods, 41 and 8 patients had consistent and inconsistent diagnoses, respectively. The McNemar and kappa values were 0.727 and 0.601, respectively. The mean duration of remote and bedside examinations was 12.2 ± 4.5 (range: 5–26) min and 7.5 ± 1.8 (range: 5–13) min (p < 0.001), respectively. The median image score for original images on the patient side and transmitted images on the doctor side was 5 points (interquartile range: [IQR]: 4.7–5.0) and 4.7 points (IQR: 4.5–5.0) (p = 0.176), respectively. No obvious complications from the examination were reported.

Conclusions: A 5G-based robot-assisted remote ultrasound system is feasible and has comparable diagnostic efficiency to traditional bedside ultrasound. This system may provide a unique solution for basic ultrasound diagnostic services in primary healthcare settings.

6,710 views

9 citations

(A, B) The scatterplots of altered tsRNAs (A) and miRNAs (B). The red and green dots represent the up- and down-regulated tsRNAs/miRNAs, respectively (fold change ≥ 1.5). (C, D) The volcano plots of significantly altered tsRNAs (C) and miRNAs (D). The red and green dots represent the significantly up- and down-regulated tsRNAs/miRNAs, respectively (fold change ≥ 1.5, p < 0.05). (E, F) A heatmap and hierarchical clustering analysis of significantly altered tsRNAs (E) and miRNAs (F) in vitreous humor samples of the PDR and control groups.

Original Research

12 July 2022

Altered Expressions of Transfer RNA-Derived Small RNAs and microRNAs in the Vitreous Humor of Proliferative Diabetic Retinopathy

Yan Yang

, 7 more and

Yedi Zhou

3,703 views

13 citations

Systematic Review

22 June 2022

Meta-Analysis of Relationship of Sleep Quality and Duration With Risk of Diabetic Retinopathy

Zhenzhen Zheng

, 11 more and

Riken Chen

Objective: A meta-analysis is used to explore the relationship of sleep quality and duration with the risk of diabetic retinopathy (DR).

Method: Cochrane Library, PubMed, Embase, and other databases are searched from their establishment to April 2022. Literature on the relationship of sleep quality and duration with DR risk published in various databases is collected, and two researchers independently screen the literature, extract data, and evaluate the quality of the included articles. The meta-analysis is performed with Review Manage 5.4.1 software.

Results: A total of 7 articles are selected, including 4,626 subjects. The results show a strong correlation between sleep quality and DR risk. When comparing the sleep quality scores of “DR” (experimental group) and “NO DR” (control group), the Pittsburgh sleep quality index(PSQI) score of the DR group is significantly higher than that of the NO DR group (MD = 2.85; 95% confidence interval [CI] 1.92, 3.78, P<0.001), while the ESS score of the DR group is also significantly higher than that of the NO DR group (MD = 1.17; 95% confidence interval [CI] 0.14 to 2.30, P=0.04), so the sleep quality score of the DR group is higher than that of the NO DR group in both the PSQI and ESS scores, which confirms that low sleep quality is a risk factor for DR. Long sleep duration is also associated with the risk of developing DR; the number of adverse events (DR prevalence) is higher for “long sleep duration” than “normal sleep duration” [OR = 1.83, 95%CI 1.36–2.47, P < 0.001], suggesting that long sleep duration can cause increased DR risk. Short sleep duration is also associated with the occurrence of DR [OR = 1.49, 95%CI 1.15–1.94), P = 0.003] and can increase DR risk.

Conclusion: Sleep quality and duration (including long and short sleep duration) are significantly associated with DR. To reduce DR risk, sleep intervention should be actively carried out, lifestyle changes should be made, and attention should be paid to the role of DR management.

4,923 views

11 citations

The mediation analysis adjusted for age, gender, body max index, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, glycosylated hemoglobin, urinary creatinine and serum creatinine.

Original Research

29 June 2022

The Association of Homocysteine and Diabetic Retinopathy in Homocysteine Cycle in Chinese Patients With Type 2 Diabetes

Wei-Ming Luo

, 7 more and

Zhong-Ze Fang

2,640 views

7 citations

These LncRNAs, in addition to affecting metabolic abnormalities associated with diabetic retinopathy including inflammation, also move inside the mitochondria, and damage mitochondrial structural, functional and genomic stability. Furthermore, possible decrease in the mitochondrial genome encoded LncCytB further damages the mitochondria, and the damaged mitochondria accelerates apoptosis, ultimately, resulting in the development of diabetic retinopathy.

Review

06 June 2022

Long Noncoding RNAs and Mitochondrial Homeostasis in the Development of Diabetic Retinopathy

Renu A. Kowluru

3,894 views

9 citations

Original Research

03 June 2022

Secreted Protein Acidic and Rich in Cysteine Mediates the Development and Progression of Diabetic Retinopathy

Liying Luo

, 8 more and

Zhi Zheng

3,735 views

8 citations

There is no edema in the macular area, the CFT value is 231 μm, and the ELM layer and IS/OS layer are continuous.

Original Research

01 June 2022

Correlation Between Retinal Microstructure Detected by Optical Coherence Tomography and Best Corrected Visual Acuity in Diabetic Retinopathy Macular Edema

Siying Li

, 3 more and

Lei Chen

1,601 views

5 citations

Original Research

27 May 2022

Exploring the Immune Infiltration Landscape and M2 Macrophage-Related Biomarkers of Proliferative Diabetic Retinopathy

Zhishang Meng

, 6 more and

Jing Luo

Backgrounds: Diabetic retinopathy (DR), especially proliferative diabetic retinopathy (PDR), is the major cause of irreversible blindness in the working-age population. Increasing evidence indicates that immune cells and the inflammatory microenvironment play an important role during PDR development. Herein, we aim to explore the immune landscape of PDR and then identify potential biomarkers correlated with specific infiltrating immune cells.

Methods: We mined and re-analyzed PDR-related datasets from the Gene Expression Omnibus (GEO) database. Using the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm, we investigated the infiltration of 22 types of immune cells in all selected samples; analyses of differences and correlations between infiltrating cells were used to reveal the immune landscape of PDR. Thereafter, weighted gene co-expression network analysis (WGCNA) and differential expression analysis were applied to identify the hub genes on M2 macrophages that may affect PDR progression.

Results: Significant differences were found between infiltration levels of immune cells in fibrovascular membranes (FVMs) from PDR and normal retinas. The percentages of follicular helper T cells, M1 macrophages, and M2 macrophages were increased significantly in FVMs. Integrative analysis combining the differential expression and co-expression revealed the M2 macrophage-related hub genes in PDR. Among these, COL5A2, CALD1, COL6A3, CORO1C, and CALU showed increased expression in FVM and may be potential biomarkers for PDR.

Conclusions: Our findings provide novel insights into the immune mechanisms involved in PDR. COL5A2, CALD1, COL6A3, CORO1C, and CALU are M2 macrophage-related biomarkers, further study of these genes could inform novel ideas and basis for the understanding of disease progression and targeted treatment of PDR.

7,825 views

32 citations

Flow chart of the study selection process.

Systematic Review

31 May 2022

Uric Acid and Diabetic Retinopathy: A Systematic Review and Meta-Analysis

Yicong Guo

, 1 more and

Huilan Xu

6,162 views

11 citations

Original Research

17 May 2022

Using Machine Learning Techniques to Develop Risk Prediction Models for the Risk of Incident Diabetic Retinopathy Among Patients With Type 2 Diabetes Mellitus: A Cohort Study

Yuedong Zhao

, 9 more and

Zhengnan Gao

Objective: To construct and validate prediction models for the risk of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus.

Methods: Patients with type 2 diabetes mellitus hospitalized over the period between January 2010 and September 2018 were retrospectively collected. Eighteen baseline demographic and clinical characteristics were used as predictors to train five machine-learning models. The model that showed favorable predictive efficacy was evaluated at annual follow-ups. Multi-point data of the patients in the test set were utilized to further evaluate the model’s performance. We also assessed the relative prognostic importance of the selected risk factors for DR outcomes.

Results: Of 7943 collected patients, 1692 (21.30%) developed DR during follow-up. Among the five models, the XGBoost model achieved the highest predictive performance with an AUC, accuracy, sensitivity, and specificity of 0.803, 88.9%, 74.0%, and 81.1%, respectively. The XGBoost model’s AUCs in the different follow-up periods were 0.834 to 0.966. In addition to the classical risk factors of DR, serum uric acid (SUA), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), estimated glomerular filtration rate (eGFR), and triglyceride (TG) were also identified to be important and strong predictors for the disease. Compared with the clinical diagnosis method of DR, the XGBoost model achieved an average of 2.895 years prior to the first diagnosis.

Conclusion: The proposed model achieved high performance in predicting the risk of DR among patients with type 2 diabetes mellitus at each time point. This study established the potential of the XGBoost model to facilitate clinicians in identifying high-risk patients and making type 2 diabetes management-related decisions.

6,063 views

37 citations

Original Research

07 April 2022

Expressions of Serum lncRNAs in Diabetic Retinopathy – A Potential Diagnostic Tool

Saumik Biswas

, 4 more and

Subrata Chakrabarti

With increasing incidence of diabetes worldwide, there is an ever-expanding number of patients with chronic diabetic complications such as diabetic retinopathy (DR), one of the leading causes of blindness in the working age population. Early screening for the onset and severity of DR is essential for timely intervention. With recent advancements in genomic technologies, epigenetic alterations in DR are beginning to unravel. Long non-coding RNAs (lncRNAs), which are key epigenetic mediators, have demonstrated implications in several (DR) related processes. Based on the previous research, we have developed a serum-based, multi-panel PCR test using 9 lncRNAs (ANRIL, MALAT1, WISPER, ZFAS1, H19, HOTAIR, HULC, MEG3, and MIAT) to identify and validate whether this panel could be used as a diagnostic and prognostic tool for DR. We initially used a cell culture model (human retinal endothelial cells) and confirmed that 25 mM glucose induces upregulations of ANRIL, HOTAIR, HULC, MALAT1, and ZFAS1, and downregulation of H19 compared to 5 mM glucose controls. Then as an initial proof-of-concept, we tested vitreous humor and serum samples from a small cohort of non-diabetic (N=10) and diabetic patients with proliferative retinopathy (PDR, N=11) and measured the levels of the 9 lncRNAs. Differential expressions of lncRNAs were found in the vitreous and serum of patients and showed significant correlations. We expanded our approach and assessed the same lncRNAs using samples from a larger cohort of diabetic (n= 59; M/F:44/15) and non-diabetic patients (n= 11; M/F:4/7). Significant increased lncRNA expressions of ANRIL, H19, HOTAIR, HULC, MIAT, WISPER and ZFAS1 were observed in the serum of diabetic patients (with varying stages of DR) compared to non-diabetics. No significant correlations were demonstrated between lncRNA expressions and creatinine or glycated hemoglobin (HbA1C) levels. Using ROC and further analyses, we identified distinct lncRNA phenotype combinations, which may be used to identify patients with DR. Data from this study indicate that a panel of serum lncRNAs may be used for a potential screening test for DR. Further large-scale studies are needed to validate this notion.

3,831 views

31 citations

Systematic Review

29 March 2022

Effectiveness of Panretinal Photocoagulation Plus Intravitreal Anti-VEGF Treatment Against PRP Alone for Diabetic Retinopathy: A Systematic Review With Meta-Analysis

Wuyue Zhang

, 1 more and

Aimin Sang

Objective: To compare the efficacy and safety of panretinal photocoagulation (PRP) combined with intravitreal anti-vascular endothelial growth factor (anti-VEGF) against PRP monotherapy for diabetic retinopathy (DR).

Methods: We searched Pubmed, Cochrane Library, Web of Science, Embase, and Science Direct Register of Controlled Trials from April 2011 to January 2021 to identify the randomized trials that compared the efficacy and safety between PRP combined with intravitreal anti-VEGF and PRP monotherapy for DR. We searched in the following databases between April 2011 and January 2021: Pubmed, Cochrane Library, Web of Science, Embase, and Science Direct without any restriction of countries or article type. The outcome measures were the best-corrected visual acuity (BCVA), neovascularization on the disc (NVD), neovascularization elsewhere (NVE), central macula thickness (CMT), and total retinal volume over time (FAS), and we also observed the adverse events (AEs) between the two groups.

Results: A total of 351 studies were identified, of which 11 studies were included in this meta-analysis (N = 1,182 eyes). Compared with PRP monotherapy, PRP plus anti-VEGF combination treatment produced a mean reduction in BCVA in units of logMAR of -0.23 [95% CI -0.32, -0.15] or a mean improvement in BCVA in units of letters of 4.99 [95% CI 3.79, 6.19], and also yielded a mean reduction in NVD of -28.41 [95% CI -30.30, -26.52], in NVE of -1.33 [95% CI -1.52, -1.14], in CMT of -1.33 [95% CI -1.52, -1.14], or in total FAS. No significant difference was observed on the risk of AEs as vitreous hemorrhage, elevation in intraocular pressure, and cataract between the two different treatments.

Conclusion: PRP with anti-VEGF combination treatment can achieve the ideal efficacy on DR by improving BCVA and NV regression, with no potential increased incidence of AEs, which proves that the combination therapy is an efficient therapeutic strategy that could improve the management of patients with DR.

4,106 views

19 citations

VA, visual acuity; CRT, central retinal thickness; RIF, retinal interlayer fluid; SRF, subretinal pigment epithelium fluid; PED, retinal pigment epithelial detachment; RHF, retinal hyperreflexia; CI, continuous injection; RF, random forest; GRNN, generalized regression neural network; PNN, probabilistic neural network; ELM, extreme learning machine; SVM, support vector machines; OLS, ordinary least squares; BP, back propagation network; RBF, radial basis function network; SVR, support vector regression; ACC, classification accuracy; AUC, area under curve; MAE, mean absolute error; RMSE, root mean square error.

Original Research

29 March 2022

The Fundus Structural and Functional Predictions of DME Patients After Anti-VEGF Treatments

Hang Xie

, 5 more and

Chun-Hung Chiu

2,847 views

5 citations

Original Research

29 October 2021

Plasma Metabolomics Reveals Metabolic Profiling For Diabetic Retinopathy and Disease Progression

Yu Sun

, 3 more and

Chao Liu

Backgrounds: Diabetic retinopathy (DR), the main retinal vascular complication of DM, is the leading cause of visual impairment and blindness among working-age people worldwide. The aim of this study was to investigate the difference of plasma metabolic profiles in patients with DR to better understand the mechanism of this disease and disease progression.

Methods: We used ultrahigh-performance liquid Q-Exactive mass spectrometry and multivariate statistical analyses to conduct a comprehensive analysis of plasma metabolites in a population with DR and proliferative DR (PDR). A risk score based on the level of the selected metabolite was established and evaluated using the least absolute shrinkage and selection operator regularization logistic regression (LASSO-LR) based machine learning model.

Results: 22 differentially expressed metabolites which belonged to different metabolic pathway were identified and confirmed to be associated with the occurrence of DR. A risk score based on the level of the selected metabolite pseudouridine was established and evaluated to strongly associated with the occurrence of DR. Four circulating plasma metabolites (pseudouridine, glutamate, leucylleucine and N-acetyltryptophan) were identified to be differentially expressed between patients with PDR and other patients, and a risk score formula based on these plasma metabolites was developed and assessed to be significantly related to PDR.

Conclusions: Our work highlights the possible use of the risk score assessment based on the plasma metabolites not only reveal in the early diagnosis of DR and PDR but also assist in enhancing current therapeutic strategies in the clinic.

6,190 views

35 citations