Saker, Saker
(2016)
Diabetic retinopathy: in vitro and clinical studies of mechanisms and pharmacological treatments.
PhD thesis, University of Nottingham.
Abstract
Diabetic retinopathy (DR) is the leading cause of visual impairment in the working-age population in developed countries and thus is one of the major ocular health problems worldwide. Diabetes seems to have paradoxical effects on the microvasculature in different tissues. The concentration of glucose in the cellular microenvironment determines the cells ability to proliferate, as well as its permeability, and react to different cytokines. The main cause of visual loss in diabetic eye disease is caused by an increase in microvascular endothelial permeability which leads to vessel leakage and fluid build-up, diabetic macular oedema (DMO). Endothelial cell permeability is influenced by multiple factors which have not been fully elucidated, particularly in human models. In addition, the gene and protein expression between retinal and choroidal endothelial cells, even in humans, has been shown to be affected differently by diabetes. Current treatments for DMO include steroid such as dexamethasone (DEX) and anti-vascular endothelial growth factor (VEGF) drugs (e.g. ranibizumab, Novartis). These target reducing vascular leakage in the macula once it has occurred, but do not attempt to treat the underlying pathology and evidence suggests treatment does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macula. With the introduction of microperimetry, we are able to determine macular sensitivity and to correlate it with a precise location of oedema. The aim of this project was to investigate, in vitro, the role of hyperglycaemia in the pathogenesis of DR through effects on the proliferation, vascular permeability and/or alteration in adhesion molecule expression of the human ocular micro-vascular endothelial cells (EC). This was supplemented with clinical studies on pharmacological treatments for DMO.
The main conclusions made were that high glucose increased retinal EC (REC) permeability in vitro and that this increase was likely caused by a decrease in selective tight junction protein expression. The levels of the angiogenic stimulator VEGF-A in the REC were not altered by high glucose, despite increased expression of the related gene hypoxia inducible factor (HIF)-1a levels. DEX both reduced permeability and restored tight junction expression and a combination of DEX and ranibizumab reduced REC permeability more than either agent alone in vitro. Fixation stability is dependent on foveal cone function. Eyes with good visual acuity normally have excellent fixation stability. However, eyes with poor visual acuity may have reduced fixation. Clinically, this study has shown that DMO eyes with good fixation stability related to good central cone function, normally demonstrate good visual acuity. Where fixation stability is impaired, VA may be reduced. VA changes following treatment of DMO correlated better with fixation stability parameters than with morphological changes on OCT. Fixation stability may, therefore, be a new important parameter in quantifying and predict the functional impact of DMO, and may be, other macular disorders.
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