Decreased Protection by HDL From Poorly Controlled Type 2 Diabetic Subjects Against LDL Oxidation May Be Due to the Abnormal Composition of HDL

Abstract

Abstract-High plasma triglyceride concentrations in diabetic subjects increase their risk for developing coronary heart disease. Numerous studies have shown that the high density lipoprotein (HDL) composition is abnormal in type 2 diabetic subjects. One study has shown that HDL (lipoprotein A-I) isolated from subjects with non-insulin-dependent diabetes mellitus exhibits a decreased capacity to induce cholesterol efflux. The current study examined the effect of HDL 2 and HDL 3 subfractions from poorly controlled type 2 diabetic and control subjects on THP-1 macrophagemediated low density lipoprotein (LDL) oxidation. The composition and protective effects of HDL 2 , but not of HDL 3 , differed significantly between control and diabetic subjects. HDL 2 from diabetics were triglyceride enriched and cholesterol depleted compared with those from controls. Control HDL 2 inhibited LDL oxidation, as assessed by lipid peroxides and electrophoretic mobility, significantly (PϽ0.05) more than did diabetic HDL 2 in both the fasting and postprandial state. In addition, HDL 2 from diabetics did not protect against apolipoprotein B-100 fragmentation in LDL. Cross-linking in apolipoprotein A-I, oxidized in the presence of LDL, was extensive in HDL 2 from diabetics compared with that from controls. Serum triglyceride concentrations were negatively correlated with protection by HDL 2 (rϭϪ0.673, PϽ0.05) in diabetic but not in control subjects. HDL 2 -associated platelet-activating factor acetylhydrolase activity was positively correlated with protection by HDL 2 in control (rϭ0.872, PϽ0.002) but not in diabetic subjects.In conclusion, compositional alterations in HDL 2 from poorly controlled type 2 diabetic subjects may reduce its antiatherogenic properties.

Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation

“…Interestingly, in type 2 diabetic patients, the antioxidant capacity of HDL can be decreased, whereas PON and PAF-AH activities are similar to those measured in controls [11], indicating that in type 2 diabetes mellitus other factors than the decrease of PON and PAF-AH activities are likely to impair HDL antioxidant activity. Thus, in our study, a normal PON activity in HDL from type 2 diabetic patients does not preclude impairment of the antioxidant capacity of these HDL.…”

“…In previously published works, HDL from patients with metabolic syndrome or type 2 diabetes mellitus were less protective against LDL oxidation than HDL from healthy subjects, and the antioxidative capacity of HDL was inversely correlated with plasma and HDL TG [11,27,28]. The lesser antioxidant capacity of HDL from type 2 diabetic patients is likely to contribute to the lesser ability of these particles to counteract the inhibitory effect of ox-LDL on endothelium-dependent vasorelaxation.…”

“…PON and PAF-AH activities have inconstantly been found to be decreased and related to HDL antioxidant capacity in type 2 diabetic patients [11,[27][28][29]. Interestingly, in type 2 diabetic patients, the antioxidant capacity of HDL can be decreased, whereas PON and PAF-AH activities are similar to those measured in controls [11], indicating that in type 2 diabetes mellitus other factors than the decrease of PON and PAF-AH activities are likely to impair HDL antioxidant activity.…”

“…The mechanisms underlying the decreased antioxidant capacity of HDL from type 2 diabetic patients are not well understood. However, TGs appear to play an important role, since a strong inverse correlation was found between the content of HDL in TGs and their antioxidant properties in several studies [11,27,28]. Moreover, it has recently been demonstrated that the replacement of cholesteryl esters by TGs in HDL abrogates the HDL-mediated protection against LDL oxidation [28].…”

“…Measurement of paraoxonase activity PON activity was measured as already described in fresh HDL samples within 2 days of isolation [11]. It was assayed in tubes containing Tris-HCl buffer (150 mmol/l NaCl, 1 mmol/l CaCl2, pH 7.4) and 100 μg proteins of HDL (final volume 800 μl).…”