Effect of insulin resistance on serum paraoxonase activity in a nondiabetic population

Paraoxonase is a high-density lipoprotein (HDL)-bound esterase that hydrolyzes various organophosphorus compounds and protects low-density lipoprotein (LDL) against accumulation of lipid peroxides. Paraoxonase activity is strongly affected by the polymorphism of the paraoxonase gene (PON1) at position 192. In addition, the enzyme activity shows a great variation within each genotype, although the underlying mechanism is unknown. Because paraoxonase activity is decreased in subjects with type 2 diabetes mellitus who have insulin resistance, we investigated the association between paraoxonase activity and insulin resistance in a nondiabetic population. The subjects were 237 healthy Japanese adults with fasting plasma glucose less than 7.0 mmol/L. Paraoxonase activity was measured using paraoxon as a routine substrate. Insulin resistance was assessed by homeostasis model assessment index (HOMA index). Paraoxonase activity was affected by HDL level. To reduce the effect of HDL on paraoxonase, paraoxonase activity/HDL ratio was used. When the subjects were divided into tertiles by HOMA index, the subjects with higher HOMA values had higher paraoxonase/HDL ratios, although the 3 groups were comparable in age, gender and the PON1 genotype distribution. Paraoxonase/HDL ratio showed significant positive correlations not only with HOMA index, but also with body mass index, waist-to-hip ratio (WHR), whereas it correlated inversely with age at borderline significance. Multiple regression analysis indicated that the association between HOMA index and paraoxonase/HDL ratio was significant and independent of PON1 genotype, age, and adipocity. The positive association between HOMA index and HDL-corrected enzyme activity was again significant when the enzyme activity was measured with diazoxon as an alternative substrate. These results suggest that insulin resistance or hyperinsulinemia is a factor contributing to the intragenotype variability of paraoxonase activity in a population without overt hyperglycemia.