Oxidative stress processes play a major role in the development of the complications associated with diabetes and other diseases via non-enzymatic glycation, the
hexosamine pathway, the
polyol pathway and
diacylglycerol-
protein kinase C. Oxidative stress may lead to the production of
hydroxyl free radicals, which can attack macromolecules, such as
lipids,
nucleic acids or
amino acids.
Phenylalanine (Phe) can be enzymatically converted to the physiological
para-tyrosine (p-Tyr); however, a
hydroxyl free radical attack on Phe may yield meta- and
ortho-tyrosine (m- and o-Tyr, respectively) in addition to p-Tyr. Hence, m- and o-Tyr may be regarded as markers of
hydroxyl free radical-induced damage. Their accumulation has been described; e.g., this accumulation has been found in the urine of patients with
diabetes mellitus (DM) and/or
chronic kidney disease, in
cataract lenses, in vessel walls, in irradiated food and in amniotic fluid, and it may serve as an
indicator of oxidative stress. The use of
resveratrol to treat patients with type 2 DM led to a decrease in the urinary excretion of o-Tyr and concomitantly led to an improvement in
insulin signaling and
insulin sensitivity. Literature data also suggest that m- and o-Tyr may interfere with intracellular signaling. Our group has shown that
erythropoietin (EPO) has
insulin-like metabolic effects on fat cells in addition to its ability to promote the proliferation of erythroid precursor cells. We have shown that the supplementation of cell culture medium with m- and o-Tyr inhibits erythroblast cell proliferation, which could be ameliorated by p-Tyr. Additionally, in vivo, the o-Tyr/p-Tyr ratio is higher in patients with
renal replacement therapy and a greater need for EPO. However, the o-Tyr/p-Tyr ratio was an independent determinant of EPO-resistance indices in our human study. The o-Tyr content of blood vessel walls inversely correlates with
insulin- and
acetylcholine-induced vasodilation, which could be further impaired by artificial oxidative stress and improved by the use of
antioxidants. In rats that receive o-Tyr supplements, decreased vasorelaxation is detected in response to
insulin. Additionally, o-Tyr supplementation led to the incorporation of the unnatural
amino acid into cellular
proteins and caused a decrease in the
insulin-induced phosphorylation of
endothelial nitric oxide synthase. Our data suggest that m- and o-Tyr may not only be markers of oxidative stress; instead, they may also be incorporated into cellular
proteins, leading to resistance to
insulin, EPO and
acetylcholine.