WHAT IS THE EFFECT OF HYPERGLYCEMIA ON ATHEROGENESIS AND CAN IT BE REVERSED BY AMINOGUANIDINE

Reducing sugars such as glucose react non-enzymatically with the amino groups of proteins and lipids to initiate a chemical modification pat hway known as advanced glycosylation. Recent progress in our understan ding of this process has affirmed the hypothesis that advanced glycosy lation endproducts (AGEs) play an important role in the evolution of b oth diabetic and non-diabetic vascular disease. Utilizing newly develo ped AGE-specific ELISA techniques, AGEs have been identified to be pre sent on a variety of vascular wall, lipoprotein, and lipid constituent s. Vascular wall AGEs contribute to vascular pathology by acting to in crease vascular permeability, enhance subintimal protein and lipoprote in deposition, and inactivate the endothelium-derived relaxing factor, nitric oxide. Lipid-linked AGEs also have been shown to initiate oxid ative modification, thus promoting the formation of oxidized low-densi ty lipoprotein. AGE-specific ELISA analysis has demonstrated. signific antly increased level of AGE-modified LDL in the plasma of diabetic pa tients when compared to normal controls. Furthermore, LDL which has be en modified by advanced glycosylation exhibits markedly impaired clear ance kinetics in vivo. Thus, AGE-modification impairs LDL-receptor-med iated clearance mechanisms and contributes to elevated LDL levels in p atients with diabetes. This concept has been substantiated recently by the clinical observation that administration of the advanced glycosyl ation inhibitor aminoguanidine to diabetic patients significantly decr eases circulating LDL levels.