Paraoxonase 1 phenotype distribution and activity differs in subjects with newly diagnosed Type 2 diabetes (the CODAM Study)

Aims Paraoxonase 1 (PON1) is an antioxidant high-density lipoprotein-bound enzyme, which was recently found to be expressed in the islets of Langerhans. A substitution (Q/R) at position 192 results in enzymes with different activity. Oxidation has been implicated in the onset of diabetes, and it can be hypothesized that PON1 may have a protective effect on diabetes. Our aim was to compare PON1 activities and PON1 Q/R phenotypes in subjects with different degrees of glucose intolerance. Methods We examined 566 members of the Cohort study of Diabetes and Atherosclerosis Maastricht (CoDAM), including subjects with normal glucose tolerance (NGT, n = 298), impaired glucose regulation (IGR, n = 128), newly diagnosed Type 2 diabetes (nDM, n = 78) and treated, that is to say known, Type 2 diabetes (kDM, n = 64). PON1 activity was measured in serum using paraoxon and diazoxon as substrates. The PON1 phenotype was determined using two-dimensional enzyme analysis. Results The RR-phenotype was significantly more frequent in nDM compared with NGT subjects (14.1 vs. 6.0%, P = 0.05). Adjusted for the PON1 phenotype, subjects with nDM had significant lower PON1 activity towards paraoxon and diazoxon than subjects with NGT. Adjusted odds ratios comparing the RR-variant with the QQ-variant were 2.17 [95% confidence interval (CI): 0.90-5.24] for impaired glucose tolerance, 2.84 (95% CI: 1.03-7.83) for nDM, 2.13 (95% CI; 0.61-7.42) for kDM and 2.65 (95% CI: 1.10-6.40) for total diabetes mellitus. Conclusions An aberrant PON1 phenotype distribution and PON1 activity were observed in early diabetes. In addition, the higher state of oxidative stress may affect the future development of complications.