Minireviews
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Apr 15, 2015; 6(3): 500-507
Published online Apr 15, 2015. doi: 10.4239/wjd.v6.i3.500
Tyrosine isomers and hormonal signaling: A possible role for the hydroxyl free radical in insulin resistance
Gergő A Molnár, Esztella Zsóka Mikolás, István András Szijártó, Szilárd Kun, Eszter Sélley, István Wittmann
Gergő A Molnár, Esztella Zsóka Mikolás, István András Szijártó, Szilárd Kun, Eszter Sélley, István Wittmann, 2nd Department of Medicine and Nephrological Center, University of Pécs, H-7624 Pécs, Hungary
Author contributions: Molnár GA and Wittmann I designed the research; Mikolás EZ, Szijártó IA, Kun S and Sélley E performed the research; Molnár GA and Wittmann I wrote the paper.
Supported by The European Union and the State of Hungary and co-financed by the European Social Fund in the framework of TÁMOP 4.2.4. A/2-11-1-2012-0001 National Excellence Program.
Conflict-of-interest: All authors have nothing to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: István Wittmann, MD, PhD, Professor of Medicine, Head of the Department, 2nd Department of Medicine and Nephrological Center, University of Pécs, Pacsirta Str. 1, H-7624 Pécs, Hungary. istvan.wittmann@aok.pte.hu
Telephone: +36-72-536050 Fax: +36-72-536051
Received: September 3, 2014
Peer-review started: September 4, 2014
First decision: November 19, 2014
Revised: December 5, 2014
Accepted: January 9, 2015
Article in press: January 12, 2015
Published online: April 15, 2015
Processing time: 228 Days and 16.2 Hours
Abstract

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.

Keywords: Acetylcholine; Insulin resistance; Hormone resistance; Oxidative stress; Para-tyrosine; Ortho-tyrosine; Meta-tyrosine; Erythropoietin

Core tip: Hydroxyl-free radical-derived amino acids, such as meta- and ortho-tyrosine (m- and o-Tyr, respectively) are regarded as free radical markers, but they may also be taken up and incorporated into blood vessel walls, erythroid precursors and endothelial cells. These pathological amino acids can induce vascular insulin and acetylcholine, as well as cellular erythropoietin resistance.