Progression of retinopathy and alteration of the blood-retinal barrier in patients with type 2 diabetes: a 7-year prospective follow-up study

Cunha-Vaz, Josè; Lobo, Conceição; Sousa, João C.; Oliveiros, Bárbara; Leite, E.; Abreu, J. R. Faria de

doi:10.1007/s004170050075

Cited by 17 publications

(5 citation statements)

References 7 publications

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“…ET alteration in DM may also serve as a surrogate marker of endothelial dysfunction. In addition to vasoconstriction, increased permeability may also contribute to nonperfusion and ischemia in target organs of late complications [44,45]. The exchange between blood and tissues represents an important function of endothelial cells.…”

Section: Structural Alterationsmentioning

confidence: 99%

Towards Newer Molecular Targets for Chronic Diabetic Complications

Khan¹,

Farhangkhoee²,

Chakrabarti

2006

CVP

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Prior to the discovery of insulin, the major cause of death in the diabetic population was ketoacidosis. Although insulin and improved glycemic control have improved the longevity of diabetic patients, they still suffer from significant morbidity and mortality due to chronic secondary complications. Long standing diabetes leads to structural and functional alterations in both the micro- and macrovasculature. These complications, involving the retina, kidney, and peripheral nerves, as well as cardiovascular system, severely compromise the quality and expectancy of life. Large scale clinical trials have identified hyperglycemia as the key determinant for the development of such complications. Therapeutic modalities have been developed to target glucose-induced alterations, such as protein kinase C activation, augmented polyol pathway activity, non-enzymatic glycation and oxidative stress to ameliorate chronic complications. However, clinical trials targeting these biochemical alterations have failed to show significant beneficial effects. The plethora of biochemical anomalies that govern the development of chronic diabetic complications may therefore be subject to cross-interaction and complex interplays. Studies in both animal and human diabetes have, however, showed alteration of several vasoactive effector molecules such as endothelins. These molecules may be instrumental in mediating diabetes-induced structural and functional deficits at both the early and late stages of the disease. This review will discuss the current mechanistic understanding of chronic diabetic complications and will explore the potential novel therapeutic interventions.

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Section: Structural Alterationsmentioning

confidence: 99%

Towards Newer Molecular Targets for Chronic Diabetic Complications

Khan¹,

Farhangkhoee²,

Chakrabarti

2006

CVP

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“…There are various approaches to quantification of iBRB dysfunction in patients, but irrespective of the technique employed [3, 4], it is established that this lesion occurs early in clinical diabetic retinopathy [5] and is associated with progression of the disease [6]. Breakdown of the iBRB is also a feature of experimental diabetes in animal models, being observed as early as 1-2-week postdiabetes induction in rodents [7, 8].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Advanced Glycation and Absence of Galectin‐3 Prevent Blood‐Retinal Barrier Dysfunction during Short‐Term Diabetes

Canning¹,

Glenn²,

Hsu

et al. 2007

Journal of Diabetes Research

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Breakdown of the inner blood-retinal barrier (iBRB) occurs early in diabetes and is central to the development of sight-threatening diabetic macular edema (DME) as retinopathy progresses. In the current study, we examined how advanced glycation end products (AGEs) forming early in diabetes could modulate vasopermeability factor expression in the diabetic retina and alter inter-endothelial cell tight junction (TJ) integrity leading to iBRB dysfunction. We also investigated the potential for an AGE inhibitor to prevent this acute pathology and examined a role of the AGE-binding protein galectin-3 (Gal-3) in AGE-mediated cell retinal pathophysiology. Diabetes was induced in C57/BL6 wild-type (WT) mice and in Gal-3−/− transgenic mice. Blood glucose was monitored and AGE levels were quantified by ELISA and immunohistochemistry. The diabetic groups were subdivided, and one group was treated with the AGE-inhibitor pyridoxamine (PM) while separate groups of WT and Gal-3−/− mice were maintained as nondiabetic controls. iBRB integrity was assessed by Evans blue assay alongside visualisation of TJ protein complexes via occludin-1 immunolocalization in retinal flat mounts. Retinal expression levels of the vasopermeability factor VEGF were quantified using real-time RT-PCR and ELISA. WT diabetic mice showed significant AGE -immunoreactivity in the retinal microvasculature and also showed significant iBRB breakdown (P < .005). These diabetics had higher VEGF mRNA and protein expression in comparison to controls (P < .01). PM-treated diabetics had normal iBRB function and significantly reduced diabetes-mediated VEGF expression. Diabetic retinal vessels showed disrupted TJ integrity when compared to controls, while PM-treated diabetics demonstrated near-normal configuration. Gal-3−/− mice showed significantly less diabetes-mediated iBRB dysfunction, junctional disruption, and VEGF expression changes than their WT counterparts. The data suggests an AGE-mediated disruption of iBRB via upregulation of VEGF in the diabetic retina, possibly modulating disruption of TJ integrity, even after acute diabetes. Prevention of AGE formation or genetic deletion of Gal-3 can effectively prevent these acute diabetic retinopathy changes.

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“…Another important ®eld is vision research, in which scienti®c assessment is particularly active at the Oftalmological Clinic, University Hospital and Faculty of Medicine of Coimbra (Cunha-Vaz, 1997, 2000aCunha-Vaz et al, 1998). Lens¯uorescence measurements, the role of cholesterol oxidation on cataract pathogenesis, the involvement of blood±retinal barrier and choroidal circulatory changes on age-related macular degeneration are among the main points of interest (Alfaiate et al, 1996;Fernandes et al, 1996a,b;Mota et al, 1996;Pereira et al, 1996;Ramalho et al, 1996;Lobo et al, 1999;Gira Äo et al, 1998Gira Äo et al, , 1999.…”

Section: Scienti®c Activity In Research On Aging In Portugalmentioning

confidence: 99%

Familial Roles and Social Transformations

Oppong

2006

Res Aging

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This review presents an analysis of the current state of gerontological and geriatric research in Portugal, and highlights the need for a national consensus and funding for age-related research projects. Such efforts must be multidisciplinary, since the process of aging encompasses biological, psychological, social, economic and cultural aspects. Demographic studies reveal a growing population of elderly in Portugal as a result of a healthier population in general. This increased life expectancy, however, is accompanied by a parallel increase in degenerative pathologies and care costs among the elderly. Preventive medicine is an important tool to reduce health care costs and avoid or abbreviate suffering from age-related syndromes, but such projects on a national basis neither exists, nor does gerontology or geriatrics receive funding to perform needed research. Consequently, research on aging depends on the initiative of individual investigators who, without funding or cohesive programs, can do little to improve the low scienti®c output in this area. The implementation of a national program, that can establish health care policy and priorities as well as fund the necessary research, will permit organized cooperation among the different scienti®c disciplines related to aging. This is a crucial step toward improving present knowledge, ensuring application of experimental and statistical results to the clinical care of the aging population, and attract young investigators to this ®eld.

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Progression of retinopathy and alteration of the blood-retinal barrier in patients with type 2 diabetes: a 7-year prospective follow-up study

Cited by 17 publications

References 7 publications

Towards Newer Molecular Targets for Chronic Diabetic Complications

Towards Newer Molecular Targets for Chronic Diabetic Complications

Inhibition of Advanced Glycation and Absence of Galectin‐3 Prevent Blood‐Retinal Barrier Dysfunction during Short‐Term Diabetes

Familial Roles and Social Transformations

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