Serum paraoxonase is reduced in type 1 diabetic patients compared to non-diabetic, first degree relatives; influence on the ability of HDL to protectLDL from oxidation

Paraoxonase is a serum enzyme with an anti-oxidant function, protecting low density lipoproteins (LDL) from oxidative modifications. Diabetic patients are suggested to be at greater risk of oxidative stress, which may contrib ute to the significantly higher incidence of vascular disease in this popul ation. Less efficient protection mechanisms may be one feature of the great er susceptibility to oxidation in diabetes. In this context, the present st udy examined the hypothesis that serum paraoxonase is reduced in type 1 (in sulin-dependent) diabetic patients and that the reduction can affect the an ti-oxidant capacity of HDL. Serum paraoxonase concentrations and activities were compared in type 1 patients and first degree, non-diabetic relatives with particular attention paid to the confounding effects of paraoxonase ge ne polymorphisms. In addition, the ability of HDL-paraoxonase to protect lo w density lipoproteins from oxidation was analysed in an in vitro system. S erum concentrations and enzyme activities of paraoxonase were significantly lower in type 1 patients compared to non-diabetic, first degree relatives. The differences were independent of promoter and coding region polymorphis ms, which influence serum concentrations and activities of the enzyme. Over all, paraoxonase concentrations were a mean 13.3 +/- 4.5% lower (P < 0.02) in type 1 patients. Specific activities did not differ between diabetic and non-diabetic groups. The concentration ratios of LDL cholesterol:paraoxona se (1.37 +/- 0.51 vs. 1.18 +/- 0.37, P = 0.003) and apolipoprotein B:paraox onase (0.84 +/- 0.33 vs. 0.71 +/- 0.40; P = 0.012) were significantly highe r in diabetic patients, consistent with a reduced capacity to protect LDL f rom oxidation. In vitro oxidation studies showed that a significantly highe r level of lipid hydroperoxides was generated in LDL in the presence of HDL , containing paraoxonase levels equivalent to those of type 1 patients, com pared to HDL containing paraoxonase levels equivalent to those of control s ubjects (mean difference 8.1%, P < 0.05). The study demonstrates that serum concentrations of the antioxidant enzyme paraoxonase are significantly low er in type 1 (insulin-dependent) diabetic patients compared to non-diabetic , first-degree relatives, independently of known gene polymorphisms. Concen trations are reduced to an extent that can affect its anti-oxidant capacity . The results are consistent with the contention that modifications to seru m paraoxonase in type 1 patients can increase risk of lipoprotein oxidation and, consequently, risk of vascular disease. (C) 2001 Elsevier Science Ire land Ltd. All rights reserved.