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Joo JH, Sharma N, Shaia J, Wu AK, Skugor M, Singh RP, Rachitskaya AV. The Effect of Glucagon-Like Peptide-1 Receptor Agonists on Diabetic Retinopathy at a Tertiary Care Center. OPHTHALMOLOGY SCIENCE 2024; 4:100547. [PMID: 39139548 PMCID: PMC11321299 DOI: 10.1016/j.xops.2024.100547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 08/15/2024]
Abstract
Objective The potential association between diabetic retinopathy (DR) worsening and glucagon-like peptide-1 receptor agonists (GLP-1RA) has affected therapeutic management of diabetic patients but remains controversial. This study compared rates of DR development or progression in patients on GLP-1RA to those on SGLT-2 inhibitors (SGLT-2I). Design Retrospective cohort study. Subjects Nine hundred eighty-one patients with diabetes mellitus taking GLP-1RA or SGLT-2I, the latter serving as controls, between 2012 and 2023. Methods Patients were one-to-one greedy matched by propensity scores on race/ethnicity, age, smoking status, baseline body mass index and hemoglobin A1c %, type of diabetes mellitus, baseline DR status and history of DR procedures, duration of drug use, whether they had taken both drug types, and change in hemoglobin A1c % after 1 year on the drug. Main Outcome Measures The primary outcome was clinical DR development or progression (termed "worsening") detected by International Classification of Diseases (ICD), 10th edition codes, confirmed by manual review, on GLP-1RA compared with SGLT-2I after propensity score matching. Secondary outcomes included DR worsening indicated by need for procedures due to complications, and time-to-first DR worsening event. Results The study included 692 GLP-1RA users and 289 SGLT-2I users. The mean follow-up periods for GLP-1RA versus SGLT-2I use were 1.54 (standard deviation [SD] 1.82) years and 1.38 (SD 1.56) years, respectively. The rates of clinical worsening were 2.3% and 2.8%, respectively. After propensity score matching, an association was not identified between GLP1-RA and DR worsening neither clinically by ICD-10 codes (odds ratio [OR] = 0.33, 95% confidence interval [CI]: 0.11-1.03) nor by indication for procedures (OR = 0.50, 95% CI 0.13-2.00). Time-to-first DR worsening did not differ between the groups in Kaplan-Meier analysis. The most common type of clinical worsening event for both drug types was vitreous hemorrhage (43.7% and 50% of worsening events in GLP-1RA and SGLT-2I users, respectively). The most common DR procedure indicated was anti-VEGF injections (34% and 35% of GLP-1RA and SGLT-2I events, respectively). Conclusions Diabetic retinopathy worsening, either clinically or by procedures, was not associated with GLP-1RA compared with SGLT-2I, both before and after propensity score matching on all analyses, including time-to-first worsening event. Financial Disclosures Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Affiliation(s)
- Julia H. Joo
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
| | - Neha Sharma
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
- Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Jacqueline Shaia
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
- Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Anna K. Wu
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
| | - Mario Skugor
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, Ohio
| | - Rishi P. Singh
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
- Cleveland Clinic Cole Eye Institute, Cleveland, Ohio
- Cleveland Clinic Martin Hospitals, Cleveland Clinic Florida, Stuart, Florida
| | - Aleksandra V. Rachitskaya
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
- Cleveland Clinic Cole Eye Institute, Cleveland, Ohio
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Jacob S, Varughese GI. Enhancing glycaemic control with impetus on weight management: Observing for early worsening of diabetic retinopathy. Eye (Lond) 2024; 38:1787-1788. [PMID: 38341496 PMCID: PMC11226659 DOI: 10.1038/s41433-024-02980-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 01/18/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Affiliation(s)
- Sarita Jacob
- Institute of Clinical Sciences, University of Birmingham, Birmingham, UK.
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
- College of Health and Life Sciences, Aston University, Birmingham, UK.
- Birmingham, Solihull and Black Country Diabetic Eye Screening Programme, Birmingham, UK.
| | - George I Varughese
- University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, North Staffordshire, UK
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Varughese GI, Jacob S. Existing and emerging GLP-1 receptor agonist therapy: Ramifications for diabetic retinopathy screening. J R Coll Physicians Edinb 2024; 54:170-173. [PMID: 38578067 DOI: 10.1177/14782715241244843] [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: 04/06/2024] Open
Abstract
GLP-1 receptor agonist treatment revolutionised the management of type 2 diabetes mellitus with significant enhancement of cardiovascular risk reduction. They have been instrumental in effectively managing the glycaemic control of this at-risk patient group. This class of drugs are associated with rapid improvement in glucose levels and consequently, transient early worsening of pre-existing diabetic retinopathy (DR) which is well-recognised, but this paradox is less commonly perceived in routine clinical practice. The recent shortage of supply has resulted in an enforced hiatus to prescribing all existing GLP-1 receptor agonists, which is expected to last all through 2024. This becomes even more pertinent as their DR could have progressed due to worsening HbA1c as a result of the unforeseen interruption to GLP-1 receptor agonist treatment. Therefore, when these medications are recommenced in a few months' time, all prescribers need to be aware of these patients' most up-to-date DR status and liaise with their affiliated screening service.
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Affiliation(s)
- George Iype Varughese
- University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, North Staffordshire, UK
| | - Sarita Jacob
- Institute of Clinical Sciences, University of Birmingham, Birmingham, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- College of Life and Health Sciences, Aston University, Birmingham, UK
- Birmingham, Solihull and Black Country Diabetic Eye Screening Programme, Birmingham, UK
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Morin H, Havlík J, Chrapek O, Hrevuš M, Nemec P, Rejmont L, Tesar J, Kalousova M, Zima T, Šín M. Correlation Between Vitreous Level of Angiogenic Growth Factors and Oxygen Saturation in Retinal Vessels in Diabetic Retinopathy. Invest Ophthalmol Vis Sci 2023; 64:4. [PMID: 38047739 DOI: 10.1167/iovs.64.15.4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2023] Open
Abstract
Purpose The aim of this study was to investigate whether there is any association between the levels of the angiogenic growth factors and the vascular oxygen saturation in eyes with diabetic retinopathy. Methods The study was designed as a prospective trial. The cohort consisted of 29 diabetic patients with scheduled vitreous procedures (intravitreal injection or pars plana vitrectomy). The control group included 30 patients scheduled for macular surgery (macular hole or epiretinal membrane). Nine patients (four from the diabetic maculopathy [DM] group and five from the control group) were excluded from the study because of unsuccessful vitreous samples. Retinal oximetry was performed several hours before the vitreous procedure was performed, and vitreous samples were obtained during the procedure. The concentrations of VEGF, Serpin F1/pigment epithelium-derived factor (PEDF), and placental growth factor (PlGF) were measured by ELISA. Results A negative correlation between level of VEGF and arteriovenous (AV) saturation difference was determined in the DM group (Pearson correlation coefficient r = -0.607; two-tailed test, P = 0.002). Also a negative correlation between level of PlGF and AV saturation difference was determined in the DM group (Pearson correlation coefficient r = -0.521; two-tailed test, P = 0.011) A positive correlation between PlGF level and the vein saturation was not statistically significant (Pearson correlation coefficient r = 0.325; two-tailed test, P = 0.130). We did not find any correlation between vitreous level of PEDF and vascular saturation within the DM group. Conclusions Our findings in diabetic patients suggests a correlation between the intravitreal level of proangiogenic factors and the AV difference measured by retinal oximetry.
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Affiliation(s)
- Hana Morin
- Department of Ophthalmology, Military University Hospital Prague, 1 st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jan Havlík
- Department of Ophthalmology, Military University Hospital Prague, 1 st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Oldrich Chrapek
- Department of Ophthalmology, Faculty of Medicine, Masaryk University Brno, Czech Republic
- Department of Ophthalmology, University Hospital, Brno, Czech Republic
| | - Michal Hrevuš
- Department of Ophthalmology, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech Republic
| | - Pavel Nemec
- Department of Ophthalmology, Military University Hospital Prague, 1 st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Leoš Rejmont
- Department of Ophthalmology, Military University Hospital Prague, 1 st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jan Tesar
- Department of Ophthalmology, Military University Hospital Prague, 1 st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Marta Kalousova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, and General University Hospital in Prague, Prague, Czech Republic
| | - Tomaš Zima
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, and General University Hospital in Prague, Prague, Czech Republic
| | - Martin Šín
- Department of Ophthalmology, Military University Hospital Prague, 1 st Faculty of Medicine, Charles University, Prague, Czech Republic
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Cigrovski Berkovic M, Strollo F. Semaglutide-eye-catching results. World J Diabetes 2023; 14:424-434. [PMID: 37122431 PMCID: PMC10130900 DOI: 10.4239/wjd.v14.i4.424] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/08/2023] [Accepted: 03/20/2023] [Indexed: 04/12/2023] Open
Abstract
Semaglutide is a glucagon-like peptide-1 receptor agonist used either orally every day or subcutaneously once a week for the treatment of type 2 diabetes mellitus and, more recently, at higher doses, for the treatment of obesity. Both diseases are reaching epidemic proportions and often coexist, posing patients with a high risk for cardiovascular disease and death. Therefore, an agent such as semaglutide, which offers clinically significant weight loss and cardiovascular benefits, is essential and will be increasingly used in high-risk patients. However, during the SUSTAIN clinical trial program (Semaglutide Unabated Sustainability in treat-ment of type 2 diabetes), a safety issue concerning the progression and worsening of diabetic retinopathy emerged. The existing explanation so far mainly supports the role of the magnitude and speed of HbA1c reduction, a phenomenon also associated with insulin treatment and bariatric surgery. Whether and to which extent the effect is direct is still a matter of debate and an intriguing topic to investigate for suitable preventative and rehabilitative purposes. In this minireview, we will summarize the available data and suggest guidelines for a comprehensive semaglutide clinical utilization until new evidence becomes available.
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Affiliation(s)
| | - Felice Strollo
- Department of Endocrinology and Metabolism, IRCCS San Raffaele Pisana, Rome 00163, Italy
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Sirakaya E, Kilic D, Aslan Sirakaya H. Comparison of intravitreal ranibizumab, aflibercept and bevacizumab therapies in diabetic macular edema with serous retinal detachment. Eur J Ophthalmol 2022; 33:1459-1466. [PMID: 36482707 DOI: 10.1177/11206721221144797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Purpose To compare the effects of ranibizumab, aflibercept and bevacizumab treatments in treatment-naive diabetic macular edema(DME) patients with serous retinal detachment(SRD). Material and methods This is a retrospective, comparative study. In a sample of 86 eyes of 86 untreated DME patients with accompanying SRD, 23 patients were treated with ranibizumab (IVR), 28 patients with aflibercept (IVA), and 35 patients with bevacizumab (IVB). All were injected intravitreally once a month for a 3-month loading dose. Subsequently, all participants were evaluated every months and if neccessary they received additional intravitreal treatments.Mean changes in best corrected visual acuity (BCVA), central retinal thickness (CRT), and SRD height over the 6-months study period were compared. Results At baseline, the groups did not differ in mean BCVA,CRT and SRD height. During the first 3 months, in IVA group the mean decrease in CRT and SRD height were significantly more than in the other two groups ( p < 0.05 for all). However, these differences disappeared at 6 months.The number of injections was similar between the groups during the study period. Conclusion In patients with DME accompanied by SRD, IVA is a more advantageous option in terms of reduction in CRT and SRD height from baseline to 3 months. In the 6-month period of treatment, IVR, IVA and IVB therapies areanatomically and functionally similar and significant effective modalities.
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Affiliation(s)
- Ender Sirakaya
- Department of Ophthalmology, Health Science University, The Kayseri City Hospital, Kayseri, Turkey
| | - Deniz Kilic
- Department of Ophthalmology, Health Science University, The Kayseri City Hospital, Kayseri, Turkey
| | - Hatice Aslan Sirakaya
- Department of Internal Medicine, Health Science University, The Kayseri City Hospital, Kayseri, Turkey
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Deng Z. A relatively low glucose promotes the proliferation of vascular endothelial cells by suppressing VEGFR2 O-GlcNAcylation and its proteasome degradation. Int Ophthalmol 2022; 43:899-914. [PMID: 36089631 DOI: 10.1007/s10792-022-02492-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 08/20/2022] [Indexed: 10/14/2022]
Abstract
PURPOSE Vascular endothelial growth factor receptors (VEGFRs) have been demonstrated to play a critical role in ischemic retinal diseases, as VEGFRs mediate hypoxia-induced neovascularization. Not only hypoxia, ischemia also induces the deficiency of glucose, yet its effects on VEGFR signal and neovascularization have seldom been studied. Bioinformatics analysis predicted that VEGFRs may be regulated by O-GlcNAcylation, while glucose deficiency influences the O-GlcNAcylation. METHODS In this study, we treated human retinal microvascular endothelial cells with low glucose (LG) alone or in combination with low oxygen (oxygen and glucose deprivation, OGD). Cell viability and apoptosis rate were used to evaluate cell growth characters. RESULTS LG (2.8 mmol/L) treatment induced mRNA and protein levels of VEGFR1, 2, 3 even in the presence of the protein synthesis inhibitor, cycloheximide (CHX), suggesting that the increase in VEGFR proteins is partially associated with post-translational modifications. Immunoprecipitation analysis showed that O-GlcNAc level was decreased by LG in both VEGFR1, 2, but a de-O-GlcNAc glycosylase inhibitor restored the O-GlcNAc levels. This inhibitor also abolished the LG-induced increase in VEGFR2 protein, whereas this effect was not disappeared in the presence of the proteasome inhibitor, MG132. Similar results were also observed under OGD condition. VEGFR2 knockdown more significantly retarded the growth of hRMECs and HUVECs than VEGFR1, 3 knockdown under LG and OGD conditions. CONCLUSIONS A relatively low glucose suppressed O-GlcNAcylation in VEGFR2, whereby inhibiting its proteasome degradation; up-regulated VEGFR2 promoted the proliferation of vascular endothelial cells under ischemic condition.
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Yoshida Y, Joshi P, Barri S, Wang J, Corder AL, O'Connell SS, Fonseca VA. Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes - A systematic review and meta-analysis. J Diabetes Complications 2022; 36:108255. [PMID: 35817678 DOI: 10.1016/j.jdiacomp.2022.108255] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/20/2022] [Accepted: 06/28/2022] [Indexed: 12/17/2022]
Abstract
AIMS The effect of Glucagon-like peptide 1 receptor agonists (GLP1 RA) on diabetic retinopathy (DR) remains controversial. Previous reviews combined data from randomized clinical trials (RCTs) with or without cardiovascular (CV) benefits and did not address confounders, therefore may have generated misleading results. The study aimed to examine the effect of GLP1RA on DR in type 2 diabetes (T2DM) in RCTs with or without CV benefits and distinguish the effect by major confounders. METHODS We conducted electronic searches of multiple databases and a manual search using references lists. We included 13 RCTs examining the effect of GLP1 RA on health outcomes/adverse events including DR or DR complications in T2DM. We performed a random-effects model meta-analysis. RESULTS GLP1RA was associated with an elevated risk of rapidly worsening DR in four major RCTs with CV benefits in T2DM (OR 1.23, 95 % CI 1.05-1.44). The association between GLP1 RA and DR was significant in subgroups of RCTs with length over 52 weeks (1.2, 1.00-1.43), using placebo as a comparator (1.22, 1.05-1.42). In subgroups with patients who had T2DM ≥10 years (1.19, 0.99-1.42) or with subjects enrolled from multiple countries (1.2, 0.99-1.46), the association appeared to be evident but did not reach statistical significance. CONCLUSIONS GLP1 RA including liraglutide, semaglutide, and dulaglutide are associated with an increased risk of rapidly worsening DR in RCTs with CV benefits. Further data from clinical studies with longer follow-up purposefully designed for DR risk assessment, particularly including patients of established DR are warranted.
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Affiliation(s)
- Yilin Yoshida
- Section of Endocrinology and Metabolism, Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States of America.
| | - Preeti Joshi
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States of America
| | - Saba Barri
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States of America
| | - Jia Wang
- Section of Endocrinology and Metabolism, Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States of America
| | - Amy L Corder
- Rudolph Matas Library of the Health Sciences, Tulane University, New Orleans, LA, United States of America
| | - Samantha S O'Connell
- Tulane University Office of Academic Affairs and Provost, United States of America
| | - Vivian A Fonseca
- Section of Endocrinology and Metabolism, Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States of America.
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Akil H, Burgess J, Nevitt S, Harding SP, Alam U, Burgess P. Early Worsening of Retinopathy in Type 1 and Type 2 Diabetes After Rapid Improvement in Glycaemic Control: A Systematic Review. Diabetes Ther 2022; 13:1-23. [PMID: 34928488 PMCID: PMC8776958 DOI: 10.1007/s13300-021-01190-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 11/30/2021] [Indexed: 11/29/2022] Open
Abstract
To systematically review the epidemiology of early worsening of diabetic retinopathy (EWDR) after substantial improvements in glycaemic control and evaluate characteristics including risk factors. This systematic review was registered with PROSPERO (CRD42020158252). An electronic literature search was performed according to PRISMA guidelines using MEDLINE, EMBASE, PubMed, Web of Science, Scopus and Cochrane databases and manual reference for the articles published until 2020. Published full-text English language articles that report data on diabetic retinopathy in people with diabetes experiencing a rapid, substantial decrease in HbA1c after going through intensive therapy were included. All articles were screened, data were extracted and methodological quality was evaluated by two independent reviewers using a priori criteria. A total of 346 articles were identified after the removal of duplicates. Data were extracted from 19 full-text articles with a total of 15,588 participants. Included studies varied considerably in terms of patient selection, timing and method of assessing the eye and retinopathy classification. EWDR was reported to occur in a wide range of prevalences; 3.3-47% of participants within 3-84 months after intensification of glycaemic control. Risk factors for EWDR included long duration of diabetes, long-term uncontrolled hyperglycemia, amplitude of and baseline retinopathy severity in both type 1 and type 2 diabetes. The occurrence of EWDR and progression of retinopathy were found to have an association with the amplitude of HbA1c reduction. EWDR has been described in a proportion of people with intensification of glycaemic control. However, the prevalence remains unclear because of methodological differences in the identified studies. Future interventional studies should report retinopathy and visual outcomes using standardized protocols.
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Affiliation(s)
- Handan Akil
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool and St. Paul's Eye Unit, Liverpool University Hospitals NHS Trust, Liverpool, UK.
| | - Jamie Burgess
- Diabetes and Endocrinology Research, Institute of Cardiovascular and Metabolic Medicine and The Pain Research Institute, University of Liverpool and Liverpool University NHS Hospital Trust, Liverpool, UK
| | - Sarah Nevitt
- Department of Health Data Science, University of Liverpool, Liverpool, UK
| | - Simon P Harding
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool and St. Paul's Eye Unit, Liverpool University Hospitals NHS Trust, Liverpool, UK
| | - Uazman Alam
- Diabetes and Endocrinology Research, Institute of Cardiovascular and Metabolic Medicine and The Pain Research Institute, University of Liverpool and Liverpool University NHS Hospital Trust, Liverpool, UK
- Division of Endocrinology, Diabetes and Gastroenterology, University of Manchester, Manchester, UK
| | - Philip Burgess
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool and St. Paul's Eye Unit, Liverpool University Hospitals NHS Trust, Liverpool, UK
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Szymanska M, Mahmood D, Yap TE, Cordeiro MF. Recent Advancements in the Medical Treatment of Diabetic Retinal Disease. Int J Mol Sci 2021; 22:ijms22179441. [PMID: 34502350 PMCID: PMC8430918 DOI: 10.3390/ijms22179441] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic retinal disease remains one of the most common complications of diabetes mellitus (DM) and a leading cause of preventable blindness. The mainstay of management involves glycemic control, intravitreal, and laser therapy. However, intravitreal therapy commonly requires frequent hospital visits and some patients fail to achieve a significant improvement in vision. Novel and long-acting therapies targeting a range of pathways are warranted, while evidence to support optimal combinations of treatments is currently insufficient. Improved understanding of the molecular pathways involved in pathogenesis is driving the development of therapeutic agents not only targeting visible microvascular disease and metabolic derangements, but also inflammation and accelerated retinal neurodegeneration. This review summarizes the current and emerging treatments of diabetic retinal diseases and provides an insight into the future of managing this important condition.
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Affiliation(s)
- Maja Szymanska
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Daanyaal Mahmood
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Timothy E. Yap
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Maria F. Cordeiro
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
- The Western Eye Hospital, Imperial College Healthcare NHS Trust (ICHNT), London NW1 5QH, UK
- Glaucoma and Retinal Neurodegeneration Group, Department of Visual Neuroscience, UCL Institute of Ophthalmology, London EC1V 9EL, UK
- Correspondence:
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Gagloev BV, Pozdeyeva NA, Al-Darraji IOH. [Concentration of VEGF-A in the intraocular fluid of rats with alloxan model of diabetes mellitus]. Vestn Oftalmol 2021; 137:12-17. [PMID: 33881258 DOI: 10.17116/oftalma202113702112] [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: 11/17/2022]
Abstract
PURPOSE To study the changes in the concentration of vascular endothelial growth factor A (VEGF-A) in the intraocular fluid (IOF) of rats with alloxan model of diabetes mellitus (DM) on insulin therapy at different time points. MATERIAL AND METHODS The alloxan model of DM was simulated in 197 rats by a single intraperitoneal injection of 100 mg/kg alloxan hydrate. The animals were divided into 3 groups 7 days after administration of alloxan hydrate. The main group consisted of animals with alloxan model of DM, which begain receiving single daily intraperitoneal injections of insulin at a dose of 0.9 U/kg body weight. The comparison group included animals with alloxan model of DM, which did not receive the therapy. The control group consisted of healthy animals. The experimental animals were withdrawn from the study 1 and 4 months after the start of insulin therapy. The concentration of VEGF-A was determined in 80-90 μL of intraocular fluid collected from both eyes of each animal. RESULTS At 1 month, the VEGF-A concentration in the intraocular fluid in the study group (n=17; 140 [136; 210] pg/mL) was statistically significantly higher than in the comparison group (n=20; 72 [58; 86] pg/mL; pm-u<0.0004), and in the control group (n=16; 76 [62.5; 88] pg/mL; pm-u=0.0045). The comparison group did not have statistically significant differences from the control group (pm-u=0.9979). At 4 months, the VEGF-A concentration in the intraocular fluid in the study group (n=18) was 84.8 [61.1; 93.2] pg/mL, in the comparison group (n=16) - 66.4 [54.4; 73.75] pg/mL. The VEGF-A concentration in the intraocular fluid in the study group at 4 months was statistically significantly lower than in the study group at 1 month (pm-u<0.0044). CONCLUSION Insulin therapy causes a statistically significant increase in the concentration of VEGF-A in the intraocular fluid of rats with alloxan model of DM after 1 month, but after 4 months of the therapy the VEGF-A concentration falls back to the initial values.
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Affiliation(s)
- B V Gagloev
- Cheboksary Branch of S.N. Fedorov National Medical Research Center «MNTK «Eye Microsurgery», Cheboksary, Russia
| | - N A Pozdeyeva
- Cheboksary Branch of S.N. Fedorov National Medical Research Center «MNTK «Eye Microsurgery», Cheboksary, Russia.,Postgraduate Doctors' Training Institute, Cheboksary, Russia
| | - I O-H Al-Darraji
- Cheboksary Branch of S.N. Fedorov National Medical Research Center «MNTK «Eye Microsurgery», Cheboksary, Russia
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Melo LGN, Morales PH, Drummond KRG, Santos DC, Pizarro MH, Barros BSV, Pinheiro AA, Mallmann F, Leal FSL, Muniz LH, Malerbi FK, Gomes MB. Relationship between Proliferative Diabetic Retinopathy and Inflammatory Markers in Patients with Type 1 Diabetes in Brazil: A Nested Case Control Study. Ophthalmologica 2020; 243:471-478. [PMID: 32799201 DOI: 10.1159/000510879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 08/13/2020] [Indexed: 01/13/2023]
Abstract
INTRODUCTION This study examined the relationship between proliferative diabetic retinopathy (PDR) and serum levels of C-reactive protein, VEGF, TNF-α, and IL-6 inflammatory biomarkers, related to the pathophysiology of diabetic retinopathy. METHODS This cross-sectional, case control study comprised 240 patients with type 1 diabetes (80 cases with PDR and 160 controls without diabetic retinopathy) who were matched for gender and duration of diabetes. RESULTS C-reactive protein was the only inflammatory biomarker that was positively related to PDR (OR 1.96; 95% CI 1.01-3.78, p = 0.0045). We also noted an association between high glycated hemoglobin levels, the use of angiotensin-converting enzyme inhibitor, low glomerular filtration rate, and PDR. CONCLUSION Patients with higher levels of C-reactive protein are more likely to present with PDR. We did not find a link between serum levels of VEGF, TNF-α, or IL-6 and PDR. The function of inflammatory biomarkers in PDR must be addressed in further studies.
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Affiliation(s)
| | | | | | - Deborah Conte Santos
- Department of Internal Medicine, Diabetes Unit, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Marcela Haas Pizarro
- Department of Internal Medicine, Diabetes Unit, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | | | - Felipe Mallmann
- Department of Ophthalmology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | | | - Luiza Harcar Muniz
- Department of Internal Medicine, Diabetes Unit, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | - Marilia Brito Gomes
- Department of Internal Medicine, Diabetes Unit, Rio de Janeiro State University, Rio de Janeiro, Brazil
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Galactose-Induced Skin Aging: The Role of Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7145656. [PMID: 32655772 PMCID: PMC7317321 DOI: 10.1155/2020/7145656] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/17/2020] [Accepted: 05/26/2020] [Indexed: 02/07/2023]
Abstract
Skin aging has been associated with a higher dietary intake of carbohydrates, particularly glucose and galactose. In fact, the carbohydrates are capable of damaging the skin's vital components through nonenzymatic glycation, the covalent attachment of sugar to a protein, and subsequent production of advanced glycation end products (AGEs). This review is focused on the role of D-galactose in the development of skin aging and its relation to oxidative stress. The interest in this problem was dictated by recent findings that used in vitro and in vivo models. The review highlights the recent advances in the underlying molecular mechanisms of D-galactose-mediated cell senescence and cytotoxicity. We have also proposed the possible impact of galactosemia on skin aging and its clinical relevance. The understanding of molecular mechanisms of skin aging mediated by D-galactose can help dermatologists optimize methods for prevention and treatment of skin senescence and aging-related skin diseases.
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Serum Vascular Endothelial Growth Factor Levels Correlate with Severity of Retinopathy in Diabetic Patients: A Systematic Review and Meta-Analysis. DISEASE MARKERS 2019; 2019:9401628. [PMID: 31019585 PMCID: PMC6451802 DOI: 10.1155/2019/9401628] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 12/31/2018] [Accepted: 01/27/2019] [Indexed: 12/26/2022]
Abstract
Background Investigations regarding serum and plasma vascular endothelial growth factor (VEGF) levels in patients with diabetic retinopathy (DR) are conflicting. This meta-analysis is aimed at determining whether serum and plasma VEGF levels are associated with DR and its severity in diabetic patients. Methods PubMed and EMBASE were used to search for published studies, and serum and plasma VEGF levels were compared among DR, nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), and nondiabetic retinopathy (NDR) patients. Standardized mean differences (SMD) and 95% confidence interval (CI) were pooled using a random effects model. Results A total of 29 studies comprising 1805 DR (or NPDR or PDR) patients and 1699 NDR patients were included. ELISA was used to evaluate serum or plasma VEGF levels in all except for two studies included in this meta-analysis. Overall, serum VEGF levels were significantly higher in DR patients (SMD: 0.74, 95% CI: 0.44-1.03) than those in NDR patients, while plasma VEGF levels were not in the comparison (SMD: 0.40, 95% CI: −0.13-0.92). Similarly, NPDR (SMD: 0.51, 95% CI: 0.22-0.80) and PDR (SMD: 1.32, 95% CI: 0.79-1.85) patients had higher serum VEGF levels compared with NDR patients, but the difference was not significant in plasma samples (SMD: 0.24, 95% CI: −0.47-0.95; SMD: 0.37, 95% CI: −0.30-1.05). In addition, serum VEGF levels were higher in PDR patients than those in NPDR patients (SMD: 0.87, 95% CI: 0.41-1.33), but plasma VEGF levels were not (SMD: −0.00, 95% CI: −0.31-0.31). The subgroup and metaregression analysis revealed that the study location, study design, and publication year of a study have certain influence on heterogeneity between studies in serum or plasma samples. Conclusions VEGF levels in the serum instead of those in the plasma correlate to the presence and severity of DR in diabetic patients. Further large-scale studies are required to confirm these findings.
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Bain SC, Klufas MA, Ho A, Matthews DR. Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review. Diabetes Obes Metab 2019; 21:454-466. [PMID: 30226298 PMCID: PMC6587545 DOI: 10.1111/dom.13538] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 09/11/2018] [Accepted: 09/13/2018] [Indexed: 12/13/2022]
Abstract
Worsening of diabetic retinopathy (DR) is associated with the initiation of effective treatment of glycaemia in some patients with diabetes. It has been associated with risk factors such as poor blood-glucose control and hypertension, and it manifests prior to the long-term benefits of optimizing glycaemic control. The majority of evidence supports an association of large and rapid reductions in blood-glucose levels with early worsening of DR. Despite a general awareness of early worsening within the diabetes community, mechanisms to explain the phenomenon remain speculative. We provide an overview of early worsening of DR and its pathophysiology based on current data. We describe the phenomenon in various settings, including in patients receiving insulin- or non-insulin-based treatments, in those undergoing bariatric surgery, and in pregnant women. We discuss various mechanisms and theories that have been suggested to explain this paradoxical phenomenon, and we summarize the implications of these in clinical practice.
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Affiliation(s)
| | | | - Allen Ho
- Wills Eye Hospital/Mid Atlantic RetinaPhiladelphiaPennsylvania
| | - David R. Matthews
- Oxford Centre for Diabetes, Endocrinology and Metabolism, and Harris Manchester CollegeUniversity of OxfordOxfordUK
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Long-term Effects of Pancreas Transplantation on Diabetic Retinopathy and Incidence and Predictive Risk Factors for Early Worsening. Transplantation 2018; 102:e30-e38. [PMID: 28968353 DOI: 10.1097/tp.0000000000001958] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Limited data are available regarding the long-term effects of pancreas transplantation on the progression of diabetic retinopathy (DR) and the incidence and associated risk factors for early worsening of DR. METHODS Patients who underwent successful pancreas transplantation between January 2007 and October 2015 and were followed for 1 year or longer were consecutively enrolled. Variables regarding demographic, systemic, metabolic, and surgical factors were reviewed for each patient. DR progression was defined as (i) development or aggravation of macular edema requiring intravitreal anti-VEGF injections and/or (ii) progression of DR severity requiring panretinal photocoagulation (PRP) and/or pars planar vitrectomy (PPV). Early worsening was defined as progression within 1 year of posttransplant. RESULTS Three hundred three eyes of 153 patients were included in the analysis. At the pretransplant ocular evaluation, 221 eyes (72.9%) showed advanced DR with history of PRP and/or PPV. During a mean follow-up period of 4.2 years, 62 eyes (20.5%) experienced DR progression, and early worsening was noted in 57 eyes (18.8%). DR with recent PRP within pretransplant 1 year and pancreas transplant alone were significant risk factors for early worsening. CONCLUSIONS In 4 of 5 patients who received pancreas transplant, the degree of DR remained stable over time after transplantation. Meanwhile, early worsening of DR could occur in patients at risk, particularly within the first posttransplant year. We suggest that physicians should have a high index of suspicion and carefully monitor for early worsening of DR and timely manage possible ocular deterioration.
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Rosa MD, Distefano G, Gagliano C, Rusciano D, Malaguarnera L. Autophagy in Diabetic Retinopathy. Curr Neuropharmacol 2017; 14:810-825. [PMID: 26997506 PMCID: PMC5333581 DOI: 10.2174/1570159x14666160321122900] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 11/08/2015] [Accepted: 11/10/2015] [Indexed: 12/19/2022] Open
Abstract
Autophagy is an important homeostatic cellular process encompassing a number of consecutive steps indispensable for degrading and recycling cytoplasmic materials. Basically autophagy is an adaptive response that under stressful conditions guarantees the physiological turnover of senescent and impaired organelles and, thus, controls cell fate by various cross-talk signals. Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and accounts for 5% of all blindness. Although, various metabolic disorders have been linked with the onset of DR, due to the complex character of this multi-factorial disease, a connection between any particular defect and DR becomes speculative. Diabetes increases inflammation, advanced glycation end products (AGEs) and oxidative stress in the retina and its capillary cells. Particularly, a great number of evidences suggest a mutual connection between oxidative stress and other major metabolic abnormalities implicated in the development of DR. In addition, the intricate networks between autophagy and apoptosis establish the degree of cellular apoptosis and the progression of DR. Growing data underline the crucial role of reactive oxygen species (ROS) in the activation of autophagy. Depending on their delicate balance both redox signaling and autophagy, being detrimental or beneficial, retain opposing effects. The molecular mechanisms of autophagy are very complex and involve many signaling pathways cooperating at various steps. This review summarizes recent advances of the possible molecular mechanisms in autophagic process that are involved in pathophysiology of DR. In-depth analysis on the molecular mechanisms leading to autophagy in the retinal pigment epithelial (RPE) will be helpful to plan new therapies aimed at preventing or improving the progression of DR.
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Affiliation(s)
| | | | | | | | - Lucia Malaguarnera
- Department of Biomedical and Biotechnological Sciences, Faculty of Medicine, University of Catania, 95124 Catania, Italy
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Bredell MG, Ernst J, El-Kochairi I, Dahlem Y, Ikenberg K, Schumann DM. Current relevance of hypoxia in head and neck cancer. Oncotarget 2016; 7:50781-50804. [PMID: 27434126 PMCID: PMC5226620 DOI: 10.18632/oncotarget.9549] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 04/28/2016] [Indexed: 01/23/2023] Open
Abstract
Head and Neck cancer (HNC) is a complex mix of cancers and one of the more common cancers with a relatively poor prognosis. One of the factors that may assist us in predicting survival and allow us to adjust our treatment strategies is the presence of tumor hypoxia. In this overview we aim to evaluate the current evidence and potential clinical relevance of tumor hypoxia in head and neck cancer according to an extensive search of current literature.An abundance of evidence and often contradictory evidence is found in the literature. Even the contradictory evidence and comparisons are difficult to judge as criteria and methodologies differ greatly, furthermore few prospective observational studies exist for verification of the pre-clinical studies. Despite these discrepancies there is clear evidence of associations between prognosis and poor tumor oxygenation biomarkers such as HIF-1α, GLUT-1 and lactate, though these associations are not exclusive. The use of genetic markers is expanding and will probably lead to significantly more and complex evidence. The lack of oxygenation in head and neck tumors is of paramount importance for the prediction of treatment outcomes and prognosis. Despite the wide array of conflicting evidence, the drive towards non-invasive prediction of tumor hypoxia should continue.
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Affiliation(s)
- Marius G. Bredell
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Jutta Ernst
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Ilhem El-Kochairi
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Yuliya Dahlem
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Kristian Ikenberg
- Department of Pathology, University Hospital of Zürich, Zürich, Switzerland
| | - Desiree M. Schumann
- Department of Cranio-, Maxillofacial and Oral Surgery, University Hospital Zürich, Zürich, Switzerland
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Liu GD, Xu C, Feng L, Wang F. The augmentation of O-GlcNAcylation reduces glyoxal-induced cell injury by attenuating oxidative stress in human retinal microvascular endothelial cells. Int J Mol Med 2015; 36:1019-27. [PMID: 26311324 PMCID: PMC4564096 DOI: 10.3892/ijmm.2015.2319] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Accepted: 08/11/2015] [Indexed: 12/13/2022] Open
Abstract
It has recently been reported that O-linked β-N-acetyl glucosamine (O-GlcNAc) modification (a simple intracellular serine (Ser)/threonine (Thr)-linked monosaccharide) in human retinal microvascular endothelial cells (HRECs) is related to diabetic retinopathy (DR). During O-GlcNAcylation, O-GlcNAc is added to Ser and Thr residues. As the generation of reactive oxygen species (ROS) is one of the characteristics of advanced glycation end product (AGE) injury, and the most important key pathogenic factor of DR, in the present study, we aimed to investigate the association between O-GlcNAcylation and ROS generation in order to ascertain whether O-GlcNAcylation mitigates cellular injury through the generation of ROS. For this purpose, HRECs were divided into 4 groups as follows: HRECs treated with normal glucose (5 mM), HRECs treated with glyoxal (500 µM), glyoxal-treated HRECs also treated with 200 µM PUGNAc, and glyoxal-treated HRECs infected with O-GlcNAc transferase (OGT) siRNA. We detected increased O-GlcNAc levels and increased ROS production in the glyoxal-treated HRECs. The cellular redox status was determined by cellular ROS staining and by measuring the expression levels of the antioxidant genes, superoxide dismutase (SOD) and glutathione peroxidase (GPX). While the augmentation of O-GlcNAcylation following treatment with PUGNAc significantly attenuated the production of ROS (p<0.01) and increased the expression levels of SOD and GPX, the reduction of O-GlcNAcylation following infection with OGT siRNA, exacerbated the production of ROS (p<0.01) and decreased the expression of antioxidant genes. The effects of O-GlcNAcylation on the viability of HRECs were significant (p<0.01), particularly in the hydrogen peroxide (H2O2)-treated HRECs. Treatment with PUGNAc reduced glyoxal-induced cell apoptosis and transfection with OGT siRNA increased HREC apoptosis; these results were confirmed by flow cytometry and by the assessment of mitochondrial membrane potential. The augmentation of O-GlcNAcylation exerted cytoprotective effects on the HRECs by reducing the generation of ROS, increasing the expression of antioxidant genes, preventing the dissipation of mitochondrial membrane potential and preventing HREC apoptosis. Therefore, it can be concluded that O-GlcNAcylation plays a role in the early developmental process of DR.
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Affiliation(s)
- Guo Dong Liu
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Chong Xu
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Le Feng
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Fang Wang
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, P.R. China
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Abstract
Diabetic retinopathy, an oculardisease, is governed by systemic as well as local ocular factors. These include primarily chronic levels of blood glucose. Individuals with chronically elevated blood glucose levels have substantially more, and more severe, retinopathy than those with lower blood glucose levels. The relationship of blood glucose to retinopathy is continuous, with no threshold although individuals with hemoglobin A1c levels (a measure of chronic glycemia) <6.5%, generally develop little or no retinopathy. Blood pressure levels have been claimed to influence retinopathy development and progression, but multiple controlled clinical trials of antihypertensive agents in diabetic subjects have produced only weak evidence of benefit from blood pressure lowering on the incidence and progression of diabetic retinopathy. Elevated blood lipids seem to play a role in the progression of retinopathy, and two trials of fenofibrate, a lipid-lowering agent that has not proved effective in preventing cardiovascular disease, have shown benefit in preventing retinopathy progression. The mechanism of this effect may not, however, be directly related to the reduction in blood lipids. Finally, there is strong, but only circumstantial, evidence for a genetic or epigenetic influence on the pathogenesis of diabetic retinopathy. Despite the power of large-scale epidemiologic studies and modern molecular biological and computational techniques, the gene or genes, which predispose or protect against the development and progression of diabetic retinopathy remain elusive.
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Affiliation(s)
- Robert N Frank
- Department of Ophthalmology, Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USA
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22
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Xu C, Liu G, Liu X, Wang F. O-GlcNAcylation under hypoxic conditions and its effects on the blood-retinal barrier in diabetic retinopathy. Int J Mol Med 2013; 33:624-32. [PMID: 24366041 DOI: 10.3892/ijmm.2013.1597] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Accepted: 12/12/2013] [Indexed: 11/06/2022] Open
Abstract
An increase in O-linked N-acetylglucosamine (O-GlcNAc) protein modifications has been observerd in db/db mouse retinas. O-GlcNAc-modified proteins in the db/db mouse retina have been shown to be localized in the ganglion cell layer, the inner nuclear layer, the retina pigment epithelium (RPE) layer and the inner plexiform layer, in which hypoxia-inducible factor 1α (HIF1α) has also been shown to be localized. In the current study, we examined whether hypoxia increases O-GlcNAcylation in retinal vascular cells under high glucose conditions and whether HIF1α activation is consistent with the response to and activation of O-GlcNAcylation in retinal lesions in diabetic retinopathy. In addition, the effects of O-GlcNAcylation on the blood-retinal barrier were verified in vitro by the inhibition of O-GlcNAcylation. A time-dependent increase in the O-GlcNAcylation in bovine retinal vascular endothelial cells (BRVECs) was observed following incubation of the cells with high glucose medium (glucose 4.5 g/l) under hypoxic (1-3% O2) conditions. Hypoxia-induced BRVEC O-GlcNAcylation was not observed when the BRVECs were transfected with siRNA targeting O-GlcNAc transferase (OGT) or treated with alloxan (an OGT inhibitor) prior to exposure to high glucose. The increase in BRVEC O-GlcNAcylation induced by high glucose, as well as by thiamet G [an O-GlcNAcase (OGA) inhibitor] led to a reduction in occludin expression levels in vitro, which was prevented by treatment with OGT siRNA and alloxan. In conclusion, the current study demonstrates the relationship between O-GlcNAc glycosylation and hypoxia during diabetic retinopathy and that hyperglycemia induced O2 consumption activates HIF1α and O-GlcNAc modification protein in the same retinal layer. The reduced protein BRVEC O-GlcNAcylation levels exert protective effects on the blood-retinal barrier and thus represent a potential therapeutic target for the treatment of diabetic retinopathy.
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Affiliation(s)
- Chong Xu
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Guodong Liu
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Xiaoqiao Liu
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Fang Wang
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, P.R. China
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Arden GB, Sivaprasad S. The pathogenesis of early retinal changes of diabetic retinopathy. Doc Ophthalmol 2012; 124:15-26. [PMID: 22302291 DOI: 10.1007/s10633-011-9305-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2011] [Accepted: 12/14/2011] [Indexed: 01/04/2023]
Abstract
Recent successful trials of antibodies to vascular endothelial growth factor (VEGF) in diabetic retinopathy implicate this cytokine as a major cause of diabetic retinopathy (DR) and diabetic macular oedema (DME). The mechanisms which cause VEGF to be over-expressed to cause the vasculopathy are not entirely clear. This review explores the earliest changes to the retina in DR and the factors that predispose or prevent DR, including sleep apnoea, receptor degenerations laser treatment and VEGF polymorphism. The review also presents the evidence that retinal hypoxia, existing in the earliest stages, causes DR. This hypoxia is much increased by dark adaptation, indicating a new and possibly superior therapy.
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Potential Therapeutic Roles for Inhibition of the PI3K/Akt/mTOR Pathway in the Pathophysiology of Diabetic Retinopathy. J Ophthalmol 2011; 2011:589813. [PMID: 22132311 PMCID: PMC3205601 DOI: 10.1155/2011/589813] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 07/13/2011] [Indexed: 02/08/2023] Open
Abstract
Novel therapeutics such as inhibitors of PI3K/Akt/mTOR pathway presents a unique opportunity for the management of diabetic retinopathy (DR). Second generation mTOR inhibitors have the prospect to be efficacious in managing various stages of disease progression in DR. During early stages, the mTOR inhibitors suppress HIF-1α, VEGF, leakage, and breakdown of the blood-retinal barrier. These mTOR inhibitors impart a pronounced inhibitory effect on inflammation, an early component with diverse ramifications influencing the progression of DR. These inhibitors suppress IKK and NF-κB along with downstream inflammatory cytokines, chemokines, and adhesion molecules. In proliferative DR, mTOR inhibitors suppress several growth factors that play pivotal roles in the induction of pathological angiogenesis. Lead mTOR inhibitors in clinical trials for ocular indications present an attractive treatment option for chronic use in DR with favorable safety profile and sustained ocular pharmacokinetics following single dose. Thereby, reducing dosing frequency and risk associated with chronic drug administration.
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The Optic UK Lecture: bench-to-bedside adventures of a diabetes researcher: results past, results present. Eye (Lond) 2011; 25:331-41. [PMID: 21212801 DOI: 10.1038/eye.2010.195] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
This presentation covers two topics. First is a basic laboratory study, designed to explore the mechanism for the phenomenon of 'early worsening,' in which individuals with type 1 diabetes and early to moderate retinopathy are rapidly placed on 'tight' blood glucose control, after which about 10% of these individuals develop a worsening of retinopathy with the appearance of multiple 'cotton wool' spots. Our studies on cultured retinal cells used vascular endothelial growth factor (VEGF) production as an index of cellular ischaemia. VEGF production increases substantially when cells are cultured in low oxygen, but VEGF production in these hypoxic cultures decreases when the medium contains a fivefold excess glucose concentration. Cultures with no medium glucose also show increased VEGF production. In the clinical situation, we infer from these results that retinas with early retinopathy have a reduced blood supply and are therefore relatively ischaemic, thus increasing their VEGF production. Adding glucose provides an alternative energy supply, thus reducing the demand for VEGF and hence, reducing the likelihood of 'early worsening.' However, reducing the glucose supply to these already compromised retinas further increases their ischaemia and, therefore, the stimulus to produce more VEGF. The second part of this presentation is a clinical exploration of possible reasons for the frequent, wide discrepancy between measured central macular thickness by optical coherence tomography (OCT) and visual acuity in eyes with diabetic macular oedema. I explore the influence of different diseases in which macular oedema appears, the presence or absence, and size, of cystoid cavities; duration of the oedema; age of the subject, different anatomic derangements including epiretinal membranes and disruptions of the photoreceptor layer, and various biochemical and physiological mechanisms.
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