Nitrosative stress in early Type 1 diabetes. David H. P. Streeten Memorial Lecture.

Although hyperglycemia has been shown to cause peripheral nerve dysfunction in patients with diabetes, the biochemical mechanisms for this effect are poorly understood. The excessive production of reactive oxygen species and reactive nitrogen species has been proven to be detrimental in experimental diabetes, but there is little evidence that these metabolic events take place clinically and are physiologically important in man. To assess this we measured nitrite and nitrate (indices of nitric oxide production), nitrotyrosine (an index of peroxynitrite), 8-isoprostaglandin F-2 alpha, an isoprostane reflective of oxidative stress and lipid peroxidation, and uric acid, an index of antioxidant defense in patients with recently diagnosed Type 1 diabetes and aged-matched controls. The diabetic patients were followed for three years. We documented the overproduction of nitric oxide and increased lipid peroxidation in early diabetes and showed these changes had detectable adverse effects on peripheral nerve function especially sympathetic sudomotor nerves. We documented the suppression of uric acid and showed this was associated with multiple abnormalities in autonomic function. In addition, we present indirect evidence that overproduction of reactive oxygen species and reactive nitrogen species have adverse effects on beta cell function and blood pressure.