Tyrosine isomers and hormonal signaling:A possible role for the hydroxyl free radical in insulin resistance

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 acetylcholineinduced 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.