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Diabetes and Retinal Vascular Dysfunction

Authors:
Eui Seok Shin at Samsung Advanced Institute of Technology
Eui Seok Shin
Christine M Sorenson
Christine M Sorenson
Christine M Sorenson
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Nader Sheibani at University of Wisconsin–Madison
Nader Sheibani
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Abstract and Figures

Diabetes predominantly affects the microvascular circulation of the retina resulting in a range of structural changes unique to this tissue. These changes ultimately lead to altered permeability, hyperproliferation of endothelial cells and edema, and abnormal vascularization of the retina with resulting loss of vision. Enhanced production of inflammatory mediators and oxidative stress are primary insults with significant contribution to the pathogenesis of diabetic retinopathy (DR). We have determined the identity of the retinal vascular cells affected by hyperglycemia, and have delineated the cell autonomous impact of high glucose on function of these cells. We discuss some of the high glucose specific changes in retinal vascular cells and their contribution to retinal vascular dysfunction. This knowledge provides novel insight into the molecular and cellular defects contributing to the development and progression of diabetic retinopathy, and will aid in the development of innovative, as well as target specific therapeutic approaches for prevention and treatment of DR.
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... constructed a new model of gastric ulcers by local injection of ferrous and ascorbic acid solutions (Fe/ASA) into the gastric wall to cause ulceration, demonstrating that lipid peroxidation mediated by superoxide radicals generated by the Fe/ASA system played an important role in ulcer development. Hyperglycaemia increases oxidative stress through the overproduction of superoxide in the mitochondrial electron transport chain [35], leading to development of diabetic vascular complications, including DR [36]. The retina itself is very sensitive to oxidative stress due to the constant attack of ROS-producing ultraviolet light and high-energy visible light and the large amount of polyunsaturated fatty acids in the outer segments of the optic rod cells of the retina, which are prone to lipid peroxidation [37]. ...
Ferrous ascorbate as a potential biomarker for diabetic retinopathy: a vitreous humour metabolomics study
Article
Full-text available
  • Jun 2024
  • BMC Ophthalmol
Background This study aimed to explore differences in vitreous humour metabolites and metabolic pathways between patients with and without diabetic retinopathy (DR) and identify potential metabolite biomarkers. Methods Clinical data and vitreous fluid samples were collected from 125 patients (40 without diabetes, 85 with DR). The metabolite profiles of the vitreous fluid samples were analysed using ultra-high performance liquid chromatography, Q-Exactive mass spectrometry, and multivariate statistical analysis. A machine learning model based on Least Absolute Shrinkage and Selection Operator Regularized logistic regression was used to build a risk scoring model based on selected metabolite levels. Candidate metabolites were regressed to glycated haemoglobin levels by a logistic regression model. Results Twenty differential metabolites were identified between the DR and control groups and were significantly enriched in five Kyoto Encyclopedia of Genes and Genomes pathways (arginine biosynthesis; tricarboxylic acid cycle; alanine, aspartate, and glutamate metabolism; tyrosine metabolism; and D-glutamate metabolism). Ferrous ascorbate significantly contributes to poorer glycaemic control outcomes, offering insights into potential new pathogenic pathways in DR. Conclusions Disorders in the metabolic pathways of arginine biosynthesis, tricarboxylic acid cycle, alanine, aspartate, glutamate metabolism, tyrosine metabolism, and D-glutamate metabolism were associated with DR. Risk scores based on vitreous fluid metabolites can be used for the diagnosis and management of DR. Ferrous ascorbate can provide insights into potential new pathogenic pathways for DR.
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Citation: Diabetes and Its Cardiovascular Complications: Comprehensive Network and Systematic Analyses
Article
Full-text available
  • Feb 2022
Diabetes mellitus is a worldwide health problem that usually comes with severe complications. There is no cure for diabetes yet and the threat of these complications is what keeps researchers investigating mechanisms and treatments for diabetes mellitus. Due to advancements in genomics, epigenomics, proteomics, and single-cell multiomics research, considerable progress has been made toward understanding the mechanisms of diabetes mellitus. In addition, investigation of the association between diabetes and other physiological systems revealed potentially novel pathways and targets involved in the initiation and progress of diabetes. This review focuses on current advancements in studying the mechanisms of diabetes by using genomic, epigenomic, proteomic, and single-cell multiomic analysis methods. It will also focus on recent findings pertaining to the relationship between diabetes and other biological processes, and new findings on the contribution of diabetes to several pathological conditions.
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Ferrous Ascorbate as A Potential Biomarker for Diabetic Retinopathy: A Vitreous Humour Metabolomics Study
Preprint
Full-text available
  • Mar 2024
Background This study aimed to explore differences in vitreous humour metabolites and metabolic pathways between patients with and without diabetic retinopathy (DR) and identify potential metabolite biomarkers. Methods Clinical data and vitreous fluid samples were collected from 125 patients (40 without diabetes, 85 with DR). The metabolite profiles of the vitreous fluid samples were analysed using ultra-high performance liquid chromatography, Q-Exactive mass spectrometry, and multivariate statistical analysis. A machine learning model based on Least Absolute Shrinkage and Selection Operator Regularized logistic regression was used to build a risk scoring model based on selected metabolite levels. Candidate metabolites were regressed to glycated haemoglobin levels by a logistic regression model. Results Twenty differential metabolites were identified between the DR and control groups and were significantly enriched in five Kyoto Encyclopedia of Genes and Genomes pathways (arginine biosynthesis; tricarboxylic acid cycle; alanine, aspartate, and glutamate metabolism; tyrosine metabolism; and D-glutamate metabolism). Ferrous ascorbate was risk factor for glycaemic control. Conclusions Disorders in the metabolic pathways of arginine biosynthesis, tricarboxylic acid cycle, alanine, aspartate, glutamate metabolism, tyrosine metabolism, and D-glutamate metabolism were associated with DR. Risk scores based on vitreous fluid metabolites can be used for the diagnosis and management of DR. Ferrous ascorbate can provide insights into potential new pathogenic pathways for DR.
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Article
Full-text available
  • Feb 2024
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Article
Full-text available
  • Jun 2024
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The glucocorticoid receptor as a master regulator of the Müller cell response to diabetic conditions in mice
Article
Full-text available
  • Jan 2024
  • J NEUROINFLAMM
Diabetic retinopathy (DR) is considered a primarily microvascular complication of diabetes. Müller glia cells are at the centre of the retinal neurovascular unit and play a critical role in DR. We therefore investigated Müller cell-specific signalling pathways that are altered in DR to identify novel targets for gene therapy. Using a multi-omics approach on purified Müller cells from diabetic db/db mice, we found the mRNA and protein expression of the glucocorticoid receptor (GR) to be significantly decreased, while its target gene cluster was down-regulated. Further, oPOSSUM TF analysis and ATAC- sequencing identified the GR as a master regulator of Müller cell response to diabetic conditions. Cortisol not only increased GR phosphorylation. It also induced changes in the expression of known GR target genes in retinal explants. Finally, retinal functionality was improved by AAV-mediated overexpression of GR in Müller cells. Our study demonstrates an important role of the glial GR in DR and implies that therapeutic approaches targeting this signalling pathway should be aimed at increasing GR expression rather than the addition of more ligand. Graphical Abstract
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Article
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Article
Full-text available
  • Jun 2013
Diabetic peripheral neuropathy (DPN) is a frequent complication of diabetes and a major cause of morbidity and increased mortality. It is typically characterized by significant deficits in tactile sensitivity, vibration sense, lower-limb proprioception, and kinesthesia. Painful diabetic neuropathy (P-DPN) is a common phenotype of DPN that affects up to one-third of the general diabetic population. P-DPN has been shown to be associated with significant reductions in overall quality of life, increased levels of anxiety and depression, sleep impairment, and greater gait variability. The purpose of this review is to examine proposed mechanisms of P-DPN, summarize current treatment regimen, and assess exercise as a potential therapy for P-PDN. Although exercise has been shown to be an effective therapeutic modality for diabetes, its specific effects on DPN and especially the painful phenotype have not been sufficiently investigated in current literature. Several rodent models and clinical trials have presented promising results in this area, and warrant further investigations examining the effect of exercise on P-DPN.
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STAT1-mediated Bim expression promotes the apoptosis of retinal pericytes under high glucose conditions
Article
Full-text available
  • Jan 2014
Hyperglycemia impacts different vascular cell functions and promotes the development and progression of various vasculopathies including diabetic retinopathy. Although the increased rate of apoptosis in pericytes (PCs) has been linked to increased oxidative stress and activation of protein kinase C-δ (PKC-δ) and SHP-1 (Src homology region 2 domain-containing phosphatase-1) tyrosine phosphatase during diabetes, the detailed mechanisms require further elucidation. Here we show that the rate of apoptosis and expression of proapoptotic protein Bim were increased in the retinal PCs of diabetic Akita/+ mice and mouse retinal PCs cultured under high glucose conditions. Increased Bim expression in retinal PCs under high glucose conditions required the sustained activation of signal transducer and activator of transcription 1 (STAT1) through production of inflammatory cytokines. PCs cultured under high glucose conditions also exhibited increased oxidative stress and diminished migration. Inhibition of oxidative stress, PKC-δ or Rho-associated protein kinase I/II was sufficient to protect PCs against apoptosis under high glucose conditions. Furthermore, PCs deficient in Bim expression were protected from high glucose-mediated increased oxidative stress and apoptosis. However, only inhibition of PKC-δ lowered Bim levels. N-acetylcysteine did not affect STAT1 levels, suggesting that oxidative stress is downstream of Bim. PCs cultured under high glucose conditions disrupted capillary morphogenesis of retinal endothelial cells (ECs) in coculture experiments. In addition, conditioned medium prepared from PCs under high glucose conditions attenuated EC migration. Taken together, our results indicate that Bim has a pivotal role in the dysfunction of retinal PCs under high glucose conditions by increasing oxidative stress and death of PCs.
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Thrombospondin-1 Deficiency Exacerbates the Pathogenesis of Diabetic Retinopathy
Article
Full-text available
  • May 2013
Diabetic retinopathy is a leading cause of blindness in the United States. Access to new animal models that exhibit retinal vasculopathies with short duration of diabetes, are vital for understanding the underlying mechanisms and examining the efficacy of new treatment modalities. Our previous studies demonstrated decreased expression of Thrombospondin-1 (TSP1), an endogenous inhibitor of angiogenesis, in eyes from both patients and rodents with diabetes. Here we examined whether TSP1 deficiency could exacerbate diabetic retinal vasculopathies. Akita/+ male mice reproducibly develop diabetes by 4 weeks of age. These mice demonstrated the early non-proliferative stages of diabetic retinopathy, including decreased numbers of pericytes and increased glial cell activation. However, Akita/+ male mice deficient in TSP1 (Akita/+; TSP1-/-) demonstrated more advanced stages of diabetic retinopathy with a 4-fold increase in acellular capillaries and increased fibronectin and GFAP expression. These vascular changes were not attributable to aberrant retinal vascular development in the absence of TSP1, since down-regulation of TSP1 postnatally in the endothelium also resulted in more severe retinopathy. In addition, lack of another endogenous inhibitor of angiogenesis, pigment epithelium derived factor (PEDF), also enhanced diabetic retinopathy in Akita/+ mice. Akita/+; PEDF-/- male mice demonstrated increased numbers of acellular capillaries compared to controls but at a level lower than that observed in Akita/+; TSP1-/- mice. Thus, the exacerbation of diabetic retinopathy in Akita/+; TSP1-/- mice will allow the study of retinal vasculopathies with a shorter duration of diabetes and facilitate future testing of treatment modalities that protect the retinal vasculature and preserve sight.
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NRF2 plays a protective role in diabetic retinopathy in mice
Article
Full-text available
  • Nov 2013
  • DIABETOLOGIA
Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR. Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human Müller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints. NRF2 was expressed prominently in Müller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood-retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes. These results indicate that NRF2 is an important protective factor regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy.
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Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina
Article
Full-text available
  • Sep 2013
  • P NATL ACAD SCI USA
Significance Studies of diabetic retinopathy have focused especially on the retinal vasculature, but recent studies suggest that the neural retina also is involved. Oxidative stress and local inflammatory changes have been shown to play important roles in the pathogenesis of this retinopathy, but the source of reactive oxygen species has been less clear. We now show that most of the oxidative stress in retinas of diabetic mice emanates from neural photoreceptor cells, and elimination of these cells in diabetes inhibits both the oxidative stress and inflammatory changes shown to cause the vascular lesions of diabetic retinopathy. These studies suggest a mechanism by which neural cells can initiate the vascular injury characteristic of diabetic retinopathy.
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Global prevalence and major risk factors of diabetic retinopathy
Article
  • Mar 2012
  • DIABETES CARE
To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20-79 years. A total of 35 studies (1980-2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5-34.8) for any DR, 6.96% (6.87-7.04) for proliferative DR, 6.81% (6.74-6.89) for diabetic macular edema, and 10.2% (10.1-10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A(1c), and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.
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The Prevalence of Diabetic Retinopathy Among Adults in the United States
Article
  • Apr 2004
  • ARCH OPHTHALMOL-CHIC
Objective: To determine the prevalence of diabetic retinopathy among adults 40 years and older in the United States. Methods: Pooled analysis of data from 8 population-based eye surveys was used to estimate the prevalence, among persons with diabetes mellitus (DM), of retinopathy and of vision-threatening retinopathy-defined as proliferative or severe nonproliferative retinopathy and/or macular edema. Within strata of age, race/ethnicity, and gender, US prevalence rates were estimated by multiplying these values by the prevalence of DM reported in the 1999 National Health Interview Survey and the 2000 US Census population. Results: Among an estimated 10.2 million US adults 40 years and older known to have DM, the estimated crude prevalence rates for retinopathy and vision-threatening retinopathy were 40.3% and 8.2%, respectively. The estimated US general population prevalence rates for retinopathy and vision-threatening retinopathy were 3.4% (4.1 million persons) and 0.75% (899000 persons). Future projections suggest that diabetic retinopathy will increase as a public health problem, both with aging of the US population and increasing age-specific prevalence of DM over time. Conclusion: Approximately 4.1 million US adults 40 years and older have diabetic retinopathy; 1 of every 12 persons with DM in this age group has advanced, vision-threatening retinopathy.
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Multifocal Electroretinogram Delays Predict Sites of Subsequent Diabetic Retinopathy
Article
  • Mar 2004
  • INVEST OPHTH VIS SCI
PURPOSE. To examine the potential of abnormal mfERGs to predict the development of diabetic retinopathy at corresponding retinal locations 1 year later. METHODS. One eye of 11 diabetic patients with nonproliferative diabetic retinopathy (NPDR) and 11 diabetic patients without retinopathy were retested 12 months after initial testing. At each time, mfERGs were recorded from 103 retinal locations, and fundus photographs were taken within 1 month of each recording. Local mfERG implicit times were measured and their z-scores were calculated based on results obtained from 20 age-matched control subjects. mfERG abnormalities were defined as z-scores of 2 or more for implicit time and z-scores of -2 or less for amplitude (P ≤ 0.023). mfERG z-scores were mapped onto fundus photographs, and the relationship between baseline abnormal z-scores and new retinopathy at follow-up was examined. RESULTS. New retinopathy developed in 7 of the eyes with NPDR after 1 year. In these eyes, 70% of the mfERGs in areas of new retinopathy had abnormal implicit times at baseline. In contrast, only 24% of the responses in regions that remained retinopathy free were abnormal at baseline. Relative risk of development of new retinopathy over 1 year in the areas with abnormal baseline mfERG implicit times was approximately 21 times greater than that in the areas with normal baseline mfERGs (odds ratio = 31.4; P < 0.001). Eyes without initial retinopathy did not develop new retinopathy within the study period, although 4 of these 11 eyes had abnormal implicit times at baseline. mfERG implicit times tended to be more delayed at follow-up than at baseline in NPDR eyes, but not in eyes without retinopathy and control eyes. mfERG amplitudes had no predictive power. CONCLUSIONS. Localized functional abnormalities of the retina reflected by mfERG delays often precede the onset of new structural signs of diabetic retinopathy. Those functional abnormalities predict the local sites of new retinopathy observed 1 year later.
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