Advanced glycosylation endproducts in the pathogenesis of the late complications of diabetes and atherosclerosis

Pathology

Lee, Wai Kwong

University:University of Glasgow

关键词: Pathology;   

Others  :  http://theses.gla.ac.uk/71829/1/10391490.pdf

来源: University of Glasgow

【 摘 要 】

The accumulation of advanced glycosylation endproducts (AGE) is important in the pathogenesis of the late complications of diabetes and atherosclerosis. This thesis examined the levels of AGE in proteins incubated with glucose in vitro, in tissues from diabetic animals, in human autopsy material and in patients with end stage renal disease. The measurement of AGE was carried out using protein-linked fluorescence. I have attempted to determine the contribution of oxidative processes to generation of protein-linked fluorescence by studying the effect of glucose, aminoguanidine and antioxidants on the formation of the early and late products of the Maillard reaction. We have demonstrated that the Maillard reaction is affected by oxidative processes at the early stages of Amadori product formation, rather than at the stage of AGE formation. In animal studies, the role of AGE in diabetic complications has been studied using alloxan and streptozotocin (STZ) to induce experimental diabetes in animals. We measured AGE in the tissues of spontaneously diabetic BB/E rats. We demonstrated that the levels of AGE are increased in diabetic rats when compared to non-diabetic rats and that the rate of AGE formation differs in different tissues. The BB/E rat offers a good model for the investigation of AGE. Interactions of lipoprotein with extracellular matrix components contribute to atherogenesis. Oxidation of LDL has been shown to affect LDL-collagen interactions. We studied the binding of native and oxidised LDL to unmodified and AGE-modified type I collagen. We have demonstrated that both AGE modification and oxidation of LDL affect LDL-collagen interactions. While the Maillard reaction is ubiquitous, changes observed in diabetic complications and atherosclerosis are tissue-specific. In this study we have demonstrated AGE-specific fluorescence in different forms of human atherosclerotic plaque. Importantly, AGE content was altered amongst the different types of atherosclerotic plaques. Also individuals with mild to moderate atheroma have lower CLP in superficial atherosclerotic plaques than patients with severe atheroma. Plasma levels of AGE are elevated in patients with end stage renal disease. It has also been shown that after renal transplantation plasma AGE decrease. Our study has focused on tissue levels of AGE in non-diabetic and diabetic patients with renal disease before and after transplantation. We have demonstrated that tissue levels of AGE decrease after renal transplantation. In summary, studies described in this thesis contributed to the validation of the measurement of collagen-linked fluorescence as a method of measurement of tissue AGE accumulation. We have demonstrated tissue differences in AGE accumulation in a spontaneously diabetic animal. Focusing on human atherosclerotic plaque we observed local differences in AGE concentration in atherosclerotic aorta. We also demonstrated that AGE-modification affects the interaction of native and oxidised LDL with type I collagen. Finally our studies were first to demonstrate that renal transplantation decreases AGE level in tissues.