Hypouricemia linked to an overproduction of nitric oxide is an early marker of oxidative stress in female subjects with type 1 diabetes

Abstract

Oxidative stress is already present in the early stages of type 1 diabetes. We conclude that the initial increase in oxidative stress could be linked to a reduction in plasmatic levels of uric acid, which is probably directly caused by an overproduction of NO.

Oxidative stress and autonomic nerve function in early type 1 diabetes

“…There is evidence that diabetes compromises these desirable effects presumably because the overabundance of the superoxide anion inactivates NO by converting it to peroxynitrite, which, in turn, is broken down to nitrate, nitrite and oxygen [9,11]. This is consistent with the animal studies [5] and clinical data just reviewed which have shown that the NOx is increased in patients with diabetes [15,29]. How can NO be both excessive and deficient?…”

“…We also measured urate in our longitudinal study of diabetes, and demonstrated that it was decreased by 25% in early type 1 diabetes (Table 1). Moreover, we and Pitocco [29] documented a negative correlation between urate and glycosylated hemoglobin which indicates that the suppression of the former is a compensatory response to hyperglycemia related oxidative stress. Peroxynitrite is the major oxidant which reacts with urate, but the superoxide anion and hydrogen peroxide can also do so, but they are not as potent oxidizers as is peroxynitrite [31].…”

“…It has been debated, however, whether oxidative stress drives nitrosative stress or vice versa. Some have argued that hyperglycemia leads to oxidative stress which, in turn, activates NFRB which then augments the gene expression of inducible NOS [26,29,38]. Accordingly, oxidative stress damages DNA in animal models, and this activates PARP (as discussed above) which also upregulates inducible NOS [9].…”

“…NO synthesized elsewhere, for example in macrophages, epithelial cells, hepatocytes and vascular smooth muscle derives from inducible NOS [38]. The gene expression of inducible NOS is mediated by NFRB, which, in turn, is activated by hyperglycemia and oxidative stress, as described above [27,29,38]. Inducible NOS is a quantitatively more important source of NO in the whole patient than endothelial NOS, and this may explain the discrepancy between the physiological studies of endothelial cells (where NO has decreased bioavailability) and the biochemical studies of the whole patient (where NOx is excessive).…”

“…2) The most parsimonious explanation of this finding is that hyperglycemia stimulates oxidative stress, which then activates PARP which, in turn, increases inducible NOS [9]. Thirdly, Pitocco et al [29] observed an inverse correlation between NOx and uric acid, an endogenous antioxidant, which suggests that patients with increased NOx had greater oxidative stress and therefore decreased uric acid. Fourthly, we have observed a correlation between NOx and free 8-iso-PGFF2 alpha in early type 1 diabetes (Fig.…”