MODIFIED LIPOPROTEINS, CYTOKINES AND MACROVASCULAR DISEASE IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS

The processes of glycation and oxidation play a significant role in th e acceleration of atherosclerosis in diabetes mellitus. Glycation is t hought not only to increase the susceptibility of low-density lipoprot ein (LDL) to oxidation but also to enhance the propensity of vessel wa ll structural proteins to bind extravasated plasma proteins, including LDL, and thus to contribute to a more marked oxidative modification o f LDL. Glycated and oxidized lipoproteins induce cholesteryl ester acc umulation in human macrophages and may promote platelet and endothelia l cell dysfunction. Furthermore, these modified lipoproteins have the ability to trigger an autoimmune response that leads to the formation of autoantibodies and subsequently to the formation of immune complexe s containing LDL. Both the modified lipoproteins and the immune comple xes formed with autoantibodies reactive with modified lipoproteins may be responsible for several alternative and not mutually exclusive pat hways leading to foam cell formation, macrophage activation and endoth elial cell damage and may thus be of potential significance in initiat ing and/or contributing to the acceleration of the development of athe rosclerosis. In this review we discuss how modified LDL affects lipopr otein metabolism, how immune complexes containing LDL induce the trans formation of macrophages into foam cells and promote macrophage activa tion leading to the release of cytokines and thus initiating a sequenc e of events leading to endothelial cell damage and to the recruitment and activation of leucocytes. We also summarize our work showing that macrophage activation by LDL containing immune complexes leads to a pa radoxical increase in LDL-receptor expression thus further impairing c holesterol homeostasis and enhancing the development of atheromatous l esions.