The Role of Oxidative Stress in Diabetic Neuropathy: Generation of Free Radical Species in the Glycation Reaction and Gene Polymorphisms Encoding Antioxidant Enzymes to Genetic Susceptibility to Diabetic Neuropathy in Population of Type I Diabetic Patients
The Role of Oxidative Stress in Diabetic Neuropathy: Generation of Free Radical Species in the Glycation Reaction and Gene Polymorphisms Encoding Antioxidant Enzymes to Genetic Susceptibility to Diabetic Neuropathy in Population of Type I Diabetic Patients
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DOI：
10.1007/s12013-014-0365-y
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发表时间：
2015-04-01
影响因子：
2.6
通讯作者：
Lankin, Vadim Z.
中科院分区：
文献类型：
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作者：
Babizhayev, Mark A.;Strokov, Igor A.;Lankin, Vadim Z.
糖尿病性神经病变（DN）是糖尿病患者发病和死亡的主要原因。临床资料支持DN的严重程度与高血糖期的发生频率和持续时间有关的结论。目前的实验和临床证据表明，氧化应激引起的细胞功能改变是DN发生发展的主要因素。高血糖和血脂异常驱动的氧化应激是一个主要因素，晚期糖基化终产物（AGE）的形成和多元醇途径的激活增强了氧化应激。在慢性高血糖中，有几种多形态的途径导致周围神经系统氧化应激。本文阐述了糖基化反应引起的氧化应激的起源以及抗氧化基因的遗传变异，这可能与DN的发病机制有关。在糖尿病状态下，不受控制的超氧化物积累和由此导致的多元醇途径活性、AGEs积累、蛋白激酶C活性和己糖胺通量的增加触发了进行性细胞功能障碍的前馈系统。在神经中，这种代谢和血管紊乱的融合导致神经功能受损和神经营养支持的丧失，并且从长期来看，可以介导神经元和雪旺细胞（周围神经系统的胶质细胞）的凋亡。在本文中，我们认为age介导的活性氧（ROS）的产生是DN发生的一个发病因素。蛋白质和其他生物分子的氧化修饰可能是赖氨酸残基（也可能是其他氨基酸）与α -酮醛相互作用时局部产生超氧化物的结果。这种非酶促超氧化物生成现象可能是羰基胁迫病理生理作用自催化增强的一个因素。在代谢途径中形成的乙二醛和甲基乙二醛由还原性谷胱甘肽作为辅助因子的乙二醛酶系统解毒。糖尿病患者的还原性谷胱甘肽浓度可能因氧化应激和原位谷胱甘肽还原酶活性降低而降低。因此，抗氧化基因的遗传变异可能与DN的发病机制有关。本研究为过氧化氢酶（CAT）基因-262T > C多态性与DN之间的关联提供了支持数据。与- 262cc基因型相比，CAT基因的- 262tt基因型与DN患者血液中较高的红细胞过氧化氢酶活性显著相关(17.8 +/- A 2.7 × 10（4) IU/g Hb vs. 13.5 +/- A 3.2 × 10(4) IU/g Hb, P = 0.0022）。这些因素在糖尿病并发症的发展中的作用，以及通过在糖基化反应中清除活性氧的含有转糖基化咪唑的肽基抗氧化剂（非水解肌肽、致癌素、n-乙酰致癌素）的配方中添加抗氧化剂来预防DN的前景。改变参与代谢过程的酶和非酶抗氧化防御的活性，并在转录水平上控制几种编码DN固有抗氧化酶的基因的差异表达，现在值得研究。
Diabetic neuropathy (DN) represents the main cause of morbidity and mortality among diabetic patients. Clinical data support the conclusion that the severity of DN is related to the frequency and duration of hyperglycemic periods. The presented experimental and clinical evidences propose that changes in cellular function resulting in oxidative stress act as a leading factor in the development and progression of DN. Hyperglycemia- and dyslipidemia-driven oxidative stress is a major contributor, enhanced by advanced glycation end product (AGE) formation and polyol pathway activation. There are several polymorphous pathways that lead to oxidative stress in the peripheral nervous system in chronic hyperglycemia. This article demonstrates the origin of oxidative stress derived from glycation reactions and genetic variations within the antioxidant genes which could be implicated in the pathogenesis of DN. In the diabetic state, unchecked superoxide accumulation and resultant increases in polyol pathway activity, AGEs accumulation, protein kinase C activity, and hexosamine flux trigger a feed-forward system of progressive cellular dysfunction. In nerve, this confluence of metabolic and vascular disturbances leads to impaired neural function and loss of neurotrophic support, and over the long term, can mediate apoptosis of neurons and Schwann cells, the glial cells of the peripheral nervous system. In this article, we consider AGE-mediated reactive oxygen species (ROS) generation as a pathogenesis factor in the development of DN. It is likely that oxidative modification of proteins and other biomolecules might be the consequence of local generation of superoxide on the interaction of the residues of l-lysine (and probably other amino acids) with alpha-ketoaldehydes. This phenomenon of non-enzymatic superoxide generation might be an element of autocatalytic intensification of pathophysiological action of carbonyl stress. Glyoxal and methylglyoxal formed during metabolic pathway are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. Genetic variations within the antioxidant genes therefore could be implicated in the pathogenesis of DN. In this work, the supporting data about the association between the -262T > C polymorphism of the catalase (CAT) gene and DN were shown. The -262TT genotype of the CAT gene was significantly associated with higher erythrocyte catalase activity in blood of DN patients compared to the -262CC genotype (17.8 +/- A 2.7 x 10(4) IU/g Hb vs. 13.5 +/- A 3.2 x 10(4) IU/g Hb, P = 0.0022). The role of these factors in the development of diabetic complications and the prospective prevention of DN by supplementation in formulations of transglycating imidazole-containing peptide-based antioxidants (non-hydrolyzed carnosine, carcinine, n-acetylcarcinine) scavenging ROS in the glycation reaction, modifying the activity of enzymic and non-enzymic antioxidant defenses that participate in metabolic processes with ability of controlling at transcriptional levels the differential expression of several genes encoding antioxidant enzymes inherent to DN in Type I Diabetic patients, now deserve investigation.