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

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.

Upregulation of GABA receptor promotes long‑term potentiation and depotentiation in the hippocampal CA1 region of mice with type 2 diabetes mellitus

“…The increase in blood glucose levels of the T2DM mice in the current study is consistent with a previous report indicating that insulin homeostasis defects lead to T2DM, resulting in an increase in blood glucose concentration (28). Furthermore, OH- content is associated with insulin resistance due to the incorporation of ortho- and meta-tyrosine, and the OH- products of L-phenylalanine into cellular proteins, which leads to insulin resistance (33,34). The link between OH- and insulin resistance may provide an explanation for the observation in the present study; that OH- content increases in T2DM mice and decreases after the upregulation of GABA-R.…”

“…Additionally, the pathological change in the neuronal morphology in the GABA-R group of the current study decreased compared with that in the blank group. Due to its high reactivity, OH- reacts with macromolecules and yields oxidation products that induce damage to neurons via oxidative stress (33,36). Therefore, the decrease in the OH- content observed in the present study may have led to the decrease in pathological changes of neuronal morphology in the GABA-R group due to the reduced possibility of oxidative stress.…”

Roles of the tyrosine isomers meta- tyrosine and ortho- tyrosine in oxidative stress

“…This correlated with a significant reduction in insulin-induced relaxation of femoral arteries isolated from o -tyrosine supplemented rats compared to controls (Szijarto et al, 2014). Further experiments observed an inverse correlation between o -tyrosine concentration within arterial walls and acetylcholine-induced vasorelaxation (Molnar et al, 2015). …”

“…Thus the accumulation of abnormal tyrosine isomers within cells could have devastating consequences and contribute to disease pathogenesis. Indeed a role for tyrosine isomers has already been hypothesized in the development of insulin resistance (Kun et al, 2015; Molnar et al, 2015; Szijarto et al, 2014). With elevations of these isomers being noted in many other diseases (see Table 1), they may likely mediate some aspects of the disruption of cellular homeostasis produced in each of these pathologic processes as well.…”

The Role of Oxidative Stress, Mitochondrial Function, and Autophagy in Diabetic Polyneuropathy

“…The target and ortho-tyrosine are considered markers of HO•-induced damage. The use of resveratrol to treat patients with type 2 DM leads to decreased urinary excretion of ortho-tyrosine and concomitantly improves insulin signaling and sensitivity to this hormone [ 67 ]. Thus, the administration of resveratrol may be an attractive therapeutic tool along with strict metabolic control in patients with DM and chronic complications of DM.…”