Evidence implicates
hyperglycemia-derived
oxygen free radicals as mediators of
diabetic complications. However, intervention studies with classic
antioxidants, such as
vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single
hyperglycemia-induced process of overproduction of
superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of
diabetic complications. These include increased
polyol pathway flux, increased advanced glycosylation end product formation, activation of
protein kinase C, and increased
hexosamine pathway flux.
Superoxide overproduction is accompanied by increased
nitric oxide generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong
oxidant peroxynitrite, which in turn damages
DNA. DNA damage is an obligatory stimulus for the activation of the nuclear
enzyme poly(ADP-ribose) polymerase.
Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate
NAD(+), slowing the rate of glycolysis, electron transport, and
ATP formation, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of
diabetic complications. These new findings may explain why classic
antioxidants, such as
vitamin E, which work by scavenging already-formed toxic oxidation products, have failed to show beneficial effects on
diabetic complications and may suggest new and attractive "causal"
antioxidant therapy. New low-molecular mass compounds that act as SOD or
catalase mimetics or L-
propionyl-carnitine and
lipoic acid, which work as intracellular
superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This "causal"
therapy would also be associated with other promising tools such as
LY 333531,
PJ34, and FP15, which block the
protein kinase beta
isoform,
poly(ADP-ribose) polymerase, and
peroxynitrite, respectively. While waiting for these focused tools, we may have other options: thiazolinediones,
statins,
ACE inhibitors, and
angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property.