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

Abstract

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 α-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 ± 2.7 × 10(4) IU/g Hb vs. 13.5 ± 3.2 × 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-enzym...

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…Chronic hyperglycaemia is widely accepted as a trigger of excessive production of reactive oxygen species (ROS) in all cells, as is the fact that this toxic process is exacerbated by a concomitant reduction in endogenous antioxidant defences 61 . For example, genetic variations and poly morphisms in endogenous antioxidant enzymes have been associated with an increased susceptibility to diabetic neuropathy 62 . Potential sources of ROS in peripheral nerves include the polyol pathway, the mitochondrial electron transport chain, RAGE (receptor for advanced glycosylation end products) signalling, and NADPH oxidases and nitric oxide synthases [63][64][65] .…”

A Clinical Trial about a Food Supplement Containing α-Lipoic Acid on Oxidative Stress Markers in Type 2 Diabetic Patients

“…Regarding the mechanism through which neuropathy develops, previously published papers showed that hyperglycemia generates free radicals, contributing to the development and progression of diabetes complications. There is large evidence that there is a relationship between the severity of diabetic neuropathy and the frequency and duration of hyperglycemic periods [8]. For this reason, improving oxidative stress may be a way to reduce diabetic complications [9,10], and this is probably the way α-lipoic acid acts.…”

Effect of hyperglycemia on hepatocellular carcinoma development in diabetes

“…These pathways includes Janus kinase/Signal transducer activator of transcription 3 pathway and extracellular signal-regulated kinases pathway; it also activates IKKa/nuclear factor-kappa B pathway, resulting in the suppression of apoptosis and cell proliferation in hepatocytes [32e34]. In this study, hepatic inflammation was not observed in the hyperglycemic STZ and Starch groups, although hyperglycemia reportedly induces inflammation in other tissues such as the microand macrovasculature through reactive oxygen species or advanced glycation end product level elevation or epigenetic changes [35]. Steatosis is the most common cause of hepatic inflammation [29].…”