Autoantibodies Against Oxidatively Modified Low-Density Lipoproteins in NIDDM

Abstract

Diabetes is an independent risk factor in the development of atherosclerosis, although the pathophysiological processes underlying this association are poorly understood. The oxidation of low-density lipoprotein (LDL) is considered a key event in the development and progression of atherosclerosis because it generates molecular epitopes that are more atherogenic than parent LDL. A total of 138 patients suffering from non-insulin-dependent diabetes mellitus (NIDDM) and 80 matched control subjects were investigated. LDL oxidation was evaluated as the presence of autoantibodies against oxidatively modified LDL, since they mirror the in vivo occurrence of oxidative processes. NIDDM patients had an antibody ratio (calculated as the ratio of antibodies against modified versus native LDL) significantly higher than control subjects for Cu2+-oxidized LDL (1.88 ± 0.6 vs. 1.05 ± 0.3, P < 0.01, for IgG), malondialdehyde-modified LDL (2.54 ± 0.73 vs. 2.04 ± 0.11, P < 0.01, for IgG and 3.96 ± 1.51 vs. 2.90 ± 0.15, P < 0.01, for IgM), and malondialdehyde-modified human serum albumin (1.79 ± 0.54 vs. 1.46 ± 0.1, P < 0.05 for IgG). The possible role played by glycation in sensitizing LDL to oxidation was investigated by measuring autoantibodies against both glycated LDL (glycLDL) and glycoxydated LDL (glycoxLDL). NIDDM patients had an antibody ratio significantly higher than control subjects for anti-glycLDL and anti-glycoxLDL IgG (1.79 ± 0.38 vs. 1.12 ± 0.23, P < 0.01 and 2.55 ± 1.03 vs. 1.39 ± 0.44, P < 0.01, respectively) but not anti-glycLDL and anti-glycox-LDL IgM. These results demonstrate that in NIDDM patients enhanced LDL oxidation occurs in vivo and that LDL glycation may represent a predisposing event that facilitates subsequent oxidative modifications.