GLUCOSE-OXIDATION AND LOW-DENSITY LIPOPROTEIN-INDUCED MACROPHAGE CEROID ACCUMULATION - POSSIBLE IMPLICATIONS FOR DIABETIC ATHEROSCLEROSIS

The exposure of proteins to high concentrations of glucose in vitro is widely considered a relevant model of the functional degeneration of tissue occurring in diabetes mellitus. In particular, the enhanced ath erosclerosis in diabetes is often discussed in terms of glycation of l ow-density lipoprotein (LDL), the nonenzymic attachment of glucose to apolipoprotein amino groups. However, glucose can undergo transition-m etal-catalysed oxidation under near-physiological conditions in vitro, producing oxidants that possess a reactivity similar to the hydroxyl radical. These oxidants can fragment protein, hydroxylate benzoic acid and induce lipid peroxidation in human LDL. In this study, glycation of LDL in vitro is accompanied by such oxidative processes. However, t he oxidation of LDL varies with glucose concentration in a manner whic h does not parallel changes in protein glycation. Glycation increases in proportion to glucose concentration, whereas in our studies maximal oxidation occurs at a glucose concentration of approx. 25 mM. The mod ification of LDL resulting from exposure to glucose alters macrophage ceroid accumulation, a process which occurs in the human atherosclerot ic plaque. The accumulation of ceroid in macrophages is shown to be re lated to LDL oxidation rather than LDL glycation, per se, as it too oc curs at a maximum of approx. 25 mM. Oxidative sequelae of protein glyc ation appear to be a major factor in LDL-macrophage interactions, at l east with respect to ceroid accumulation. Our observations are discuss ed in the context of the observed increase in the severity of atherosc lerosis in diabetes.