Nourooz-Zadeh, Jaffar; (2004) Biomarkers of oxidative stress in diabetic polyneuropathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Aims/Hypothesis: Oxidative stress has been implicated in the development of diabetic neuropathy. The objective of this study was to establish if type 1 or type 2 diabetes in the presence of polyneuropathy (PNP) and/or cardiovascular autonomic neuropathy (CAN) is associated with alterations in plasma and urinary measures of oxidative stress. Studied population: Diabetic patients (n=185; type1: n=61 and type 2: n=124) were recruited. Of these, 60 patients were without PNP and CAN, 103 patients with PNP but without CAN and 22 patients with PNP and CAN. Non-diabetic subjects (n=70) were employed as controls. Methods: Plasma and urinary 8-epi-PGF2α and its metabolites were measured by gas- chromatography/mass-spectrometry. Plasma total antioxidant capacity (TAC) was assessed by quenching of peroxiynitrite Pholasin® chemiluminescence (peroxynitrite-QPC), quenching of superoxide anion Pholasin® chemiluminescence (superoxide anion-QPC) and quenching of hypochlorous acid Pholasin® chemiluminescence (hypochlorous acid-QPC). Plasma vitamin C was assayed spectrofluorometrically. Plasma vitamin E was determined by HPLC with fluorometric detection. Results: Type 1 diabetic patients (PNP-/CAN-) had lower TAC (peroxynitrite-QPC, superoxide anion-QPC), vitamin C levels, vitamin E cholesterol/ratios, and 8-epi-PGF2α concentrations than in control subjects. Lower TAC (superoxide anion-QPC) and increased 8-epi-PGF2α concentrations were seen in the presence PNP. The additional presence of CAN was associated with further reductions in TAC (peroxynitrite-QPC and superoxide anion-QPC) and vitamin E/cholesterol ratios. Type 2 diabetic patients (PNP-/CAN-) exhibited lower TAC (peroxynitrite-QPC, superoxide anion-QPC), and vitamin E cholesterol/ratios compared to control subjects. Lower TAC (peroxynitrite-QPC and superoxide anion-QPC), vitamin C levels and vitamin E/cholesterol ratios, and increased 8-epi-PGP2α concentrations were observed the presence of PNP. Lower TAC (superoxide anion-QPC) was seen in the presence of additional CAN. Correlations occurred between neurological impairment score of the lower limb (NIS-LL) and peroxynitrite-QPC, superoxide anion-QPC as well as vitamin C levels. Multiple regression analysis revealed that peroxynitrite-QPC was independently associated with the neurological impairment score of the lower limb. Urinary 8-epi-PGF2α and its metabolites levels were lower in diabetic patients than in control subjects. However, no firm conclusion could be drawn concerning urinary 8-epi-PGF2α and its metabolites because the results exhibited substantial variability. Conclusions: This study has revealed that oxidative stress is enhanced in diabetic patients (PNP-/CAN-). Oxidative stress was more pronounced in patients with PNP and that the additional presence of CAN was without influence. Measurement of TAC, as assessed by peroxynitrite-QPC or superoxide anion-QPC, was superior in the terms of simplicity, cost and diagnostic value to nutrient antioxidants and lipid-oxidation products in assessing oxidative stress. These results indicate improved strategies for patient selection for clinical trials involving antioxidants aimed at the prevention or treatment of diabetic neuropathy.

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