Figure 2: Function of HDL in normal versus hyperglycemic state. (A) In early atherogenesis, hypercholesterolemia promotes accumulation of LDL particles in the arterial subendothelial space. LDL accumulation provokes an inflammatory response that results in oxidative modification of LDL and, subsequently, an augmented expression of various leukocyte adhesion molecules expressed on the surface of the arterial endothelial cells. Healthy HDL functions to sequester oxidized lipid products from LDL and promote reverse cholesterol transport from macrophages whose scavenger receptors preferentially bind modified lipoproteins, thereby preventing atheroma formation. (B) Under hyperglycemic conditions, the ability of HDL to metabolize and remove oxidized lipids is compromised by glycation. The enhanced lipid peroxidation causes the endothelium to produce monocyte chemoattractants and express leukocyte adhesion molecules. Continued macrophage uptake of oxidized LDL phospholipids and diminished HDL-mediated cholesterol efflux results in atheroma formation. The oxidation of HDL-associated antioxidants via glucose-mediated oxidative stress eventually results in HDL particles that act as pro-inflammatory molecules, further exacerbating the local inflammatory cycle. Abbreviations: Gly-HDL, glycosylated high-density lipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCP-1, monocyte chemotactic protein 1; Ox-LDL, oxidized low-density lipoprotein.