Increased basal levels of plasma nitric oxide in Type 2 diabetic subjects. Relationship to microvascular complications.

To assess the underlying mechanisms of decreased endothelial function and advanced vascular complications in patients with Type 2 diabetes, we determined basal levels of plasma nitric oxide (NO(x): NO(2)(-) and NO(3)(-)) using a newly developed high-performance liquid chromatography (HPLC)-Griess method in hospitalized 129 diabetic and 76 nondiabetic subjects, and examined their clinical characteristics. Serum lipid peroxide and advanced glycation end products (AGEs) as markers of oxidative stress were also measured, and intima-media thickness (IMT) of the carotid artery was evaluated as a marker of atherosclerosis. In diabetic subjects, microvascular complications were newly evaluated during their admission. There were no differences in age or sex between the diabetic and nondiabetic subjects. Although there was no difference in basal plasma NO(2)(-) levels between the two groups, the basal levels of plasma NO(3)(-) in diabetic subjects were significantly higher than those in nondiabetic subjects. Plasma NO(x) levels in neither diabetic nor nondiabetic subjects correlated with serum lipids, HbA1c, or IMT. In diabetic subjects, plasma NO(3)(-) levels were related not only to the presence of hypertension but also to advanced microvascular complications. Moreover, plasma NO(3)(-) levels were positively correlated with both serum lipid peroxide and AGEs. Multiple regression analysis revealed that serum AGEs level was strongly associated with plasma NO(3)(-) level. Thus, the findings are consistent with the hypothesis that decreased endothelium-dependent vasodilation in diabetic subjects is associated with the impaired action of NO secondary to its inactivation resulting from increased oxidative stress, rather than decreased NO production from vascular endothelium, and that abnormal NO metabolism is related to advanced diabetic microvascular complications.