Glycation impairs high-density lipoprotein function

Aims/hypothesis. To examine the effects of incubation of high-density lipop rotein (HDL) under hyperglycaemic conditions on several functions of HDL in vitro. Methods. Human HDL (5 mg protein) was incubated for 1 week at 37 degrees C in the presence or absence of 25 mmol/l glucose. Additional samples of huma n HDL were incubated in butylated hydroxytoluene to control for oxidation. Results. High-density lipoprotein incubated for 1 week in 25 mmol/l glucose had significant increases in the glycation product, fructoselysine and in the advanced glycation end product, N-epsilon-(carboxymethyl)lysine. High-d ensity lipoprotein apolipoprotein AI and AII concentrations were not altere d but glycated HDL had a 65 % reduction in paraoxonase enzymatic activity. Glycated HDL did not inhibit monocyte adhesion to human aortic endothelial cells in response to oxidised low-density lipoprotein in vitro (43 +/- 4 mo nocytes bound vs 21 +/- 2monocytes for control HDL, p < 0.0001). Hepatic li pase-mediated non-esterified fatty acid release from HDL lipids was enhance d in glycated HDL compared with control HDL (25 +/- 1 vs 16 +/- 1 nmol non- esterified fatty acid hydrolysed/min. respectively, p < 0.0001). Direct gly cation of purified paraoxonase protein by incubation in 25 mmol/l glucose c aused a 40 % reduction in enzymatic activity. This glycated paraoxonase did not inhibit monocyte adhesion to human aortic endothelial cells in vitro ( 68 +/- 3 monocytes vs 49 +/- 2 monocytes bound for control paraoxonase, res pectively, p < 0.001). We also measured a 40% reduction in paraoxonase acti vity in patients with Type II (non-insulin-dependent) diabetes mellitus and documented coronary artery disease compared with nondiabetic subjects, p < 0.0001. Conclusions/interpretation. Alterations in function of HDL caused by exposu re to hyperglycaemic conditions could contribute to the accelerated atheros clerosis observed in Type II diabetes.