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Pu L, Beale O, Meng X. Geometric Self-Supervised Learning: A Novel AI Approach Towards Quantitative and Explainable Diabetic Retinopathy Detection. Bioengineering (Basel) 2025; 12:157. [PMID: 40001677 PMCID: PMC11852169 DOI: 10.3390/bioengineering12020157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults. Early detection is crucial to reducing DR-related vision loss risk but is fraught with challenges. Manual detection is labor-intensive and often misses tiny DR lesions, necessitating automated detection. OBJECTIVE We aimed to develop and validate an annotation-free deep learning strategy for the automatic detection of exudates and bleeding spots on color fundus photography (CFP) images and ultrawide field (UWF) retinal images. MATERIALS AND METHODS Three cohorts were created: two CFP cohorts (Kaggle-CFP and E-Ophtha) and one UWF cohort. Kaggle-CFP was used for algorithm development, while E-Ophtha, with manually annotated DR-related lesions, served as the independent test set. For additional independent testing, 50 DR-positive cases from both the Kaggle-CFP and UWF cohorts were manually outlined for bleeding and exudate spots. The remaining cases were used for algorithm training. A multiscale contrast-based shape descriptor transformed DR-verified retinal images into contrast fields. High-contrast regions were identified, and local image patches from abnormal and normal areas were extracted to train a U-Net model. Model performance was evaluated using sensitivity and false positive rates based on manual annotations in the independent test sets. RESULTS Our trained model on the independent CFP cohort achieved high sensitivities for detecting and segmenting DR lesions: microaneurysms (91.5%, 9.04 false positives per image), hemorrhages (92.6%, 2.26 false positives per image), hard exudates (92.3%, 7.72 false positives per image), and soft exudates (90.7%, 0.18 false positives per image). For UWF images, the model's performance varied by lesion size. Bleeding detection sensitivity increased with lesion size, from 41.9% (6.48 false positives per image) for the smallest spots to 93.4% (5.80 false positives per image) for the largest. Exudate detection showed high sensitivity across all sizes, ranging from 86.9% (24.94 false positives per image) to 96.2% (6.40 false positives per image), though false positive rates were higher for smaller lesions. CONCLUSIONS Our experiments demonstrate the feasibility of training a deep learning neural network for detecting and segmenting DR-related lesions without relying on their manual annotations.
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Affiliation(s)
- Lucas Pu
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA;
| | - Oliver Beale
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA;
| | - Xin Meng
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA;
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Tesfaye H, Paik JM, Roh M, Htoo PT, Zakoul H, Schmedt N, Koeneman L, Wexler DJ, Patorno E. Empagliflozin and the Risk of Retinopathy in Patients With Type 2 Diabetes. JAMA Ophthalmol 2025; 143:62-71. [PMID: 39636645 PMCID: PMC11622102 DOI: 10.1001/jamaophthalmol.2024.5219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/06/2024] [Indexed: 12/07/2024]
Abstract
Importance Empagliflozin might lower the risk of diabetic retinopathy (DR) by preventing retinal pericyte loss. However, the role of empagliflozin with respect to DR in patients with type 2 diabetes (T2D) remains unclear. Objective To compare the risk of incident nonproliferative DR (NPDR) and DR progression in patients with T2D initiating empagliflozin vs a dipeptidyl peptidase 4 inhibitor (DPP4i). Design, Setting, and Participants A new-user active-comparator cohort study was conducted using US nationwide insurance claims data from 2 commercial insurers and Medicare from August 2014 to September 2019. Adults with T2D initiating study drugs without prior diagnosis or treatment for proliferative DR or other advanced retinal diseases were included. To assess incident NPDR, patients with a history of NPDR were additionally excluded, while for the DR progression outcome, patients were required to have a history of NPDR. Data were analyzed from August 2022 to May 2024. Exposures Initiation of empagliflozin or a DPP4i. Main Outcomes and Measures Incident NPDR was defined using diagnostic codes for mild, moderate, or severe NPDR. The DR progression outcome was defined as a composite of incident proliferative DR, vitreous hemorrhage, initiation of intravitreal anti-vascular endothelial growth factor injection, or panretinal photocoagulation. Incidence rates, hazard ratios (HRs), and rate differences (RDs) with 95% CIs were estimated. Results A total of 34 239 pairs of propensity-score matched adults were identified in the incident NPDR cohort and 7831 pairs in the DR progression cohort. In the incident NPDR cohort, 35 867 patients (52.4%) were male, and the mean (SD) age was 65.6 (10.3) years. In the DR progression cohort, 8229 patients (52.5%) were male, and the mean (SD) age was 67.0 (10.0) years. Over a mean (SD) follow-up period of 8 (7.5) months receiving treatment, the risk of incident NPDR was not different across groups (HR, 1.04; 95% CI, 0.94 to 1.15; RD, 1.30; 95% CI, -1.83 to 4.44), while the risk of DR progression was lower among individuals who initiated empagliflozin compared with those who began DPP4i therapy (HR, 0.78; 95% CI, 0.63 to 0.96; RD, -9.44; 95% CI, -16.90 to -1.98). Results were consistent across multiple subgroups and sensitivity analyses. Conclusions and Relevance Compared with initiation of a DPP4i, empagliflozin initiation was not associated with incident NPDR, although it may be associated with a lower risk of DR progression. Although residual confounding cannot be entirely ruled out due to the observational nature of our study, these findings may be helpful when weighing the risks and benefits of various glucose-lowering agents in adults with T2D.
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Affiliation(s)
- Helen Tesfaye
- Department of Medicine, Division of Pharmacoepidemiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Julie M. Paik
- Department of Medicine, Division of Pharmacoepidemiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Division of Renal (Kidney) Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Miin Roh
- Department of Visual Services, Atrius Health, Boston, Massachusetts
| | - Phyo T. Htoo
- Department of Medicine, Division of Pharmacoepidemiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Heidi Zakoul
- Department of Medicine, Division of Pharmacoepidemiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | | | | | - Deborah J. Wexler
- Department of Medicine, Division of Endocrinology, Massachusetts General Hospital Diabetes Center, Massachusetts General Hospital, Harvard Medical School, Boston
| | - Elisabetta Patorno
- Department of Medicine, Division of Pharmacoepidemiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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Abràmoff MD, Lavin PT, Jakubowski JR, Blodi BA, Keeys M, Joyce C, Folk JC. Mitigation of AI adoption bias through an improved autonomous AI system for diabetic retinal disease. NPJ Digit Med 2024; 7:369. [PMID: 39702673 DOI: 10.1038/s41746-024-01389-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/12/2024] [Indexed: 12/21/2024] Open
Abstract
Where adopted, Autonomous artificial Intelligence (AI) for Diabetic Retinal Disease (DRD) resolves longstanding racial, ethnic, and socioeconomic disparities, but AI adoption bias persists. This preregistered trial determined sensitivity and specificity of a previously FDA authorized AI, improved to compensate for lower contrast and smaller imaged area of a widely adopted, lower cost, handheld fundus camera (RetinaVue700, Baxter Healthcare, Deerfield, IL) to identify DRD in participants with diabetes without known DRD, in primary care. In 626 participants (1252 eyes) 50.8% male, 45.7% Hispanic, 17.3% Black, DRD prevalence was 29.0%, all prespecified non-inferiority endpoints were met and no racial, ethnic or sex bias was identified, against a Wisconsin Reading Center level I prognostic standard using widefield stereoscopic photography and macular Optical Coherence Tomography. Results suggest this improved autonomous AI system can mitigate AI adoption bias, while preserving safety and efficacy, potentially contributing to rapid scaling of health access equity. ClinicalTrials.gov NCT05808699 (3/29/2023).
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Affiliation(s)
- Michael D Abràmoff
- Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.
- Veterans Administration Medical Center, Iowa City, IA, USA.
- Digital Diagnostics, Inc., Coralville, IA, USA.
| | - Philip T Lavin
- Boston Biostatistics Research Foundation, Inc., Framingham, MA, USA
| | | | - Barbara A Blodi
- Department of Ophthalmology and Visual Sciences, Wisconsin Reading Center, University of Wisconsin, Madison, WI, USA
| | - Mia Keeys
- Department of Public Health, George Washington University, Washington, DC, USA
- Womens' Commissioner, Washington, DC, USA
| | - Cara Joyce
- Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Chicago, IL, USA
| | - James C Folk
- Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
- Veterans Administration Medical Center, Iowa City, IA, USA
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Rojekar S, Parit S, Gholap AD, Manchare A, Nangare SN, Hatvate N, Sugandhi VV, Paudel KR, Ingle RG. Revolutionizing Eye Care: Exploring the Potential of Microneedle Drug Delivery. Pharmaceutics 2024; 16:1398. [PMID: 39598522 PMCID: PMC11597228 DOI: 10.3390/pharmaceutics16111398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 08/09/2024] [Accepted: 09/16/2024] [Indexed: 11/29/2024] Open
Abstract
Microneedle technology revolutionizes ocular drug delivery by addressing challenges in treating ocular diseases. This review explores its potential impact, recent advancements, and clinical uses. This minimally invasive technique offers precise control of drug delivery to the eye, with various microneedle types showing the potential to penetrate barriers in the cornea and sclera, ensuring effective drug delivery. Recent advancements have improved safety and efficacy, offering sustained and controlled drug delivery for conditions like age-related macular degeneration and glaucoma. While promising, challenges such as regulatory barriers and long-term biocompatibility persist. Overcoming these through interdisciplinary research is crucial. Ultimately, microneedle drug delivery presents a revolutionary method with the potential to significantly enhance ocular disease treatment, marking a new era in eye care.
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Affiliation(s)
- Satish Rojekar
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Swapnali Parit
- Institute of Chemical Technology, Marathwada Campus, Jalna 431203, India; (S.P.); (A.M.); (N.H.)
| | - Amol D. Gholap
- Department of Pharmaceutics, St. John Institute of Pharmacy and Research, Palghar 401404, India;
| | - Ajit Manchare
- Institute of Chemical Technology, Marathwada Campus, Jalna 431203, India; (S.P.); (A.M.); (N.H.)
| | - Sopan N. Nangare
- Department of Pharmaceutics, H. R. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, India;
| | - Navnath Hatvate
- Institute of Chemical Technology, Marathwada Campus, Jalna 431203, India; (S.P.); (A.M.); (N.H.)
| | - Vrashabh V. Sugandhi
- College of Pharmacy & Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA;
| | - Keshav Raj Paudel
- Centre for Inflammation, School of Life Sciences, Faculty of Science, Centenary Institute and University of Technology Sydney, Sydney, NSW 2007, Australia;
| | - Rahul G. Ingle
- Datta Meghe College of Pharmacy, Datta Meghe Institute of Higher Education and Research (Deemed to Be University)—DMIHER, Wardha 442107, India
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Andersson K, Halling A, Agvall B. Factors associated with development of retinopathy in patients with type 2 diabetes mellitus at onset and within three years after diagnosis. Scand J Prim Health Care 2024; 42:408-414. [PMID: 38647202 PMCID: PMC11332278 DOI: 10.1080/02813432.2024.2329215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 03/06/2024] [Indexed: 04/25/2024] Open
Abstract
OBJECTIVE To investigate the prevalence of diabetes retinopathy and evaluate the factors influencing its occurrence both at the onset of type 2 diabetes (T2D) and three years into its duration. DESIGN Retrospective population-based study. SETTING Data was retrieved from Regional Healthcare Information Platform in Region Halland 2016-2020. SUBJECTS Patients 35-75 years old in Region Halland receiving first-time diabetes diagnosis according to ICD-code E11-14 in 2016-17. The total cohort consisted of 1659 patients. MAIN OUTCOME MEASURES The main outcome measure of the study was the occurrence of diabetes retinopathy at onset and within three years from the diabetes diagnosis. Multivariate logistic regression analysis was conducted for diabetes retinopathy at onset and within three years, adjusted for age, gender, comorbidities, levels of HbA1c, cholesterol, kidney functional and blood pressure. RESULTS At onset, there were 12% with diabetes retinopathy and after three years, 32% of the patients had developed diabetes retinopathy. In the study cohort, 71 of patients who were examined with fundus photography within three years after onset, and 8% had had dietary recommendation without pharmacotherapy. High HbA1c levels, blood pressure values and impaired renal function already at onset were associated with development of diabetes retinopathy at onset and this association persisted after three years. The odds ratio for diabetes retinopathy was increased adjusted for HbA1c elevations, renal impairment, and increased blood pressure at index and when adjusted for these variables three years from index. CONCLUSION These findings indicate that the risk of developing diabetes retinopathy is present early on at onset and within the first three years of diabetes diagnosis. This highlights the importance of promptly regulating glucose- and blood-pressure levels and follow up kidney dysfunction to mitigate the risk of diabetes retinopathy.
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Affiliation(s)
- Kajsa Andersson
- Capio Husläkarna Vallda, Kungsbacka, Region Halland, Halmstad, Sweden
| | - Anders Halling
- Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | - Björn Agvall
- Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
- Department of Research and Development, Region Halland, Halmstad, Sweden
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Luo J, Yu F, Zhou H, Wu X, Zhou Q, Liu Q, Gan S. AST/ALT ratio is an independent risk factor for diabetic retinopathy: A cross-sectional study. Medicine (Baltimore) 2024; 103:e38583. [PMID: 38941365 PMCID: PMC11466165 DOI: 10.1097/md.0000000000038583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 05/23/2024] [Indexed: 06/30/2024] Open
Abstract
The aspartate to alanine transaminase (AST/ALT) ratio indicates oxidative stress and inflammatory reactions related to the occurrence of diabetic retinopathy (DR). Currently, there are no reports on the correlation between AST/ALT ratio and DR. Hence, this study aimed to explore the relationship between AST/ALT ratio and DR. This cross-sectional study utilized data from the Metabolic Management Center of the First People's Hospital in City. In total, 1365 patients with type 2 diabetes mellitus (T2DM) participated in the study, including 244 patients with DR and 1121 patients without DR. We collected the results of fundus photography, liver function, and other research data and grouped them according to tertiles of AST/ALT ratios. DR prevalence was the highest in the group with the highest AST/ALT ratio (22.12%, P = .004). Both univariate (OR = 2.25, 95% CI: 1.51-3.34, P < .001) and multivariable logistic regression analyses (adjusted for confounding factors) showed that the risk of DR increased by 36% when the AST/ALT ratio increased by 1 standard deviation (SD) (OR = 1.36, 95% CI: 1.16-1.59, P < .001), and 29.3% was mediated by the duration of diabetes. A sensitivity analysis confirmed the stability of the results. This study showed that an increase in AST/ALT ratio is an independent risk factor for DR.
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Affiliation(s)
- Jian Luo
- Department of Endocrinology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Fang Yu
- Department of Endocrinology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Haifeng Zhou
- Department of Endocrinology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Xueyan Wu
- Department of Gastroenterology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Quan Zhou
- Department of Science and Education, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Qin Liu
- Department of Endocrinology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
| | - Shenglian Gan
- Department of Endocrinology, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, China
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Yang F, Zou W, Li Z, Du Y, Gao W, Zhang J, Ji X, Huang J. Optical coherence tomography angiography for detection of microvascular changes in early diabetes: A systematic review and meta-analysis. Diabetes Metab Res Rev 2024; 40:e3812. [PMID: 38738481 DOI: 10.1002/dmrr.3812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 02/04/2024] [Accepted: 03/27/2024] [Indexed: 05/14/2024]
Abstract
AIMS To evaluate the effectiveness of optical coherence tomography angiography (OCTA) in detecting early intraocular microvascular changes in diabetic patients. MATERIALS AND METHODS A systematic study search was performed on PubMed, Medline, Embase, and the Cochrane Library, ranging from January 2012 to March 2023. Controlled studies compared diabetes mellitus (DM) patients with non-diabetic retinopathy (NDR) or patients with mild non-proliferative diabetic retinopathy (mild NPDR) to healthy people. These studies included parameters of OCTA such as foveal avascular zone (FAZ), vessel density of superficial capillary plexus (VDscp), vessel density of deep capillary plexus (VDdcp), and peripapillary VD. The relevant effect model was used according to the heterogeneity, and the mean difference and 95% confidence intervals were calculated. RESULTS A total of 18 studies with 2101 eyes were eventually included in this meta-analysis. Our results demonstrated that early alterations of VDscp, VDdcp, and peripapillary VD in NDR patients had a significant difference compared with healthy people by OCTA (VDscp: WMD = -1.34, 95% CI: -1.99 to -0.68, P < 0.0001. VDdcp: WMD = -2.00, 95% CI: -2.95 to -1.04, P < 0.0001. Peripapillary VD: WMD = -1.07, 95% CI: -1.70 to -0.43, P = 0.0010). However, there was no statistically significant difference in total FAZ between them (WMD = -0.00, 95% CI: -0.02-0.01, P = 0.84). In addition, for patients with mild NPDR, OCTA could illustrate prominent changes in VDscp, VDdcp, and total FAZ compared with healthy people (VDscp: WMD = -6.11, 95% CI: -9.90 to -2.32, P = 0.002. VDdcp: WMD = -4.26, 95% CI: -5.95 to -2.57, P < 0.00001. FAZ: WMD = 0.06, 95% CI: 0.01-0.11, P = 0.03). CONCLUSIONS In diabetic patients with or without retinopathy, the parameters of OCTA such as VDscp, VDdcp, and peripapillary vessel density were demonstrated as potential biomarkers in monitoring the early alterations of retinal microangiopathy, while total FAZ may have no significant changes in diabetic patients without retinopathy.
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Affiliation(s)
- Fan Yang
- Department of Ophthalmology, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Weijie Zou
- Department of Ophthalmology, Changshu No. 1 People's Hospital, Suzhou, China
| | - Zhiwei Li
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuanyuan Du
- Department of Ophthalmology, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Weiyun Gao
- Department of Ophthalmology, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Ji Zhang
- Department of Ophthalmology, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaoyan Ji
- Department of Ophthalmology, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiang Huang
- Department of Ophthalmology, Second Affiliated Hospital of Soochow University, Suzhou, China
- State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Shou BL, Venkatesh K, Chen C, Ghidey R, Lee JH, Wang J, Channa R, Wolf RM, Abramoff MD, Liu TYA. Risk Factors for Nondiagnostic Imaging in a Real-World Deployment of Artificial Intelligence Diabetic Retinal Examinations in an Integrated Healthcare System: Maximizing Workflow Efficiency Through Predictive Dilation. J Diabetes Sci Technol 2024; 18:302-308. [PMID: 37798955 PMCID: PMC10973867 DOI: 10.1177/19322968231201654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
OBJECTIVE In the pivotal clinical trial that led to Food and Drug Administration De Novo "approval" of the first fully autonomous artificial intelligence (AI) diabetic retinal disease diagnostic system, a reflexive dilation protocol was used. Using real-world deployment data before implementation of reflexive dilation, we identified factors associated with nondiagnostic results. These factors allow a novel predictive dilation workflow, where patients most likely to benefit from pharmacologic dilation are dilated a priori to maximize efficiency and patient satisfaction. METHODS Retrospective review of patients who were assessed with autonomous AI at Johns Hopkins Medicine (8/2020 to 5/2021). We constructed a multivariable logistic regression model for nondiagnostic results to compare characteristics of patients with and without diagnostic results, using adjusted odds ratio (aOR). P < .05 was considered statistically significant. RESULTS Of 241 patients (59% female; median age = 59), 123 (51%) had nondiagnostic results. In multivariable analysis, type 1 diabetes (T1D, aOR = 5.82, 95% confidence interval [CI]: 1.45-23.40, P = .01), smoking (aOR = 2.86, 95% CI: 1.36-5.99, P = .005), and age (every 10-year increase, aOR = 2.12, 95% CI: 1.62-2.77, P < .001) were associated with nondiagnostic results. Following feature elimination, a predictive model was created using T1D, smoking, age, race, sex, and hypertension as inputs. The model showed an area under the receiver-operator characteristics curve of 0.76 in five-fold cross-validation. CONCLUSIONS We used factors associated with nondiagnostic results to design a novel, predictive dilation workflow, where patients most likely to benefit from pharmacologic dilation are dilated a priori. This new workflow has the potential to be more efficient than reflexive dilation, thus maximizing the number of at-risk patients receiving their diabetic retinal examinations.
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Affiliation(s)
- Benjamin L. Shou
- School of Medicine, The Johns Hopkins
University, Baltimore, MD, USA
| | - Kesavan Venkatesh
- Whiting School of Engineering, The
Johns Hopkins University, Baltimore, MD, USA
| | - Chang Chen
- Bloomberg School of Public Health, The
Johns Hopkins University, Baltimore, MD, USA
| | - Ronel Ghidey
- Bloomberg School of Public Health, The
Johns Hopkins University, Baltimore, MD, USA
| | - Jae Hyoung Lee
- Bloomberg School of Public Health, The
Johns Hopkins University, Baltimore, MD, USA
| | - Jiangxia Wang
- Bloomberg School of Public Health, The
Johns Hopkins University, Baltimore, MD, USA
| | - Roomasa Channa
- Department of Ophthalmology and Visual
Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Risa M. Wolf
- Department of Pediatrics, Division of
Pediatric Endocrinology, The Johns Hopkins University, Baltimore, MD, USA
| | - Michael D. Abramoff
- Department of Ophthalmology and Visual
Sciences, The University of Iowa, Iowa City, IA, USA
| | - T. Y. Alvin Liu
- Wilmer Eye Institute, The Johns Hopkins
University, Baltimore, MD, USA
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Gholami Chahkand MS, Esmaeilpour Moallem F, Qezelgachi A, Seifouri K, Pesaran Afsharian A, sheikhzadeh F, poursalehi A, Fani Sadrabadi FS, Saghab Torbati M, Ramezanzade M, Alishiri G, Ansari A, Zare Dehabadi E, Karimi Matloub S, Sheikh Z, Deravi N, Mehrtabar S, Chichagi F, Faal Hamedanchi N, Arzaghi M, Asadi M, Alsadat Dadkhah P, Ansari A. Lipoprotein (a) as a predictor of diabetic retinopathy in patients with type 2 diabetes: A systematic review. Diab Vasc Dis Res 2023; 20:14791641231197114. [PMID: 38018132 PMCID: PMC10685788 DOI: 10.1177/14791641231197114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Lipoprotein a (LP(a)), an LDL-like lipoprotein, known as a risk factor for cardiovascular diseases, has a controversial association with diabetic retinopathy in patients with type 2 diabetes-the current systematic review aimed to critically assess the association between LP(a) and diabetic retinopathy. METHODS A systematic review of relevant studies was conducted after a thorough search in PubMed, Scopus, and Google Scholar electronic databases. We used English observational, case-control, and prospective cohort studies published up to August 2022, including type 2 diabetic patients as the population, diabetic retinopathy as the outcome, and LP(a) as the intervention. RESULT 17 relevant studies, including 4688 patients with diabetes, were included in this systematic review. While in 13 studies, Lipoprotein(a) was recognized as a risk factor for diabetic retinopathy, only three studies reported no evidence of a relationship between the two. Also, another study showed a mixed outcome of the relationship between LP(a) and diabetic retinopathy. CONCLUSION High serum lipoprotein(a) in patients with type 2 diabetes is considered a risk factor for diabetic retinopathy. However, further large-scaled cohort studies are still required to validate this finding.
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Affiliation(s)
| | | | - Abolfazl Qezelgachi
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Kiana Seifouri
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Farzad sheikhzadeh
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Atefe poursalehi
- Student Research Committee, School of Paramedical, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | | | - Goharsharieh Alishiri
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Arina Ansari
- Student Research Committee, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Emad Zare Dehabadi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Zahra Sheikh
- Student Research Committee, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saba Mehrtabar
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Chichagi
- Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Faal Hamedanchi
- Faculty of Medicine, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, Iran
| | | | - Mahla Asadi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Akram Ansari
- Medical College, Shantou University, Shantou, China
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Yuan Z, Tian Y, Zhang C, Wang M, Xie J, Wang C, Huang J. Integration of systematic review, lipidomics with experiment verification reveals abnormal sphingolipids facilitate diabetic retinopathy by inducing oxidative stress on RMECs. Biochim Biophys Acta Mol Cell Biol Lipids 2023; 1868:159382. [PMID: 37659619 DOI: 10.1016/j.bbalip.2023.159382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 08/21/2023] [Accepted: 08/28/2023] [Indexed: 09/04/2023]
Abstract
OBJECTIVE This study aims to explore the potential biomarkers in the development of diabetes mellitus (DM) into diabetic retinopathy (DR). METHODS Systematic review of diabetic metabolomics was used to screen the differential metabolites and related pathways during the development of DM. Non-targeted lipidomics of rat plasma was performed to explore the differential metabolites in the development of DM into DR in vivo. To verify the effects of differential metabolites in inducing retinal microvascular endothelial cells (RMECs) injury by increasing oxidative stress, high glucose medium containing differential metabolites was used to induce rat RMECs injury and cell viability, malondialdehyde (MDA) contents, superoxide dismutase (SOD) activities, reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were evaluated in vitro. Network pharmacology was performed to explore the potential mechanism of differential metabolites in inducing DR. RESULTS Through the systematic review, 148 differential metabolites were obtained and the sphingolipid metabolic pathway attracted our attention. Plasma non-targeted lipidomics found that sphingolipids were accompanied by the development of DM into DR. In vitro experiments showed sphinganine and sphingosine-1-phosphate aggravated rat RMECs injury induced by high glucose, further increased MDA and ROS levels, and further decreased SOD activities and MMP. Network pharmacology revealed sphinganine and sphingosine-1-phosphate may induce DR by regulating the AGE-RAGE and HIF-1 signaling pathways. CONCLUSIONS Integrated systematic review, lipidomics and experiment verification reveal that abnormal sphingolipid metabolism facilitates DR by inducing oxidative stress on RMECs. Our study could provide the experimental basis for finding potential biomarkers for the diagnosis and treatment of DR.
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Affiliation(s)
- Zhenshuang Yuan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yue Tian
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Cong Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Mingshuang Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jiaqi Xie
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Can Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Jianmei Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
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11
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Begum F, Manandhar S, Kumar G, Keni R, Sankhe R, Gurram PC, Beegum F, Teja MS, Nandakumar K, Shenoy RR. Dehydrozingerone promotes healing of diabetic foot ulcers: a molecular insight. J Cell Commun Signal 2023; 17:673-688. [PMID: 36280629 PMCID: PMC10409929 DOI: 10.1007/s12079-022-00703-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 09/26/2022] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION One of the most common problems of diabetes are diabetic foot ulcers (DFUs). According to National Institute for Health, initial management of DFUs can decrease the complication of limb amputations and can improve the patient's quality of life. DFU treatment can be optimized with the help of multidisciplinary approach. Based on many studies, control of glucose levels in blood, antioxidant activity, reduction in cytokine levels, re-epithelialization, collagen formation, migration of fibroblasts are major phases involved in managing DFU. Dehydrozingerone (DHZ), has been known for its anti-inflammatory, antioxidant and wound healing properties. METHODOLOGY Three months high-fat diet and low dose of streptozotocin-induced type-II diabetic foot ulcer model was used to evaluate the effectiveness of dehydrozingerone. DHZ was given orally to rats for 15 days post wounding. TNF-α, IL-1β and antioxidant parameters like lipid peroxidation, glutathione reductase were estimated. Immunoblotting was done to investigate the effect of DHZ on the expression of ERK, JNK, HSP-27, P38, SIRT-1, NFκB, SMA, VEGF and MMP-9 in skin tissue. Histopathology was performed for analyzing DHZ effect on migration of fibroblasts, formation of epithelium, granulation tissue formation, angiogenesis and collagen formation. RESULTS DHZ decreased the levels of malondialdehyde, TNF-α, IL-1β and increased glutathione levels in wound tissue. Western blotting results suggested that DHZ activated ERK1/2/JNK/p38 signaling, increased expression of HSP-27, SIRT-1, VEGF, SMA thus facilitating the migration and proliferation of fibroblasts, angiogenesis and decreased inflammation. Masson Trichrome & histopathology showed an increase in collagen, epithelial and granulation tissue formation. CONCLUSION DHZ significantly accelerates the healing of diabetic foot ulcers in high fat diet fed plus low dose streptozotocin induced type-II diabetic Wistar rats.
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Affiliation(s)
- Farmiza Begum
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Suman Manandhar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Gautam Kumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Raghuvir Keni
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Runali Sankhe
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Prasada Chowdari Gurram
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Fathima Beegum
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Meka Sai Teja
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Krishnadas Nandakumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Rekha R Shenoy
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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12
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García Almeida JM, Vegas Aguilar IM, Calleja Fernández A, Porca Fernández C, Casañas Quintana T, Tejera Pérez C, Tinahones Madueño FJ, Bellido Guerrero D. Glycaemic and insulinaemic impact of a diabetes-specific oral nutritional supplement with extra-virgin olive oil in patients with type 2 diabetes mellitus at nutritional risk: a randomized, double-blind, crossover, multicentre clinical trial (DIACARE). NUTR HOSP 2023; 40:692-700. [PMID: 37409714 DOI: 10.20960/nh.04577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2023] Open
Abstract
Introduction Introduction: there is controversy about the usefulness of specific enteral nutrition formulas in malnourished patients with diabetes. The effects on blood glucose and other aspects of metabolic control are not fully understood in the scientific literature. Objective: the aim of the study was to compare the glycaemic and insulinaemic response of patients with type 2 diabetes at risk of malnutrition after oral feed between a diabetes-specific formula with AOVE (DSF) and a standard one (STF). Methods: A randomized, double-blind, crossover, multicentre clinical trial was conducted in patients with type 2 diabetes at risk of malnutrition (SGA). The patients were randomized to receive either DSF or STF, a week apart. A glycaemia and insulinaemia curve was made at times 0 minutes, 30 min, 60 min, 90 min, 120 min, and 180 min after the patients drank 200 ml of the oral nutritional supplement (ONS). The principal variables were the area under the curve (AUC0-t) of glucose and insulin. Results: 29 patients (51 % women) were included, who were on average 68.84 (SD 11.37) years old. Regarding the degree of malnutrition, 86.2 % presented moderate malnutrition (B) and 13.8 % severe (C). When the patients received the DSF, they had a lower mean of glucose AUC0-t (-3,325.34 mg/min/dl [95 % CI: -4,3608.34 to -2,290.07]; p = 0.016) and also a lower mean of insulin AUC0-t (-451.14 uU/min/ml [95 % CI: -875,10 to -27.17]; p = 0.038). There were no differences in the degree of malnutrition. Conclusion: compared with STF, DSF with AOVE showed a better glycaemic and insulinaemic response in patients with type 2 diabetes at risk of malnutrition.
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Affiliation(s)
| | | | | | | | | | - Cristina Tejera Pérez
- Servicio de Endocrinología y Nutrición. Complejo Hospitalario Universitario de Ferrol
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Alharbi AD, Alotayk NI, Alaboudi AA, Alammar AY, Aldekhail MI, Alharbi MA, Alsamel TA, Aljutayli MA, Aljarbou AM, Aljameeli OM. Prevalence and Visual Consequences of Non-adherent Patients Receiving Anti-vascular Endothelial Growth Factor (VEGF) Injections at King Fahad Specialist Hospital (KFSH), Qassim Region. Cureus 2023; 15:e44340. [PMID: 37779785 PMCID: PMC10538945 DOI: 10.7759/cureus.44340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2023] [Indexed: 10/03/2023] Open
Abstract
BACKGROUND Anti-vascular endothelial growth factor (VEGF) injection treatment is a widely utilized therapy for various retinal diseases, including diabetic macular edema (DME). Therefore, the importance of compliance and follow-up should be discussed with the patient. There have been no studies conducted in the Qassim region to estimate the prevalence of patients missing their anti-VEGF appointments. To fulfill this need, we conducted this study to evaluate the compliance rate of patients treated with anti-VEGF injections for DME as well as to determine the visual consequences of the delay in anti-VEGF treatment in the Qassim region. METHODOLOGY This observational retrospective cohort study was conducted at King Fahad Specialist Hospital (KFSH) in the Qassim region of Saudi Arabia. We extracted all file numbers of patients who were using intravitreal anti-VEGF injections to treat DME. The data were managed and analyzed using the IBM Statistical Package for the Social Sciences (SPSS) software (IBM Corp., Armonk, NY, USA). RESULTS In the current study, we were able to collect data from 198 patients who received anti-VEGF treatment in the hospital. Among the participants, 57.6% were male, with a mean age of 61.7 years old (standard deviation (SD) = 10.23). Among the patients, we found that the rate of non-adherence to the anti-VEGF injection was 54.5%, and those patients delayed their scheduled doses for more than 56 days. In 47.5% of the patients, delaying or stopping their appointments had no known reason; however, blepharitis was the main reason for delaying or stopping the dose in 27.7% of the patients, followed by endophthalmitis in 18.7% of the patients. There is no significant difference between before and after stopping the treatment, considering visual acuity (VA) or optical coherence tomography (OCT). However, regarding the disease progression, we found that 15 out of the 30 patients had worsened in the OCT after they missed their injections (mean increase in the VA was 6.069 (SD = 97.45), t = -0.278, P = 0.783, and decrease in the OCT was -14.9667 (SD = 133.87, P = 0.454). CONCLUSION There is a high rate of patients who missed their appointments for an anti-VEGF injection. This resulted in the worsening of OCT in half of the 30 patients who were enrolled in the visual consequences study, which had a negative impact on treatment and disease progression.
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14
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Amorim M, Martins B, Fernandes R. Immune Fingerprint in Diabetes: Ocular Surface and Retinal Inflammation. Int J Mol Sci 2023; 24:9821. [PMID: 37372968 DOI: 10.3390/ijms24129821] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 05/29/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetes is a prevalent global health issue associated with significant morbidity and mortality. Diabetic retinopathy (DR) is a well-known inflammatory, neurovascular complication of diabetes and a leading cause of preventable blindness in developed countries among working-age adults. However, the ocular surface components of diabetic eyes are also at risk of damage due to uncontrolled diabetes, which is often overlooked. Inflammatory changes in the corneas of diabetic patients indicate that inflammation plays a significant role in diabetic complications, much like in DR. The eye's immune privilege restricts immune and inflammatory responses, and the cornea and retina have a complex network of innate immune cells that maintain immune homeostasis. Nevertheless, low-grade inflammation in diabetes contributes to immune dysregulation. This article aims to provide an overview and discussion of how diabetes affects the ocular immune system's main components, immune-competent cells, and inflammatory mediators. By understanding these effects, potential interventions and treatments may be developed to improve the ocular health of diabetic patients.
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Affiliation(s)
- Madania Amorim
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Beatriz Martins
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Rosa Fernandes
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-561 Coimbra, Portugal
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Tarasewicz D, Karter AJ, Pimentel N, Moffet HH, Thai KK, Schlessinger D, Sofrygin O, Melles RB. Development and Validation of a Diabetic Retinopathy Risk Stratification Algorithm. Diabetes Care 2023; 46:1068-1075. [PMID: 36930723 PMCID: PMC10257789 DOI: 10.2337/dc22-1168] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 02/23/2023] [Indexed: 03/19/2023]
Abstract
OBJECTIVE Although diabetic retinopathy is a leading cause of blindness worldwide, diabetes-related blindness can be prevented through effective screening, detection, and treatment of disease. The study goal was to develop risk stratification algorithms for the onset of retinal complications of diabetes, including proliferative diabetic retinopathy, referable retinopathy, and macular edema. RESEARCH DESIGN AND METHODS Retrospective cohort analysis of patients from the Kaiser Permanente Northern California Diabetes Registry who had no evidence of diabetic retinopathy at a baseline diabetic retinopathy screening during 2008-2020 was performed. Machine learning and logistic regression prediction models for onset of proliferative diabetic retinopathy, diabetic macular edema, and referable retinopathy detected through routine screening were trained and internally validated. Model performance was assessed using area under the curve (AUC) metrics. RESULTS The study cohort (N = 276,794) was 51.9% male and 42.1% White. Mean (±SD) age at baseline was 60.0 (±13.1) years. A machine learning XGBoost algorithm was effective in identifying patients who developed proliferative diabetic retinopathy (AUC 0.86; 95% CI, 0.86-0.87), diabetic macular edema (AUC 0.76; 95% CI, 0.75-0.77), and referable retinopathy (AUC 0.78; 95% CI, 0.78-0.79). Similar results were found using a simpler nine-covariate logistic regression model: proliferative diabetic retinopathy (AUC 0.82; 95% CI, 0.80-0.83), diabetic macular edema (AUC 0.73; 95% CI, 0.72-0.74), and referable retinopathy (AUC 0.75; 95% CI, 0.75-0.76). CONCLUSIONS Relatively simple logistic regression models using nine readily available clinical variables can be used to rank order patients for onset of diabetic eye disease and thereby more efficiently prioritize and target screening for at risk patients.
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Affiliation(s)
| | | | - Noel Pimentel
- Division of Research, Kaiser Permanente, Oakland, CA
| | | | - Khanh K. Thai
- Division of Research, Kaiser Permanente, Oakland, CA
| | | | - Oleg Sofrygin
- Division of Research, Kaiser Permanente, Oakland, CA
| | - Ronald B. Melles
- Department of Ophthalmology, The Permanente Medical Group, Oakland, CA
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16
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Advanced Glycation End-Products and Diabetic Neuropathy of the Retina. Int J Mol Sci 2023; 24:ijms24032927. [PMID: 36769249 PMCID: PMC9917392 DOI: 10.3390/ijms24032927] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/29/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Diabetic retinopathy is a tissue-specific neurovascular impairment of the retina in patients with both type 1 and type 2 diabetes. Several pathological factors are involved in the progressive impairment of the interdependence between cells that consist of the neurovascular units (NVUs). The advanced glycation end-products (AGEs) are one of the major pathological factors that cause the impairments of neurovascular coupling in diabetic retinopathy. Although the exact mechanisms for the toxicities of the AGEs in diabetic retinopathy have not been definitively determined, the AGE-receptor of the AGE (RAGE) axis, production of reactive oxygen species, inflammatory reactions, and the activation of the cell death pathways are associated with the impairment of the NVUs in diabetic retinopathy. More specifically, neuronal cell death is an irreversible change that is directly associated with vision reduction in diabetic patients. Thus, neuroprotective therapies must be established for diabetic retinopathy. The AGEs are one of the therapeutic targets to examine to ameliorate the pathological changes in the NVUs in diabetic retinopathy. This review focuses on the basic and pathological findings of AGE-induced neurovascular abnormalities and the potential therapeutic approaches, including the use of anti-glycated drugs to protect the AGE-induced impairments of the NVUs in diabetic retinopathy.
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17
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A Nonrandomized Phase 2 Trial of EG-Mirotin, a Novel, First-in-Class, Subcutaneously Deliverable Peptide Drug for Nonproliferative Diabetic Retinopathy. Medicina (B Aires) 2023; 59:medicina59010178. [PMID: 36676801 PMCID: PMC9862301 DOI: 10.3390/medicina59010178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
Background and objectives: EG-Mirotin (active ingredient EGT022) targets nonproliferative diabetic retinopathy (NPDR), the early stage of retinopathy. EG-Mirotin reverses capillary damage before NPDR progresses to an irreversible stage. EG-Mirotin safety and efficacy were investigated in patients with type 1 or type 2 diabetes mellitus and moderate to severe NPDR. Methods: In this open-label, single-arm, single-center, exploratory phase II study, 10 patients (20 eyes) received EG-Mirotin once a day (3 mg/1.5 mL sterile saline) for 5 days and were evaluated for ischemic index changes and safety. End of study was approximately 8 ± 1 weeks (57 ± 7 days) after the first drug administration. Results: EG-Mirotin injections were well tolerated, with no dose-limiting adverse events, serious adverse events, or deaths. Four treatment-emergent adverse events (TEAEs) unrelated to the investigational drug were observed in 2 out of 10 participants (20%) who had received the investigational drug. The overall average percent change in ischemic index at each evaluation point compared with baseline was statistically significant (Greenhouse-Geisser F = 9.456, p = 0.004 for the main effect of time), and a larger change was observed when the baseline ischemic index value was high (Greenhouse-Geisser F = 10.946, p = 0.002 for time × group interaction). Conclusions: The EG-Mirotin regimen established in this study was shown to be feasible and safe and was associated with a trend toward potential improvement in diabetes-induced ischemia and retinal capillary leakage.
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Wang WM, Ou HT, Wen MJ, Su PF, Yang CY, Kuo TH, Wang MC, Lin WH. Association of retinopathy severity with cardiovascular and renal outcomes in patients with type 1 diabetes: a multi-state modeling analysis. Sci Rep 2022; 12:4177. [PMID: 35264740 PMCID: PMC8907198 DOI: 10.1038/s41598-022-08166-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 02/16/2022] [Indexed: 11/21/2022] Open
Abstract
This study aimed to assess the impact of diabetic retinopathy (DR) severity on the incidence of major adverse cardiac events (MACE) and end-stage renal disease (ESRD) in T1D patients. Patients diagnosed with T1D between 1999 and 2013 were identified from patient-level data of Taiwan’s National Health Insurance Research database. A total of 1135 patients were included and classified into mild DR (n = 454), severe DR (n = 227), or non-DR (n = 454) by using propensity score matching. Multi-state model analyses, an extension of competing risk models with adjustment for transition-specific covariates for prediction of subsequent MACE and ESRD, were performed. MACE and ESRD risks were significantly higher in the severe DR patients; a 2.97-fold (1.73, 5.07) and 12.29-fold (6.50, 23.23) increase in the MACE risk among the severe DR patients compared to the mild DR and DR-free patients, respectively; and, a 5.91-fold (3.50, 9.99) and 82.31-fold (29.07, 233.04) greater ESRD risk of severe DR patients than that of the mild DR and DR-free groups, respectively (p < 0.001). Severity of DR was significantly associated with the late diabetes-related vascular events (i.e., MACE, ESRD) among T1D patients.
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Affiliation(s)
- Wei-Ming Wang
- Department of Statistics and Institute of Data Science, College of Management, National Cheng Kung University, Tainan, Taiwan
| | - Huang-Tz Ou
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Miin-Jye Wen
- Department of Statistics and Institute of Data Science, College of Management, National Cheng Kung University, Tainan, Taiwan.,Institute of International Management, College of Management, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Fang Su
- Department of Statistics and Institute of Data Science, College of Management, National Cheng Kung University, Tainan, Taiwan
| | - Chen-Yi Yang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Te-Hui Kuo
- Department and Institute of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan
| | - Ming-Cheng Wang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan
| | - Wei-Hung Lin
- Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70428, Taiwan. .,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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A Classification Tree Model with Optical Coherence Tomography Angiography Variables to Screen Early-Stage Diabetic Retinopathy in Diabetic Patients. J Ophthalmol 2022; 2022:9681034. [PMID: 35211344 PMCID: PMC8863461 DOI: 10.1155/2022/9681034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/17/2022] [Indexed: 11/25/2022] Open
Abstract
Aim To establish a classification tree model in DR screening and to compare the DR screening accuracy between the classification tree model and the logistic regression model in type 2 diabetes mellitus (T2DM) patients based on OCTA variables. Methods Two hundred forty-one eyes of 241 T2DM patients were included and divided into two groups: the development cohort and the validation cohort. Optical coherence tomography angiography (OCTA) images were acquired in these patients. The data of foveal avascular zone area, superficial capillary plexus (SCP) density, and deep capillary plexus (DCP) density were exported after automatically analyzing the macular 6 × 6 mm OCTA images, while the data of radial peripapillary capillary plexus (RPCP) density was exported after automatically analyzing the optic nerve head 4.5 × 4.5 mm OCTA images. These OCTA variables were adopted to establish and validate the logistic regression model and the classification tree model. The area under the curve (AUC), sensitivity, specificity, and statistical power for receiver operating characteristic curves of two models were calculated. Results In the logistic regression model, best-corrected visual acuity (BCVA) (LogMAR) and SCP density were entered (BVCA : OR= 60.30, 95% CI= [2.40, 1513.82], p = 0.013; SCP density: OR= 0.86, 95% CI= [0.78, 0.96], p = 0.006). The AUC, sensitivity, and specificity for detecting early-stage DR (mild to moderate NPDR) in the development cohort were 0.75 (95% CI: [0.66, 0.85]), 63%, and 83%, respectively. The AUC, sensitivity, and specificity in the validation cohort were 0.75 (95% CI: [0.66, 0.84]), 79%, and 72%, respectively. In the classification tree model, BVCA (LogMAR), DM duration, SCP density, and DCP density were entered. The AUC, sensitivity, and specificity for detecting early-stage DR were 0.72 (95% CI: [0.60, 0.84]), 66%, and 76%, respectively. The AUC, sensitivity, and specificity in the validation cohort were 0.74 (95% CI: [0.65, 0.83]), 74%, and 72%, respectively. The statistical power of the development and validation cohorts in two models was all more than 99%. Conclusions Compared to the logistic regression model, the classification tree model has similar accuracy in predicting early-stage DR. The classification tree model with OCTA variables may be a simple tool for clinical practitioners to identify early-stage DR in T2DM patients. Moreover, SCP density is significantly reduced in mild-to-moderate NPDR eyes and might be a biomarker in early-stage DR detection. Further improvement and validation of the DR diagnostic model are awaiting to be performed.
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20
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Entezari M, Hashemi D, Taheriazam A, Zabolian A, Mohammadi S, Fakhri F, Hashemi M, Hushmandi K, Ashrafizadeh M, Zarrabi A, Ertas YN, Mirzaei S, Samarghandian S. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation. Biomed Pharmacother 2022; 146:112563. [PMID: 35062059 DOI: 10.1016/j.biopha.2021.112563] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 12/16/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus (DM) is considered as a main challenge in both developing and developed countries, as lifestyle has changed and its management seems to be vital. Type I and type II diabetes are the main kinds and they result in hyperglycemia in patients and related complications. The gene expression alteration can lead to development of DM and related complications. The AMP-activated protein kinase (AMPK) is an energy sensor with aberrant expression in various diseases including cancer, cardiovascular diseases and DM. The present review focuses on understanding AMPK role in DM. Inducing AMPK signaling promotes glucose in DM that is of importance for ameliorating hyperglycemia. Further investigation reveals the role of AMPK signaling in enhancing insulin sensitivity for treatment of diabetic patients. Furthermore, AMPK upregulation inhibits stress and cell death in β cells that is of importance for preventing type I diabetes development. The clinical studies on diabetic patients have shown the role of AMPK signaling in improving diabetic complications such as brain disorders. Furthermore, AMPK can improve neuropathy, nephropathy, liver diseases and reproductive alterations occurring during DM. For exerting such protective impacts, AMPK signaling interacts with other molecular pathways such as PGC-1α, PI3K/Akt, NOX4 and NF-κB among others. Therefore, providing therapeutics based on AMPK targeting can be beneficial for amelioration of DM.
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Affiliation(s)
- Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Danial Hashemi
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirhossein Zabolian
- Department of Orthopedics, School of Medicine, 5th Azar Hospital, Golestan University of Medical Sciences, Golestan, Iran
| | - Shima Mohammadi
- Kerman University of Medical Sciences, Kerman 7616913555, Iran
| | - Farima Fakhri
- Kerman University of Medical Sciences, Kerman 7616913555, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonosis, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer 34396, Istanbul, Turkey
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri 38039, Turkey
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Utzschneider KM. Reduced β-cell function and risk of retinopathy: What's the connection? J Diabetes Complications 2022; 36:108045. [PMID: 34802901 DOI: 10.1016/j.jdiacomp.2021.108045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 09/02/2021] [Indexed: 11/30/2022]
Affiliation(s)
- Kristina M Utzschneider
- Research and Development, Department of Medicine, VA Puget Sound Health Care System; Division of metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, United States of America.
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22
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Neurovascular Impairment and Therapeutic Strategies in Diabetic Retinopathy. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 19:ijerph19010439. [PMID: 35010703 PMCID: PMC8744686 DOI: 10.3390/ijerph19010439] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/25/2021] [Accepted: 12/30/2021] [Indexed: 12/15/2022]
Abstract
Diabetic retinopathy has recently been defined as a highly specific neurovascular complication of diabetes. The chronic progression of the impairment of the interdependence of neurovascular units (NVUs) is associated with the pathogenesis of diabetic retinopathy. The NVUs consist of neurons, glial cells, and vascular cells, and the interdependent relationships between these cells are disturbed under diabetic conditions. Clinicians should understand and update the current knowledge of the neurovascular impairments in diabetic retinopathy. Above all, neuronal cell death is an irreversible change, and it is directly related to vision loss in patients with diabetic retinopathy. Thus, neuroprotective and vasoprotective therapies for diabetic retinopathy must be established. Understanding the physiological and pathological interdependence of the NVUs is helpful in establishing neuroprotective and vasoprotective therapies for diabetic retinopathy. This review focuses on the pathogenesis of the neurovascular impairments and introduces possible neurovascular protective therapies for diabetic retinopathy.
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Pöstyéni E, Szabadfi K, Sétáló G, Gabriel R. A Promising Combination: PACAP and PARP Inhibitor Have Therapeutic Potential in Models of Diabetic and Hypertensive Retinopathies. Cells 2021; 10:cells10123470. [PMID: 34943979 PMCID: PMC8700737 DOI: 10.3390/cells10123470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/06/2021] [Accepted: 12/06/2021] [Indexed: 11/16/2022] Open
Abstract
Diabetes and hypertension are complex pathologies with increasing prevalence nowadays. Their interconnected pathways are frequently manifested in retinopathies. Severe retinal consequences and their tight connections as well as their possible treatments are particularly important to retinal research. In the present, work we induced diabetes with streptozotocin in spontaneously hypertensive rats and treated them either with PACAP or olaparib and alternatively with both agents. Morphological and immunohistochemical analyses were carried out to describe cell-specific changes during pathologies and after different treatments. Diabetes and hypertension caused massive structural and cellular changes especially when they were elicited together. Hypertension was crucial in the formation of ONL and OPL damage while diabetes caused significant differences in retinal thickness, OPL thickness and in the cell number of the GCL. In diabetes, double neuroprotective treatment ameliorated changes of calbindin-positive cells, rod bipolar cells and dopaminergic amacrine cells. Double treatment was curative in hypertensive diabetic rat retinas, especially in the case of rod bipolar and parvalbumin-positive cells compared to untreated or single-treated retinas. Our results highlighted the promising therapeutic benefits of olaparib and PACAP in these severe metabolic retinal disorders.
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Affiliation(s)
- Etelka Pöstyéni
- Department of Experimental Zoology and Neurobiology, University of Pécs, 7624 Pécs, Hungary; (E.P.); (K.S.)
| | - Krisztina Szabadfi
- Department of Experimental Zoology and Neurobiology, University of Pécs, 7624 Pécs, Hungary; (E.P.); (K.S.)
| | - György Sétáló
- Department of Medical Biology, Medical School, University of Pécs, 7624 Pécs, Hungary;
| | - Robert Gabriel
- Department of Experimental Zoology and Neurobiology, University of Pécs, 7624 Pécs, Hungary; (E.P.); (K.S.)
- Correspondence:
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24
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Awareness of Diabetic Retinopathy: Insight From the National Health and Nutrition Examination Survey. Am J Prev Med 2021; 61:900-909. [PMID: 34426057 PMCID: PMC8608699 DOI: 10.1016/j.amepre.2021.05.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION This study determines the prevalence and associated correlates of people unaware of their diabetic retinopathy diagnosis in the U.S. METHODS Participants unaware of diabetic retinopathy from the National Health and Nutrition Examination Survey from 2005 to 2008 were identified. The prevalence of those unaware of their diabetic retinopathy diagnosis was determined. Descriptive statistics and logistic regression were used to determine correlates associated with being unaware of one's diabetic retinopathy diagnosis (completed in 2018‒2020). RESULTS Among 5,563 participants aged ≥40 years who underwent fundus photography, the prevalence of those unaware of their diabetic retinopathy diagnosis was 10.6% (9.8 million). This included 23.1% of those with self-reported diabetes (2.9 million) and 6.8% of those who reported not having diabetes (6.9 million). Among participants reporting diabetes with photographic evidence of retinopathy, 70.1% were unaware. Among individuals with self-reported diabetes, correlates of being unaware of one's diabetic retinopathy diagnosis included diabetes diaganosis for ≥10 years (OR=3.15, 95% CI=1.78, 5.56), HbA1c ≥6.5% (OR=2.92, 95% CI=1.65, 5.18), and treatment with insulin only (OR=4.04, 95% CI=1.43, 11.39). Self-reported hypertension was associated with decreased odds of undiagnosed diabetic retinopathy (OR=0.48, 95% CI=0.28, 0.82). Among those without self-reported diabetes, correlates of being unaware of diabetic retinopathy included older age (OR=1.02, 95% CI=1.01, 1.04), male sex (OR=1.83, 95% CI=1.31, 2.56), Black race (OR=1.81, 95% CI=1.12, 2.92), Hispanic race/ethnicity (OR=1.60, 95% CI=1.14, 2.25), elevated blood pressure (OR=1.54, 95% CI=1.23, 1.93), current smoking (OR=1.74, 95% CI=1.21, 2.51), and history of stroke (OR=2.20, 95% CI=1.06, 4.58). CONCLUSIONS A substantial proportion of individuals with diabetic retinopathy are unaware of the diagnosis. These data provide a path toward refining efforts to diagnose and treat diabetic retinopathy to decrease the burden of preventable blindness.
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Palma F, Camacho P. The role of Optical Coherence Tomography Angiography to detect early microvascular changes in Diabetic Retinopathy: a systematic review. J Diabetes Metab Disord 2021; 20:1957-1974. [PMID: 34900835 PMCID: PMC8630307 DOI: 10.1007/s40200-021-00886-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/22/2021] [Indexed: 12/18/2022]
Abstract
PURPOSE To evaluate quantitative parafoveal microvascular changes using Optical Coherence Tomography Angiography (OCTA) by comparing the area of foveal avascular zone (FAZ) and vessel density (VD) between nondiabetic controls and patients with different levels of Diabetic Retinopathy (DR). METHODS A systematic review was performed according to the recommendations of the "Cochrane Handbook for Systematic Reviews of Interventions" and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Three electronic databases including PubMed, Web of Science and Cochrane Library were systematically retrieved by using key terms with Boolean operators. The data extracted from each study included: first author, year of publication, study design, sample size and participant characteristics (mean age, type of diabetes mellitus and mean duration of diabetic disease). Outcome variables included: VD and area of FAZ, in superficial and deep capillary plexuses of parafovea. RESULTS 355 articles were identified from our search of databases and 10 studies were included in this systematic review. Patients with diabetes with or without clinical signs of DR have a significantly enlarged area of FAZ and decreased parafoveal VD compared to healthy controls, as well as an association between these microvascular changes and worsening DR. CONCLUSION OCTA can provide valuable information about early and subtle microvascular changes of parafoveal capillary plexuses in patients with diabetes and can identify preclinical DR before the manifestation of clinically apparent retinopathy. The non-invasive nature of OCTA allows routine imaging of the retinal vasculature, so this approach may be a promising tool for screening programmes of DR.
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Affiliation(s)
- Filipa Palma
- ESTeSL- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, Lisbon, Portugal
| | - Pedro Camacho
- H&TRC- Health & Technology Research Center, ESTeSL- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, Lisbon, Portugal
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Effect of type 2 diabetes on Gd-EOB-DTPA uptake into liver parenchyma: replication study in human subjects. Abdom Radiol (NY) 2021; 46:4682-4688. [PMID: 34164726 DOI: 10.1007/s00261-021-03184-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/13/2021] [Accepted: 06/14/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is a contrast agent for magnetic resonance imaging (MRI), which specifically taken up by hepatocytes through organic anion-transporting polypeptides (OATPs). Previous research in mice has shown that type 2 diabetes is associated with reduced uptake of Gd-EOB-DTPA into the liver parenchyma, reflecting reduced expression of OATP. Since considerable differences in OATP expression exist between mice and humans, human studies are necessary to clarify the effect of diabetes to Gd-EOB-DTPA uptake. The purpose of this study was to validate the effect of diabetes to Gd-EOB-DTPA liver uptake by a confirmatory study in humans. METHODS Patients who underwent Gd-EOB-DTPA-enhanced MRI were retrospectively reviewed and divided into two groups: severe or uncontrolled diabetic group (patients with insulin therapy and/or HbA1c ≥ 8.4%) and the control group. Liver-to-spleen ratio (LSR) and relative enhancement of the liver (REL) were calculated to represent Gd-EOB-DTPA liver uptake. RESULTS A total of 94 patients fulfilled the criteria. The severe or uncontrolled diabetic group (n = 15) showed significantly lower LSR (1.74 ± 0.26 vs. 1.98 ± 0.31, p = 0.007) and REL (0.69 ± 0.23 vs. 0.87 ± 0.31, p = 0.005), compared to the control group (n = 79). CONCLUSION Our study revealed decreased uptake of Gd-EOB-DTPA into liver parenchyma in the severe or uncontrolled diabetic patients. Further studies to determine the impact of the reduced liver enhancement on clinical diagnostic practice will be needed.
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Mkhombe NF, Clarke-Farr P. Diabetic retinopathy and retinal screening awareness amongst female diabetic patients at a day hospital diabetic clinic in Cape Town, South Africa. AFRICAN VISION AND EYE HEALTH 2021. [DOI: 10.4102/aveh.v80i1.614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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Silva VAO, André ND, E Sousa TA, Alves VM, Do Carmo Kettelhut I, De Lucca FL. Nuclear PKR in retinal neurons in the early stage of diabetic retinopathy in streptozotocin‑induced diabetic rats. Mol Med Rep 2021; 24:614. [PMID: 34184090 PMCID: PMC8258468 DOI: 10.3892/mmr.2021.12253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 02/16/2021] [Indexed: 01/01/2023] Open
Abstract
Retinal neuron apoptosis is a key component of diabetic retinopathy (DR), one of the most common complications of diabetes. Stress due to persistent hyperglycaemia and corresponding glucotoxicity represents one of the primary pathogenic mechanisms of diabetes and its complications. Apoptosis of retinal neurons serves a critical role in the pathogenesis of DR observed in patients with diabetes and streptozotocin (STZ)‑induced diabetic rats. Retinal neuron apoptosis occurs one month after STZ injection, which is considered the early stage of DR. The molecular mechanism involved in the suppression of retinal neuron apoptosis during the early stage of DR remains unclear. RNA‑dependent protein kinase (PKR) is a stress‑sensitive pro‑apoptotic kinase. Our previous study indicated that PKR‑associated protein X, a stress‑sensitive activator of PKR, is upregulated in the early stage of STZ‑induced diabetes. In order to assess the role of PKR in DR prior to apoptosis of retinal neurons, immunofluorescence and western blotting were performed to investigate the cellular localization and expression of PKR in the retina in the early stage of STZ‑induced diabetes in rats. PKR activity was indirectly assessed by expression levels of phosphorylated eukaryotic translation initiation factor 2α (p‑eIF2‑α) and the presence of apoptotic cells in the retina was investigated by TUNEL assay. The findings revealed that PKR was localized in the nucleus of retinal ganglion and inner nuclear layer cells from normal and diabetic rats. To the best of our knowledge, the present study is the first to demonstrate nuclear localization of PKR in retinal neurons. Immunofluorescence analysis demonstrated that PKR was expressed in the nuclei of retinal neurons at 3 and 6 days and its expression was decreased at 15 days after STZ treatment. In addition, p‑eIF2‑α expression and cellular localization followed the trend of PKR, suggesting that this pro‑apoptotic kinase was active in the nuclei of retinal neurons. These findings are consistent with the hypothesis that nuclear translocation of PKR may be a mechanism to sequester active PKR, thus preventing upregulation of cytosolic signalling pathways that induce apoptosis in retinal neurons. Apoptotic cells were not detected in the retina in the early stage of DR. A model was proposed to explain the mechanism by which apoptosis of retinal neurons by PKR is suppressed in the early stage of DR. The possible role of mitochondrial RNA (mtRNA) and Alu RNA in this phenomenon is also discussed since it was demonstrated that the cellular stress due to prolonged hyperglycaemia induces the release of mtRNA and transcription of Alu RNA. Moreover, it mtRNA activates PKR, whereas Alu RNA inhibits the activation of this protein kinase.
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Affiliation(s)
| | | | - Thaís Amaral E Sousa
- Federal Institute of Education, Science and Technology of Goiás, Formosa, Goiás 73813-816, Brazil
| | - Vâni Maria Alves
- Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil
| | - Isis Do Carmo Kettelhut
- Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil
| | - Fernando Luiz De Lucca
- Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil
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Wu JH, Liu TYA, Hsu WT, Ho JHC, Lee CC. Performance and Limitation of Machine Learning Algorithms for Diabetic Retinopathy Screening: Meta-analysis. J Med Internet Res 2021; 23:e23863. [PMID: 34407500 PMCID: PMC8406115 DOI: 10.2196/23863] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 11/19/2020] [Accepted: 04/30/2021] [Indexed: 12/23/2022] Open
Abstract
Background Diabetic retinopathy (DR), whose standard diagnosis is performed by human experts, has high prevalence and requires a more efficient screening method. Although machine learning (ML)–based automated DR diagnosis has gained attention due to recent approval of IDx-DR, performance of this tool has not been examined systematically, and the best ML technique for use in a real-world setting has not been discussed. Objective The aim of this study was to systematically examine the overall diagnostic accuracy of ML in diagnosing DR of different categories based on color fundus photographs and to determine the state-of-the-art ML approach. Methods Published studies in PubMed and EMBASE were searched from inception to June 2020. Studies were screened for relevant outcomes, publication types, and data sufficiency, and a total of 60 out of 2128 (2.82%) studies were retrieved after study selection. Extraction of data was performed by 2 authors according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), and the quality assessment was performed according to the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Meta-analysis of diagnostic accuracy was pooled using a bivariate random effects model. The main outcomes included diagnostic accuracy, sensitivity, and specificity of ML in diagnosing DR based on color fundus photographs, as well as the performances of different major types of ML algorithms. Results The primary meta-analysis included 60 color fundus photograph studies (445,175 interpretations). Overall, ML demonstrated high accuracy in diagnosing DR of various categories, with a pooled area under the receiver operating characteristic (AUROC) ranging from 0.97 (95% CI 0.96-0.99) to 0.99 (95% CI 0.98-1.00). The performance of ML in detecting more-than-mild DR was robust (sensitivity 0.95; AUROC 0.97), and by subgroup analyses, we observed that robust performance of ML was not limited to benchmark data sets (sensitivity 0.92; AUROC 0.96) but could be generalized to images collected in clinical practice (sensitivity 0.97; AUROC 0.97). Neural network was the most widely used method, and the subgroup analysis revealed a pooled AUROC of 0.98 (95% CI 0.96-0.99) for studies that used neural networks to diagnose more-than-mild DR. Conclusions This meta-analysis demonstrated high diagnostic accuracy of ML algorithms in detecting DR on color fundus photographs, suggesting that state-of-the-art, ML-based DR screening algorithms are likely ready for clinical applications. However, a significant portion of the earlier published studies had methodology flaws, such as the lack of external validation and presence of spectrum bias. The results of these studies should be interpreted with caution.
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Affiliation(s)
- Jo-Hsuan Wu
- Shiley Eye Institute and Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, United States
| | - T Y Alvin Liu
- Retina Division, Wilmer Eye Institute, The Johns Hopkins Medicine, Baltimore, MD, United States
| | - Wan-Ting Hsu
- Harvard TH Chan School of Public Health, Boston, MA, United States
| | | | - Chien-Chang Lee
- Health Data Science Research Group, National Taiwan University Hospital, Taipei, Taiwan.,The Centre for Intelligent Healthcare, National Taiwan University Hospital, Taipei, Taiwan.,Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Mudaliar S, Hupfeld C, Chao DL. SGLT2 Inhibitor-Induced Low-Grade Ketonemia Ameliorates Retinal Hypoxia in Diabetic Retinopathy-A Novel Hypothesis. J Clin Endocrinol Metab 2021; 106:1235-1244. [PMID: 33512450 DOI: 10.1210/clinem/dgab050] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Indexed: 02/03/2023]
Abstract
Diabetic retinopathy (DR) is a well-recognized microvascular complication of diabetes. Growing evidence suggests that, in addition to retinal vascular damage, there is significant damage to retinal neural tissue in DR. Studies reveal neuronal damage before clinically evident vascular lesions and DR is now classified as a neurovascular complication. Hyperglycemia causes retinal damage through complex metabolic pathways leading to oxidative stress, inflammation, vascular damage, capillary ischemia, and retinal tissue hypoxia. Retinal hypoxia is further worsened by high oxygen consumption in the rods. Persistent hypoxia results in increases in vascular endothelial growth factor (VEGF) and other pro-angiogenic factors leading to proliferative DR/macular edema and progressive visual impairment. Optimal glucose control has favorable effects in DR. Other treatments for DR include laser photocoagulation, which improves retinal oxygenation by destroying the high oxygen consuming rods and their replacement by low oxygen consuming glial tissue. Hypoxia is a potent stimulator of VEGF, and intravitreal anti-VEGF antibodies are effective in regressing macular edema and in some studies, retinal neovascularization. In this review, we highlight the complex pathophysiology of DR with a focus on retinal oxygen/fuel consumption and hypoxic damage to retinal neurons. We discuss potential mechanisms through which sodium-glucose cotransporter 2 (SGLT2) inhibitors improve retinal hypoxia-through ketone bodies, which are energetically as efficient as glucose and yield more ATP per molecule of oxygen consumed than fat, with less oxidative stress. Retinal benefits would occur through improved fuel energetics, less hypoxia and through the anti-inflammatory/oxidative stress effects of ketone bodies. Well-designed studies are needed to explore this hypothesis.
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Affiliation(s)
- Sunder Mudaliar
- Veterans Affairs Medical Center, San Diego, CA, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - Christopher Hupfeld
- Veterans Affairs Medical Center, San Diego, CA, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - Daniel L Chao
- Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California, San Diego School of Medicine, San Diego, CA, USA
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Miller WP, Sunilkumar S, Dennis MD. The stress response protein REDD1 as a causal factor for oxidative stress in diabetic retinopathy. Free Radic Biol Med 2021; 165:127-136. [PMID: 33524531 PMCID: PMC7956244 DOI: 10.1016/j.freeradbiomed.2021.01.041] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/12/2022]
Abstract
Diabetic Retinopathy (DR) is a major cause of visual dysfunction, yet much remains unknown regarding the specific molecular events that contribute to diabetes-induced retinal pathophysiology. Herein, we review the impact of oxidative stress on DR, and explore evidence that supports a key role for the stress response protein regulated in development and DNA damage (REDD1) in the development of diabetes-induced oxidative stress and functional defects in vision. It is well established that REDD1 mediates the cellular response to a number of diverse stressors through repression of the central metabolic regulator known as mechanistic target of rapamycin complex 1 (mTORC1). A growing body of evidence also supports that REDD1 acts independent of mTORC1 to promote oxidative stress by both enhancing the production of reactive oxygen species and suppressing the antioxidant response. Collectively, there is strong preclinical data to support a key role for REDD1 in the development and progression of retinal complications caused by diabetes. Furthermore, early proof-of-concept clinical trials have found a degree of success in combating ischemic retinal disease through intravitreal delivery of an siRNA targeting the REDD1 mRNA. Overall, REDD1-associated signaling represents an intriguing target for novel clinical therapies that go beyond addressing the symptoms of diabetes by targeting the underlying molecular mechanisms that contribute to DR.
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Affiliation(s)
- William P Miller
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Siddharth Sunilkumar
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Michael D Dennis
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, 17033, USA; Department of Ophthalmology, Penn State College of Medicine, Hershey, PA, 17033, USA.
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Jin S, Xia N, Han L. Association between serum fibroblast growth factor 21 level and sight-threatening diabetic retinopathy in Chinese patients with type 2 diabetes. BMJ Open Diabetes Res Care 2021; 9:9/1/e002126. [PMID: 33789910 PMCID: PMC8016097 DOI: 10.1136/bmjdrc-2021-002126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/25/2021] [Accepted: 03/06/2021] [Indexed: 01/03/2023] Open
Abstract
INTRODUCTION We conducted this cross-sectional study to explore the relationship between serum fibroblast growth factor 21 (FGF21) level and sight-threatening diabetic retinopathy (STDR). RESEARCH DESIGN AND METHODS A total of 654 patients with type 2 diabetes were recruited. Diabetic retinopathy (DR) was evaluated by the bilateral retinal photography, and patients were assigned into groups of no DR (NDR) (n=345, 52.75%), non-sight-threatening diabetic retinopathy (NSTDR) (n=207, 31.65%), involving patients with mild or moderate non-proliferative retinopathy (NPDR) and STDR (n=102, 15.60%), including those with severe NPDR or proliferative diabetic retinopathy (PDR). Serum FGF21 levels were quantified by a sandwich ELISA. Patients were divided into quartiles according to their serum FGF21 level. RESULTS There was a significant difference in serum FGF21 level among the three groups of patients (p<0.01). Compared with other quartiles (Q1-Q3), the patients in Q4 had a higher prevalence of DR and STDR (p<0.05). Compared with Q1, a positive association was observed between serum FGF21 level and DR in Q3 and Q4 (p<0.01). After adjusting for age, gender and other risk factors, serum FGF21 level in Q4 was found to be associated with increased risk of DR and STDR (p<0.01). Serum FGF21 level was noted as an independent risk factor for DR and STDR (p<0.01). Serum FGF21 level >478.76 pg/mL suggested the occurrence of DR and that level >554.69 pg/mL indicated STDR (p<0.01). CONCLUSIONS Serum FGF21 level was a biomarker for the risk of developing DR or STDR. The risk of STDR increased when the serum FGF21 level of patients with type 2 diabetes was >554.69 pg/mL.
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Affiliation(s)
- Shi Jin
- Department of Endocrinology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Ning Xia
- Department of Ophthalmology, the Fourth People's Hospital of Shenyang, Shenyang, China
| | - Lingling Han
- Department of Endocrinology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China
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Abstract
Diabetic retinopathy remains a leading cause of blindness despite recent advance in therapies. Traditionally, this complication of diabetes was viewed predominantly as a microvascular disease but research has pointed to alterations in ganglion cells, glia, microglia, and photoreceptors as well, often occurring without obvious vascular damage. In neural tissue, the microvasculature and neural tissue form an intimate relationship with the neural tissue providing signaling cues for the vessels to form a distinct barrier that helps to maintain the proper neuronal environment for synaptic signaling. This relationship has been termed the neurovascular unit (NVU). Research is now focused on understanding the cellular and molecular basis of the neurovascular unit and how diabetes alters the normal cellular communications and disrupts the cellular environment contributing to loss of vision in diabetes.
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Affiliation(s)
- David A Antonetti
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
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Zhou Y, Li H, Luo L, Chen Y, Chen Q, Bian W, Yang Y, Tang J. Acupoint injection therapy for diabetic retinopathy: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e24119. [PMID: 33429782 PMCID: PMC7793313 DOI: 10.1097/md.0000000000024119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a common diabetic microvascular complication, and it is also the main cause of blindness in adults. At present, some studies have reported acupoint injection for the treatment of DR. However, the effectiveness and safety are still uncertain. This study aims to evaluate the efficacy and safety of acupoint injection for the treatment of patients with DR. METHODS The databases of English databases (PubMed, Embase, Cochrane Library, Web of Science) and Chinese databases (China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, and Chinese Biomedical Literatures Database) will be retrieved. Published randomized controlled trials and quasi-randomized controlled trials on the topic will be retrieved by 2 investigators independently. We will apply a fixed-effect model or random effect model basis on the heterogeneity test and employ with RevMan 5.3 software for data synthesis. The total effective rate will be selected as the primary outcome, visual acuity, hemorrhage areas, exudates, capillary nonperfusion areas, hemorheological indicators, mean defect of visual field, glycated hemoglobin, and adverse events as secondary outcomes. RESULTS This study will comprehensively summarize the high-quality trials to determine the effectiveness and safety of acupoint injection treatment for patients with DR. CONCLUSION The systematic review of this study will summarize the currently published evidence of acupoint injection treatment for DR to further guide its promotion and application. PROTOCOL REGISTRATION NUMBER INPLASY2020110026.
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Affiliation(s)
- Yanni Zhou
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
| | - Hui Li
- Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou
| | - Lisi Luo
- Guangzhou First People's Hospital, Guangzhou, Guangdong Province
| | - Yue Chen
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
| | - Qiang Chen
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
| | - Wei Bian
- Chongqing Yongchuan Traditional Chinese Medicine Hospital, Chongqing, China
| | - Yanlin Yang
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
| | - Ju Tang
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
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Xue P, Covassin N, Ran X, Zhou J, Zhang X, Yan D, Li X, Gao Y, Tang X. Association of parameters of nocturnal hypoxemia with diabetic microvascular complications: A cross-sectional study. Diabetes Res Clin Pract 2020; 170:108484. [PMID: 33031843 DOI: 10.1016/j.diabres.2020.108484] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 07/28/2020] [Accepted: 09/25/2020] [Indexed: 02/08/2023]
Abstract
AIMS To examine the association between obstructive sleep apnea (OSA)-related nocturnal hypoxemia parameters and diabetic microvascular complications in patients with type 2 diabetes mellitus (T2DM). METHODS A total of 463 Chinese patients with T2DM underwent overnight polysomnography, followed by diagnosis of diabetic microvascular complications including diabetic peripheral neuropathy (DPN), diabetic retinopathy (DR) and diabetic nephropathy (DN). Parameters of nocturnal hypoxemia, including apnea-hypopnea index (AHI), oxygen desaturation index (ODI), time spent with SpO2 < 90% (T90%) or <85% (T85%), mean SpO2 and lowest SpO2, were recorded. RESULTS AHI was independently associated with higher odds of DPN (OR 1.19; 95% CI, 1.05-1.36; P = 0.008) after adjustment for possible confounders. Moreover, patients with severe OSA (AHI ≥ 30 events/h) had higher likelihood of having DPN than those with mild OSA (OR 2.36; 95% CI, 1.31-4.25; P = 0.004). When combining DPN, DR and DN into an overall diabetic microvascular complication index, AHI was also independently associated with higher odds of having any diabetic microvascular complication (OR 1.21; 95% CI, 1.06-1.38; P = 0.006). CONCLUSIONS The AHI may be the OSA-related index that most strongly reflects the association of OSA and diabetic microvascular complications, compared with other OSA-related hypoxemia parameters.
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Affiliation(s)
- Pei Xue
- Sleep Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Naima Covassin
- Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, USA.
| | - Xingwu Ran
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Junying Zhou
- Sleep Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaohan Zhang
- Johns Hopkins University School of Medicine, Baltimore, USA
| | - Donge Yan
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiao Li
- Sleep Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yun Gao
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Xiangdong Tang
- Sleep Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Scisciola L, Rizzo MR, Cataldo V, Fontanella RA, Balestrieri ML, D'Onofrio N, Marfella R, Paolisso G, Barbieri M. Incretin drugs effect on epigenetic machinery: New potential therapeutic implications in preventing vascular diabetic complications. FASEB J 2020; 34:16489-16503. [PMID: 33090591 DOI: 10.1096/fj.202000860rr] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 09/25/2020] [Accepted: 10/06/2020] [Indexed: 11/11/2022]
Abstract
The effect of GLP-1R agonists on DNA methylation levels of NF-κB and SOD2 genes in human aortic endothelial cells exposed to high glucose and in diabetic patients treated and not with incretin-based drugs, was evaluated. Methylation levels, mRNA and protein expression of NF-κB and SOD2 genes were measured in human endothelial cells exposed to high glucose for 7 days and treated with GLP-1R agonists. Methylation status of NF-κB and SOD2 promoter was also analyzed in 128 diabetics and 116 nondiabetics and correlated with intima media thickness (ITM), an early marker of atherosclerotic process. Cells exposed to high glucose showed lower NF-κB and SOD2 methylation levels, increased NF-κB and reduced SOD2 expression compared to normal glucose cells. Co-treatment with GLP-1 agonists prevented methylation and genes expression changes induced by high glucose. Both high glucose and incretins exposure increased DNA methyltransferases and demethylases levels. In diabetics, incretin treatment resulted a significant predictor of NF-κB DNA methylation, independently of age, sex, body mass index (BMI), glucose and plasma lipid levels. NF-κB DNA methylation inversely correlated with IMT after adjusting for multiple covariates. Our results firstly provide new evidences of an additional mechanism by which incretin drugs could prevent vascular diabetic complications.
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Affiliation(s)
- Lucia Scisciola
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Rosaria Rizzo
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Vittoria Cataldo
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Rosaria Anna Fontanella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Nunzia D'Onofrio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Paolisso
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michelangela Barbieri
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Singh R, Chandel S, Dey D, Ghosh A, Roy S, Ravichandiran V, Ghosh D. Epigenetic modification and therapeutic targets of diabetes mellitus. Biosci Rep 2020; 40:BSR20202160. [PMID: 32815547 PMCID: PMC7494983 DOI: 10.1042/bsr20202160] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 08/07/2020] [Accepted: 08/17/2020] [Indexed: 12/11/2022] Open
Abstract
The prevalence of diabetes and its related complications are increasing significantly globally. Collected evidence suggested that several genetic and environmental factors contribute to diabetes mellitus. Associated complications such as retinopathy, neuropathy, nephropathy and other cardiovascular complications are a direct result of diabetes. Epigenetic factors include deoxyribonucleic acid (DNA) methylation and histone post-translational modifications. These factors are directly related with pathological factors such as oxidative stress, generation of inflammatory mediators and hyperglycemia. These result in altered gene expression and targets cells in the pathology of diabetes mellitus without specific changes in a DNA sequence. Environmental factors and malnutrition are equally responsible for epigenetic states. Accumulated evidence suggested that environmental stimuli alter the gene expression that result in epigenetic changes in chromatin. Recent studies proposed that epigenetics may include the occurrence of 'metabolic memory' found in animal studies. Further study into epigenetic mechanism might give us new vision into the pathogenesis of diabetes mellitus and related complication thus leading to the discovery of new therapeutic targets. In this review, we discuss the possible epigenetic changes and mechanism that happen in diabetes mellitus type 1 and type 2 separately. We highlight the important epigenetic and non-epigenetic therapeutic targets involved in the management of diabetes and associated complications.
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Affiliation(s)
- Rajveer Singh
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Shivani Chandel
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Dhritiman Dey
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Arijit Ghosh
- Department of Chemistry, University of Calcutta, Kolkata 700009, India
| | - Syamal Roy
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Velayutham Ravichandiran
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Dipanjan Ghosh
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
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Petrachkov DV, Budzinskaya MV, Arzhukhanov DD. [The role of internal limiting membrane peeling in the treatment of diabetic macular edema]. Vestn Oftalmol 2020; 136:359-366. [PMID: 32880162 DOI: 10.17116/oftalma2020136042359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Analysis of the current understanding of the role of internal limiting membrane in the pathogenesis of diabetic macular edema and the feasibility of its surgical removal is based on data from domestic and international literature on pathogenesis, clinical manifestations, outcomes of multicenter studies of treatment and prognosis of this disease. The advantages and disadvantages of both peeling and preservation of the inner limiting membrane are described. The limitations and inconsistencies of data provided by the authors of each theory requires more complete functional studies in the pre- and postoperative periods, increasing the selection of patients, modifying the criteria for inclusion in groups, and microscopic examination of removed membranes. Thus, this issue requires further study due to the ambiguity of the conclusions and the lack of comparative data on the long-term prospects of each of the methods.
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Lutein and zeaxanthin attenuates VEGF-induced neovascularisation in human retinal microvascular endothelial cells through a Nox4-dependent pathway. Exp Eye Res 2020; 197:108104. [PMID: 32522479 DOI: 10.1016/j.exer.2020.108104] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/15/2020] [Accepted: 06/01/2020] [Indexed: 01/08/2023]
Abstract
Age-related macular degeneration (AMD) and proliferative diabetic retinopathy (DR) are two of the most common and severe causes of vision loss in the population. Both conditions are associated with excessive levels of vascular endothelial growth factor (VEGF) in the eye which results in an increase in the formation of new blood vessels through a process called neovascularisation. As such, anti-VEGF therapies are currently utilised as a treatment for patients with AMD however they are associated with painful administration of injections and potential degeneration of healthy endothelium. There is therefore growing interest in alternate treatment options to reduce neovascularisation in the eye. The use of carotenoids, lutein (L) and zeaxanthin (Z), has been shown to improve vision loss parameters in patients with AMD, however the underlying mechanisms are not well-understood. We studied the impact of these compounds on neovascularisation processes using an in vitro cell model of the retinal microvascular endothelium. Our findings show that L and Z reduced VEGF-induced tube formation whilst, in combination (5:1 ratio), the compounds significantly blocked VEGF-induced neovascularisation. The carotenoids, individually and in combination, reduced VEGF-induced oxidative stress concomitant with increased activity of the NADPH oxidase, Nox4. We further demonstrated that the Nox4 inhibitor, GLX7013114, attenuated the protective effect of L and Z. Taken together, these findings indicate the protective effect of the carotenoids, L and Z, in reducing VEGF-mediated neovascularisation via a Nox4-dependent pathway. These studies implicate the potential for these compounds to be used as a therapeutic approach for patients suffering from AMD and proliferative DR.
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Stefanowicz-Rutkowska MM, Matuszewski W, Bandurska-Stankiewicz EM. Autoimmune Thyroid Disease is Associated with a Lower Prevalence of Diabetic Retinopathy in Patients with Type 1 Diabetic Mellitus. Medicina (B Aires) 2020; 56:medicina56060255. [PMID: 32466561 PMCID: PMC7353863 DOI: 10.3390/medicina56060255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/12/2020] [Accepted: 05/21/2020] [Indexed: 12/30/2022] Open
Abstract
Background and objectives: The aim of the study was to assess the correlation of autoimmune thyroid diseases (AITD) in patients with diabetes mellitus type 1 (DM1) with the occurrence of diabetic retinopathy (DR). Materials and Methods: The inclusion criteria for the study were: type 1 diabetes diagnosed on the basis of WHO criteria lasting at least a year, presence of AITD for at least a year, and age over 18 years. The control group consisted of patients without diagnosed AITD (DM1noAITD), selected according to age, BMI and DM1 duration. Anthropometric parameters, metabolic risk factors such as glycated hemoglobin (HbA1c), lipids and blood pressure, thyroid status and the presence of DR were assessed. Results: The study involved 200 patients with type 1 diabetes aged 36 ± 12 years, 70 men and 130 women. Patients from the study group (DM1AITD) had significantly lower creatinine concentration, significantly lower systolic blood pressure (SBP), glycated hemoglobin (HbA1c) percentage and triglyceride (TG) concentration, and higher high-density lipoprotein (HDL-cholesterol) concentration than the control group (DM1noAITD). There was a significantly lower chance of non-proliferative diabetic retinopathy (NPDR) among DM1AITD than in the control group. Conclusions: Patients with DM1 and AITD were metabolically better balanced, as evidenced by a significantly lower SBP, percentage of HbA1c and TG, as well as significantly higher HDL-cholesterol in this group. Patients with DM1 and AITD were significantly less likely to have NPDR than the control group.
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Ellis MP, Bacorn C, Luu KY, Lee SC, Tran S, Lillis C, Lim MC, Yiu G. Cost Analysis of Teleophthalmology Screening for Diabetic Retinopathy Using Teleophthalmology Billing Codes. Ophthalmic Surg Lasers Imaging Retina 2020; 51:S26-S34. [PMID: 32484898 DOI: 10.3928/23258160-20200108-04] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 03/02/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND OBJECTIVE To evaluate the financial sustainability of teleophthalmology screening for diabetic retinopathy (DR) using telehealth billing codes. PATIENTS AND METHODS The authors performed an Institutional Review Board-approved retrospective review of medical records, billing data, and quality metrics at the University of California Davis Health System from patients screened for DR through an internal medicine-based telemedicine program using CPT codes 92227 or 92228. RESULTS A total of 290 patients received teleophthalmology screening over a 12-month period, resulting in an increase in the DR screening rate from 49% to 63% (P < .0001). The average payment per patient was $19.86, with an estimated cost of $41.02 per patient. The projected per-patient incentive bonus was $43.06 with a downstream referral revenue of $39.38 per patient. One hundred seventy-eight clinic visits were eliminated, providing an estimated cost savings of $42.53 per patient. CONCLUSION Sustainable teleophthalmology screening may be achieved by billing telehealth codes but only with health care incentive bonuses, patient referrals, and by accounting for the projected cost-savings of eliminating office visits. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:S26-S34.].
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Mamillapalli CK, Prentice JR, Garg AK, Hampsey SL, Bhandari R. Implementation and challenges unique to teleretinal diabetic retinal screening (TDRS) in a private practice setting in the United States. J Clin Transl Endocrinol 2020; 19:100214. [PMID: 31956513 PMCID: PMC6957819 DOI: 10.1016/j.jcte.2019.100214] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 12/08/2019] [Accepted: 12/19/2019] [Indexed: 11/26/2022] Open
Abstract
PURPOSE Adherence rates to published guidelines for diabetic retinopathy (DR) screening is between 35 and 60%. We evaluate a teleretinal DR screening (TDRS) program in a private practice vertically integrated system to increase compliance with retinal screening. METHODS A retrospective pre-post intervention longitudinal study was conducted in a private endocrinology practice using TDRS as the primary intervention. Compliance rates for diabetic retinal screening were compared between December 31, 2016 and December 31, 2018. RESULTS A total population of 3479 patients were evaluated. Retinal screening compliance improved from 56.5% of patients (1964) pre-intervention to 59.3% of patients (2064) post intervention. The McNemar test was used for statistical analysis and found the change significant (p = 0.004). CONCLUSIONS TDRS as an adjunct tool in a private practice endocrinology office significantly improved screening rates and can increase access to recommended diabetic eye care. However, the improvement in screening rates was smaller than other types of practice settings. We explore some of the unique challenges to implementation of TDRS in private practice settings.
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Affiliation(s)
| | | | | | | | - Ramanath Bhandari
- Springfield Clinic, 1025 S 6th Street, Springfield, IL 62703, United States
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KANSE SHILPASAMEER, YADAV DM. HG-SVNN: HARMONIC GENETIC-BASED SUPPORT VECTOR NEURAL NETWORK CLASSIFIER FOR THE GLAUCOMA DETECTION. J MECH MED BIOL 2020. [DOI: 10.1142/s0219519419500659] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Glaucoma has emerged as the one of the leading causes of blindness. Even though the diagnosis of this disease has not yet been found, the early detection can cure the glaucoma disease. Various works presented for the glaucoma detection have many disadvantages such as increased run time, complex architecture, etc., during the real-time implementations. This work introduces the glaucoma detection system based on the proposed harmonic genetic-based support vector neural network (HG-SVNN) classifier. The proposed system detects glaucoma in the database through four major steps, (1) pre-processing, (2) proposed hybrid feature extraction, (3) segmentation and (4) classification through the proposed HG-SVNN classifier. The proposed model uses both the statistical and the vessel features from the segmented and the pre-processed images to construct the feature vector. The proposed HG-SVNN classifier uses both the harmonic operator and the genetic algorithm (GA) for the neural network training. From the simulation results, it is evident that the proposed glaucoma detection system has better performance than the existing works with the values of 0.945, 0.9, 0.9333 and 0.86667 for the segmentation accuracy, accuracy, sensitivity and specificity metric.
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Affiliation(s)
| | - D. M. YADAV
- Academic Dean G. H. Raisoni College of Engineering and Management, Wagholi, Pune, Maharashtra 412207, India
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Abstract
Diabetes mellitus (DM) is the most common endocrine and metabolic disease caused by absolute or insufficient insulin secretion. Under the context of an aging population worldwide, the number of diabetic patients is increasing year by year. Most patients with diabetes have multiple complications that severely threaten their survival and living quality. DM is mainly divided into type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM is caused by absolute lack of insulin secretion, so the current treatment for T1DM patients is exogenous insulin replacement therapy. At present, exercise therapy has been widely recognized in the prevention and treatment of diabetes, and regular aerobic exercise has become an important part of T1DM treatment. At the same time, exercise therapy is also used in conjunction with other treatments in the prevention and treatment of diabetic complications. However, for patients with T1DM, exercise still has the risk of hypoglycemia or hyperglycemia. T1DM Patients and specialist physician need to fully understand the effects of exercise on metabolism and implement individualized exercise programs. This chapter reviews the related content of exercise and T1DM.
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Affiliation(s)
- Xiya Lu
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Cuimei Zhao
- Department of Cardiology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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Yang YX, Shen HH, Cao F, Xie LY, Zhu GL, Sam NB, Wang DG, Pan HF. Therapeutic potential of enhancer of zeste homolog 2 in autoimmune diseases. Expert Opin Ther Targets 2019; 23:1015-1030. [PMID: 31747802 DOI: 10.1080/14728222.2019.1696309] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Autoimmune diseases (ADs) are idiopathic and heterogeneous disorders with contentious pathophysiology. Great strides have been made in epigenetics and its involvement in ADs. Zeste homolog 2 (EZH2) has sparked extensive interest because of its pleiotropic roles in distinct pathologic contexts.Areas covered: This review summarizes the epigenetic functions and the biological significance of EZH2 in the etiology of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), inflammatory bowel disease (IBD), multiple sclerosis (MS), and systemic sclerosis (SSc). A brief recapitulation of the therapeutic potential of EZH2 targeting is provided.Expert opinion: There are questions marks and controversies surrounding the feasibility and safety of EZH2 targeting; it is recommended in RA and SLE, but queried in T1D, IBD, MS, and SSc. Future work should focus on contrast studies, systematic analyses and preclinical studies with optimizing methodologies. Selective research studies conducted in a stage-dependent manner are necessary because of the relapsing-remitting clinical paradigms.
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Affiliation(s)
- Yue-Xin Yang
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hui-Hui Shen
- Department of Clinical Medicine, The second School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Fan Cao
- Department of Clinical Medicine, The second School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Liang-Yu Xie
- Department of Clinical Medicine, The second School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Guang-Lin Zhu
- Department of Clinical Medicine, The second School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Napoleon Bellua Sam
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, China
| | - De-Guang Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, China
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Kamble SP, Ghadyale VA, Patil RS, Haldavnekar VS, Arvindekar AU. Inhibition of GLUT2 transporter by geraniol from Cymbopogon martinii: a novel treatment for diabetes mellitus in streptozotocin-induced diabetic rats. J Pharm Pharmacol 2019; 72:294-304. [DOI: 10.1111/jphp.13194] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 10/21/2019] [Indexed: 12/13/2022]
Abstract
Abstract
Objective
To isolate and identify the bioactive component from Cymbopogon martinii having GLUT2 transporter inhibitory activity – towards development of a novel strategy for treatment of diabetes mellitus.
Method
Isolation of bioactive component was carried out using differential solvent extraction, HPTLC and HPLC, and identification was done by GC-MS. In-vitro studies on intestine, liver, kidney and in-vivo assessment by OGTT and long-term treatment on diabetic rats were carried out.
Key findings
Geraniol was isolated and identified as bioactive component. Intestinal glucose absorption demonstrated 60.28% inhibition of transport at 648.34 μm of geraniol. It was found to inhibit glucose release from liver on adrenaline challenge by 89.82% at 324.17 μm/ml. Kidney glycogen content doubled using 648.34 μm of geraniol as compared to control. Geraniol demonstrated 2.14 times higher renal glucose output than diabetic control. OGTT demonstrated prevention of postprandial spikes. Prolonged treatment for 60 days with 29.37 mm/kg B.W. twice a day of geraniol improved the lipid profile, HbA1C levels and renal parameters. In mRNA studies for 10 days, over expression of GLUT2 was prevented by geraniol.
Conclusions
Inhibition of GLUT2 by geraniol has the potential to reduce hyperglycaemia and prevent secondary complications in diabetes.
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Zhong Y, Yue S, Wu J, Guan P, Zhang G, Liu L, Chen L. Association of the Serum Total Cholesterol to Triglyceride Ratio with Diabetic Retinopathy in Chinese Patients with Type 2 Diabetes: A Community-Based Study. Diabetes Ther 2019; 10:597-604. [PMID: 30758833 PMCID: PMC6437234 DOI: 10.1007/s13300-019-0579-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION The relationship of total cholesterol (TC) or triglyceride (TG) to diabetic retinopathy (DR) has proven difficult to determine. In addition, there is no report of any study of the correlation between the TC/TG ratio and DR. This study was therefore undertaken to investigate the relationship between the TC/TG ratio and DR in Chinese adults with type 2 diabetes mellitus. METHODS A community-based study was conducted from August to October 2014 in Fengyutan, Shenyang, China. DR was assessed based on the modified Airlie House classification of DR. Multivariable logistic regression models were used to evaluate the association between the TC/TG ratio and the presence of DR. RESULTS Among the 420 diabetic participants in the study (157 men; mean (SD) age 61.7 (10.0) years), 76 (18.1%) presented with DR. When the TC/TG ratio was analyzed categorically, participants with T2DM in tertile 2 (i.e., TC/TG 2.91-4.00) were more likely (OR 2.01; 95% CI 1.01-3.99) to suffer from DR than patients in tertile 1 (i.e., TC/TG < 2.91) in multivariable models. Similarly, participants in tertile 3 (TC/TG > 4.00) were more likely (OR 2.59; 95% CI 1.11-3.14; P = 0.011) to suffer from DR than patients in tertile 1. This association persisted when the TC/TG ratio was analyzed continuously (P = 0.014). CONCLUSION We found a novel positive association between TC/TG ratio and presence of DR in Chinese individuals with T2DM. Although longitudinal data are needed, this finding contributes to the accumulating evidence that a high TC/TG ratio may be implicated in DR.
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Affiliation(s)
- Yifan Zhong
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Song Yue
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Jingyang Wu
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Peng Guan
- Department of Epidemiology, School of Public Health, China Medical University, Taichung, 110122, China
| | - Guisen Zhang
- Department of Ophthalmology, Hohhot Chao Ju Eye Hospital, Hohhot, 010000, China
| | - Lei Liu
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
| | - Lei Chen
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
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Kim CS, Kim J, Kim YS, Jo K, Lee YM, Jung DH, Lee IS, Kim JH, Kim JS. Improvement in Diabetic Retinopathy through Protection against Retinal Apoptosis in Spontaneously Diabetic Torii Rats Mediated by Ethanol Extract of Osteomeles schwerinae C.K. Schneid. Nutrients 2019; 11:nu11030546. [PMID: 30836664 PMCID: PMC6470872 DOI: 10.3390/nu11030546] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 02/27/2019] [Accepted: 02/27/2019] [Indexed: 12/14/2022] Open
Abstract
Retinal apoptosis plays a critical role in the progression of diabetic retinopathy (DR), a common diabetic complication. Currently, the tight control of blood glucose levels is the standard approach to prevent or delay the progression of DR. However, prevalence of DR among diabetic patients remains high. Focusing on natural nutrients or herbal medicines that can prevent or delay the onset of diabetic complications, we administered an ethanol extract of the aerial portion of Osteomeles schwerinae (OSSCE), a Chinese herbal medicine, over a period of 17 weeks to spontaneously diabetic Torii (SDT) rats. OSSCE was found to ameliorate retinal apoptosis through the regulation of advanced glycation end product (AGE) accumulation, oxidative stress, and mitochondrial function via the inhibition of NF-κB activity, in turn, through the downregulation of PKCδ, P47phox, and ERK1/2. We further demonstrated in 25 mM glucose-treated human retinal microvascular endothelial cells (HRMECs) that hyperoside (3-O-galactoside-quercetin), quercitrin (3-O-rhamnoside-quercetin), and 2″-O-acetylvitexin (8-C-(2″-O-acetyl-glucoside)-apigenin) were the active components of OSSCE that mediated its pharmacological action. Our results provide evidence that OSSCE is a powerful agent that may directly mediate a delay in the development or disease improvement in patients of DR.
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Affiliation(s)
- Chan-Sik Kim
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
- Korean Convergence Medicine, University of Science and Technology (UST), Daejeon 34113, Korea.
| | - Junghyun Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
- Department of Oral Pathology, School of Dentistry, Chonbuk National University, Jeonju 54896, Korea.
| | - Young Sook Kim
- Korean Convergence Medicine, University of Science and Technology (UST), Daejeon 34113, Korea.
- Clinical Research Coordination Team, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Kyuhyung Jo
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Yun Mi Lee
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Dong Ho Jung
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Ik Soo Lee
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Joo-Hwan Kim
- Department of Life Science. Gachon University, 1342, Seongnamdaero, Seongnam, Gyeonggido 13120, Korea.
| | - Jin Sook Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
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50
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Wang M, Wang Y, Xie T, Zhan P, Zou J, Nie X, Shao J, Zhuang M, Tan C, Tan J, Dai Y, Sun J, Li J, Li Y, Shi Q, Leng J, Wang X, Yao Y. Prostaglandin E 2/EP 2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes. Diabetologia 2019; 62:335-348. [PMID: 30411254 DOI: 10.1007/s00125-018-4755-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 09/20/2018] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS Diabetic retinopathy is a common microvascular complication of diabetes mellitus and is initiated by inflammation and apoptosis-associated retinal endothelial cell damage. Prostaglandin E2 (PGE2) has emerged as a critical regulator of these biological processes. We hypothesised that modulating PGE2 and its E-prostanoid receptor (EP2R) would prevent diabetes mellitus-induced inflammation and microvascular dysfunction. METHODS In a streptozotocin (STZ)-induced rat model of diabetes, rats received intravitreal injection of PGE2, butaprost (a PGE2/EP2R agonist) or AH6809 (an EP2R antagonist). Retinal histology, optical coherence tomography, ultrastructure of the retinal vascular and biochemical markers were assessed. RESULTS Intravitreal injection of PGE2 and butaprost significantly accelerated retinal vascular leakage, leucostasis and endothelial cell apoptosis in STZ-induced diabetic rats. This response was ameliorated in diabetic rats pre-treated with AH6809. In addition, pre-treatment of human retinal microvascular endothelial cells with AH6809 attenuated PGE2- and butaprost-induced activation of caspase 1, activation of the complex containing nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment domain (ASC), and activation of the EP2R-coupled cAMP/protein kinase A/cAMP response element-binding protein signalling pathway. CONCLUSIONS/INTERPRETATION The PGE2/EP2R signalling pathway is involved in STZ-induced diabetic retinopathy and could be considered as a potential target for diabetic retinopathy prevention and treatment.
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Affiliation(s)
- Man Wang
- Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Yangningzhi Wang
- Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Tianhua Xie
- Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Pengfei Zhan
- Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Jian Zou
- Center of Clinical Research, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Xiaowei Nie
- Center of Clinical Research, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
- Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, People's Republic of China
| | - Jun Shao
- Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Miao Zhuang
- Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Chengye Tan
- Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Jianxin Tan
- Center of Clinical Research, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Youai Dai
- Center of Clinical Research, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Jie Sun
- Center of Clinical Research, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China
| | - Jiantao Li
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Yuehua Li
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Qian Shi
- Yixing Eye Hospital, Wuxi, Jiangsu, People's Republic of China
| | - Jing Leng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Xiaolu Wang
- Center of Clinical Research, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China.
- Wuxi Institute of Translational Medicine, Wuxi, Jiangsu, People's Republic of China.
| | - Yong Yao
- Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, People's Republic of China.
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