scholarly journals Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes

2021 ◽  
Vol 22 (21) ◽  
pp. 11876
Author(s):  
Eimear M. Byrne ◽  
María Llorián-Salvador ◽  
Timothy J. Lyons ◽  
Mei Chen ◽  
Heping Xu
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
High Glucose ◽  
Macular Oedema ◽  
Diabetic Macular Oedema ◽  
Janus Kinase ◽  
Blood Retinal Barrier ◽  
Albumin Leakage

We have previously reported that inhibition of the Janus kinase 1 (JAK1) signaling ameliorates IL-17A-mediated blood-retinal barrier (BRB) dysfunction. Higher levels of IL-17A have been observed in the blood and intraocular fluids in patients with diabetic retinopathy (DR), in particular those with diabetic macular oedema. This study aimed to understand whether JAK1 inhibition could prevent BRB dysfunction in db/db mice, a model of type 2 diabetes (T2D). An in vitro study showed that high glucose treatment disrupted the junctional distribution of claudin-5 in bEnd3 cells and ZO-1 in ARPE19 cells and that tofacitinib citrate treatment prevented high glucose-mediated tight junction disruption. Albumin leakage, accompanied by increased levels of the phosphorylated form of JAK1 (pJAK1), was observed in three-month-old db/db mice. Treatment of two-and-a-half-month-old db/db mice with tofacitinib citrate for two weeks significantly reduced retinal albumin leakage and reduced pJAK1 expression. pJAK1 expression was also detected in human DR retina. Our results suggest that JAK1 inhibition can ameliorate BRB dysfunction in T2D, and JAK1 inhibitors such as tofacitinib citrate may be re-purposed for the management of diabetic macular oedema.

scholarly journals IL-17A Damages the Blood–Retinal Barrier through Activating the Janus Kinase 1 Pathway

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 831
Author(s):  
Eimear M. Byrne ◽  
María Llorián-Salvador ◽  
Miao Tang ◽  
Andriana Margariti ◽  
Mei Chen ◽  
...  
Keyword(s):  
Macular Oedema ◽  
Retinal Pigment ◽  
Diabetic Macular Oedema ◽  
Janus Kinase ◽  
Age Related Macular Degeneration ◽  
Blood Retinal Barrier ◽  
Age Related ◽  
Albumin Leakage ◽  
Janus Kinase 1

Blood–retinal barrier (BRB) dysfunction underlies macular oedema in many sight-threatening conditions, including diabetic macular oedema, neovascular age-related macular degeneration and uveoretinitis. Inflammation plays an important role in BRB dysfunction. This study aimed to understand the role of the inflammatory cytokine IL-17A in BRB dysfunction and the mechanism involved. Human retinal pigment epithelial (RPE) cell line ARPE19 and murine brain endothelial line bEnd.3 were cultured on transwell membranes to model the outer BRB and inner BRB, respectively. IL-17A treatment (3 days in bEnd.3 cells and 6 days in ARPE19 cells) disrupted the distribution of claudin-5 in bEnd.3 cells and ZO-1 in ARPE19 cells, reduced the transepithelial/transendothelial electrical resistance (TEER) and increased permeability to FITC-tracers in vitro. Intravitreal (20 ng/1 μL/eye) or intravenous (20 ng/g) injection of recombinant IL-17A induced retinal albumin leakage within 48 h in C57BL/6J mice. Mechanistically, IL-17A induced Janus kinase 1 (JAK1) phosphorylation in bEnd.3 but not ARPE19 cells. Blocking JAK1 with Tofacitinib prevented IL-17A-mediated claudin-5 dysmorphia in bEnd.3 cells and reduced albumin leakage in IL-17A-treated mice. Our results suggest that IL-17A can damage the BRB through the activating the JAK1 signaling pathway, and targeting this pathway may be a novel approach to treat inflammation-induced macular oedema.

scholarly journals Prevalence and associated risk factors of diabetic retinopathy and macular oedema in patients recently diagnosed with type 2 diabetes

2020 ◽  
Vol 5 (1) ◽  
pp. e000304
Author(s):  
Enrique O Graue-Hernandez ◽  
David Rivera-De-La-Parra ◽  
Sergio Hernandez-Jimenez ◽  
Carlos A Aguilar-Salinas ◽  
David Kershenobich-Stalnikowitz ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Plasma Glucose ◽  
Macular Oedema ◽  
Diabetic Macular Oedema ◽  
Diabetes Duration ◽  
Haemoglobin A1c ◽  
Associated Risk Factors

ObjectiveTo determine the prevalence of diabetic retinopathy (DR) and diabetic macular oedema (DME) and their associated risk factors in patients recently diagnosed with type 2 diabetes.Methods and analysisWe carried out a cross-sectional study from April 2014 to August 2017. We included patients aged ≥18 years. Diabetes was defined as fasting plasma glucose of >7.8 mmol/L or 2-hour postload plasma glucose of >11.1 mmol/L. Non-mydriatic fundus examination with a digital-fundus camera was performed. Three images centred in the macula, optic disc and temporal to the macula were obtained and graded according to the Scottish Scale Classification of Diabetic Retinopathy.Results1232 patients (mean age 51.5 years) with a diabetes duration of 0–5 years were examined. Age-adjusted and sex-adjusted prevalence of DR and DME was 17.4% (95% CI 15.3% to 19.6%) and 6.6% (95% CI 5.4% to 8.2%), respectively. DR was associated with diabetes duration (OR per year=1.20, p<0.001), haemoglobin A1c (HbA1c) from 7.0 to 8.9 (OR=2.19, p<0.001), HbA1c≥9 (OR=2.98, p<0.001) and systolic blood pressure (SBP) (OR=1.16 per 5 mm Hg, p<0.001). DME was associated with diabetes duration (OR per year=1.26, p<0.01), HbA1c from 7.0 to 8.9 (OR=2.26, p<0.05), HbA1c≥9 (OR=2.38, p<0.01), SBP (OR per mm Hg=1.15, p<0.001) and albuminuria (OR=2.45, p<0.01).ConclusionOur study contributes to the evidence of progressive increase in DR and DME risk in early stages of diabetes, supporting the urgent need for early screening.

scholarly journals Update on the Treatment of Diabetic Retinopathy

2008 ◽  
Vol 8 ◽  
pp. 98-120 ◽  
Author(s):  
Jennifer L. Wilkinson-Berka ◽  
Antonia G. Miller
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Vision Loss ◽  
Fibrous Tissue ◽  
Diabetic Macular Oedema ◽  
Renin Angiotensin System ◽  
Neovascular Glaucoma ◽  
Western Society ◽  
Blood Retinal Barrier

Retinopathy is the most feared complication of diabetes, compromising quality of life in most sufferers. Almost all patients with type 1 diabetes will develop retinopathy over a 15- to 20-year period, and approximately 20–30% will advance to the blinding stage of the disease[1]. Greater than 60% of patients with type 2 diabetes will have retinopathy. This situation is highlighted by the frightening statistic that diabetic retinopathy (DR) remains the most common cause of vision impairment in people of working age in Western society. With the global epidemic of type 2 diabetes, this predicament is set to worsen as over 360 million people are projected to suffer from diabetes and its complications by 2030. Vision loss from diabetes is due to a number of factors, including haemorrhage from new and poorly formed blood vessels, retinal detachment due to contraction of deposited fibrous tissue, and neovascular glaucoma resulting in an increase in intraocular pressure. Diabetic macular oedema is now the principal cause of vision loss in diabetes and involves leakage from a disrupted blood-retinal barrier. In terms of treatment, there is clear evidence that strict metabolic and blood pressure control can lower the risk of developing DR and reduce disease progression. Laser photocoagulation and vitrectomy are effective in preventing severe vision loss in DR, particularly in the most advanced stages of the disease. However, both procedures have limitations. This review examines evidence from preclinical and clinical studies that shows that targeting inhibition of the renin-angiotensin system, vascular endothelial growth factor, corticosteroids, protein kinase C, growth hormone, and advanced glycation end-products are potential treatments for DR.

Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

2019 ◽  
Vol 105 (4) ◽  
pp. e1549-e1560 ◽  
Author(s):  
Bénédicte Gaborit ◽  
Jean-Baptiste Julla ◽  
Samaher Besbes ◽  
Matthieu Proust ◽  
Clara Vincentelli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Fundus Photography ◽  
Endothelial Cell Proliferation ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Aims Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. Methods We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs. We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. Results In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800–1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. Conclusions The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.

scholarly journals High-glucose 3D INS-1 cell model combined with a microfluidic circular concentration gradient generator for high throughput screening of drugs against type 2 diabetes

RSC Advances ◽  
2018 ◽  
Vol 8 (45) ◽  
pp. 25409-25416 ◽  
Author(s):  
Yong Luo ◽  
Xiuli Zhang ◽  
Yujiao Li ◽  
Jiu Deng ◽  
Xiaorui Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pharmaceutical Industry ◽  
High Throughput ◽  
Concentration Gradient ◽  
High Glucose ◽  
High Throughput Screening ◽  
Cell Model ◽  
Gradient Generator

In vitro models for screening of drugs against type 2 diabetes are crucial for the pharmaceutical industry.

scholarly journals Optical Coherence Tomography Biomarkers of the Outer Blood—Retina Barrier in Patients with Diabetic Macular Oedema

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Ioana Damian ◽  
Simona Delia Nicoara
Keyword(s):  
Diabetic Retinopathy ◽  
Macular Oedema ◽  
Statistical Tests ◽  
Diabetic Macular Oedema ◽  
Control Group ◽  
Main Role ◽  
Blood Retinal Barrier ◽  
Retinal Layers ◽  
Set Up ◽  
Almost All

Background. Numerous studies confirmed the main role of the inner blood-retinal barrier in the development of Diabetic Macular Oedema (DMO). Lately, the focus of research shifted towards the external retinal barrier with potential involvement in the pathogenesis of DMO. Objective. We aim to identify the OCT changes of the external blood-retinal barrier in patients with DMO and to define them as biomarkers with predictive value. Materials and method. We set up retrospectively 3 groups of patients diagnosed with nonproliferative diabetic retinopathy (NPDR) and DMO, proliferative diabetic retinopathy (PDR) and DMO, and controls. We compared the RPE thickness in every quadrant between groups and performed correlations between best-corrected visual acuity (BCVA) and the thickness of the retinal layers. The Social Science Statistics platform was used for statistical tests. Results. The NPDR-DMO group consisted of 18 eyes, the PDR-DMO group consisted of 19 eyes, and the control group included 36 eyes. In the PDR-DMO group, RPE thickness was decreased in almost all quadrants ( p < 0.001 ); in the NPDR-DMO group, only the central minimum and central maximum values of the RPE thickness were significantly different from the control group. We did not find any strong correlation between BCVA and the thickness of the retinal layers. Conclusion. The thickness of the RPE layer is an OCT biomarker able to predict the functioning of the outer BRB. Eyes with PDR-DMO exhibited decreased thickness of the RPE layer in almost all quadrants, highlighting the degenerative changes occurring in a hypoxic environment. The thickness of a specific layer could not be identified as a biomarker to correlate significantly with BCVA, most likely because we did not analyze specific morphologic features, such as continuity and reflectivity. The analysis of the RPE thickness could clarify the unexplained decrease of BCVA and predict early the evolution of DR.

scholarly journals Associations with sight-threatening diabetic macular oedema among Indigenous adults with type 2 diabetes attending an Indigenous primary care clinic in remote Australia: a Centre of Research Excellence in Diabetic Retinopathy and Telehealth Eye and Associated Medical Services Network study

2021 ◽  
Vol 6 (1) ◽  
pp. e000559
Author(s):  
Laima Brazionis ◽  
Anthony Keech ◽  
Christopher Ryan ◽  
Alex Brown ◽  
David O'Neal ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Primary Care ◽  
Renal Impairment ◽  
Macular Oedema ◽  
Primary Care Clinic ◽  
Diabetic Macular Oedema ◽  
Diabetes Duration ◽  
Care Clinic ◽  
Men And Women

ObjectiveTo identify factors associated with sight-threatening diabetic macular oedema (STDM) in Indigenous Australians attending an Indigenous primary care clinic in remote Australia.Methods and analysisA cross-sectional study design of retinopathy screening data and routinely-collected clinical data among 236 adult Indigenous participants with type 2 diabetes (35.6% men) set in one Indigenous primary care clinic in remote Australia. The primary outcome variable was STDM assessed from retinal images.ResultsAge (median (range)) was 48 (21–86) years, and known diabetes duration (median (range)) was 8.0 (0–24) years. Prevalence of STDM was high (14.8%) and similar in men and women. STDM was associated with longer diabetes duration (11.7 vs 7.9 years, respectively; p<0.001) and markers of renal impairment: abnormal estimated Glomerular Filtration Rate (eGFR) (62.9 vs 38.3%, respectively; p=0.007), severe macroalbuminuria (>300 mg/mmol) (20.6 vs 5.7%, respectively; p=0.014) and chronic kidney disease (25.7 vs 12.2%, respectively; p=0.035). Some clinical factors differed by sex: anaemia was more prevalent in women. A higher proportion of men were smokers, prescribed statins and had increased albuminuria. Men had higher blood pressure, but lower glycated Haemoglobin A1c (HbA1c) levels and body mass index, than women.ConclusionSTDM prevalence was high and similar in men and women. Markers of renal impairment and longer diabetes duration were associated with STDM in this Indigenous primary care population. Embedded teleretinal screening, known diabetes duration-based risk stratification and targeted interventions may lower the prevalence of STDM in remote Indigenous primary care services.Trial registration numberAustralia and New Zealand Clinical Trials Register: ACTRN 12616000370404.

scholarly journals A New Human Blood–Retinal Barrier Model Based on Endothelial Cells, Pericytes, and Astrocytes

2020 ◽  
Vol 21 (5) ◽  
pp. 1636 ◽  
Author(s):  
Claudia G. Fresta ◽  
Annamaria Fidilio ◽  
Giuseppe Caruso ◽  
Filippo Caraci ◽  
Frank J. Giblin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
High Glucose ◽  
Potential Effect ◽  
Blood Retinal Barrier ◽  
Retinal Astrocytes ◽  
Set Up ◽  
The Impact

Blood–retinal barrier (BRB) dysfunction represents one of the most significant changes occurring during diabetic retinopathy. We set up a high-reproducible human-based in vitro BRB model using retinal pericytes, retinal astrocytes, and retinal endothelial cells in order to replicate the human in vivo environment with the same numerical ratio and layer order. Our findings showed that high glucose exposure elicited BRB breakdown, enhanced permeability, and reduced the levels of junction proteins such as ZO-1 and VE-cadherin. Furthermore, an increased expression of pro-inflammatory mediators (IL-1β, IL-6) and oxidative stress-related enzymes (iNOS, Nox2) along with an increased production of reactive oxygen species were observed in our triple co-culture paradigm. Finally, we found an activation of immune response-regulating signaling pathways (Nrf2 and HO-1). In conclusion, the present model mimics the closest human in vivo milieu, providing a valuable tool to study the impact of high glucose in the retina and to develop novel molecules with potential effect on diabetic retinopathy.

scholarly journals Lower Hemoglobin Concentration Is Associated with Retinal Ischemia and the Severity of Diabetic Retinopathy in Type 2 Diabetes

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Alicia Traveset ◽  
Esther Rubinat ◽  
Emilio Ortega ◽  
Nuria Alcubierre ◽  
Beatriz Vazquez ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Oxygen Transport ◽  
Macular Oedema ◽  
Retinal Ischemia ◽  
Blood Oxygen ◽  
Transport Capacity ◽  
Oxygen Transport Capacity ◽  
Beta Coefficient

Aims. To assess the association of blood oxygen-transport capacity variables with the prevalence of diabetic retinopathy (DR), retinal ischemia, and macular oedema in patients with type 2 diabetes mellitus (T2DM).Methods. Cross-sectional, case-control study (N=312) with T2DM: 153 individuals with DR and 159 individuals with no DR. Participants were classified according to the severity of DR and the presence of retinal ischemia or macular oedema. Hematological variables were collected by standardized methods. Three logistic models were adjusted to ascertain the association between hematologic variables with the severity of DR and the presence of retinal ischemia or macular oedema.Results.Individuals with severe DR showed significantly lower hemoglobin, hematocrit, and erythrocyte levels compared with those with mild disease and in individuals with retinal ischemia and macular oedema compared with those without these disorders. Hemoglobin was the only factor that showed a significant inverse association with the severity of DR [beta-coefficient = −0.52,P value = 0.003] and retinal ischemia [beta-coefficient = −0.49,P value = 0.001]. Lower erythrocyte level showed a marginally significant association with macular oedema [beta-coefficient = −0.86,P value = 0.055].Conclusions.In patients with DR, low blood oxygen-transport capacity was associated with more severe DR and the presence of retinal ischemia. Low hemoglobin levels may have a key role in the development and progression of DR.

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