Date of Award
Doctor of Philosophy (PhD)
Moom R. Roosan
Untreated diabetes mellitus leads to development of microvascular and macrovascular complications affecting heart, nerves, kidney, and eyes. While the etiological mechanisms of diabetes-associated retinopathy and cataract have been well characterized, the time kinetics and the severity of diabetes-mediated injury to the ocular surface and its various components like tear film, goblet cells and glycocalyx, has not yet been investigated. These pathological changes can potentially cause dry eye and corneal injury including epithelial erosion, impaired wound healing and keratopathy. As the mainstay treatment option for the management of dry eye disease due to diabetes mellitus, artificial tears are frequently used. Therefore, we critically reviewed the ingredients present in artificial tears and also their formulation aspects and how these factors impact the biological activity and therapeutic effectiveness of artificial tears. Further, using mouse models of type 1 and type 2 diabetes mellitus, our data for the first time demonstrates that, in addition to chronic hyperglycemia, short-duration hyperglycemia causes a rapid-onset ocular surface injury as demonstrated by a decrease in tear film volume, loss of goblet cells, and reduction in corneal glycocalyx. This hyperglycemia-mediated ocular surface injury presents much earlier on and is more severe in type 1 diabetes mellitus compared to type 2 diabetes mellitus. Our data also shows that maintaining euglycemia remarkably prevents the development of diabetes associated early-onset ocular surface injury. We next investigated the mechanism underlying the high glucose-mediated damage to the glycocalyx and its various components. High glucose exposure did not significantly alter the expression and spatial distribution of membrane-tethered mucins (MUC1, MUC4 and MUC16), their o-glycosylated side chains and glycosyltransferases. However, high glucose reduced the gene expression of several key protein mediators involved in the cell cycle and proliferation of ocular surface epithelial cells, suggesting that this is a novel mechanism underlying hyperglycemia-mediated damage to the glycocalyx. Furthermore, compromised glycocalyx and barrier function was also associated with concomitant upregulation of proinflammatory genes and genes involved in apoptosis and cellular stress in the diabetic cornea 28 days after the onset of hyperglycemia. This mechanism could be responsible for a vicious cycle of inflammation to perpetuate diabetes-associated ocular surface injury.
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Weng, J. Characterization of Ocular Surface Pathology and Tear Film Dysfunction Due to Type 1 and Type 2 Diabetes Mellitus. [dissertation]. Irvine, CA: Chapman University; 2023. https://doi.org/10.36837/chapman.000508
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