Diabetic Neuropathy - Pathology

Oxidative stress - updated: 15 March 2008

Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment perspectives

Diabetes Metab Res Rev. 2002 May-Jun;18(3):176-84

van Dam PS.

Increased oxidative stress is a mechanism that probably plays a major role in the development of diabetic complications, including peripheral neuropathy. This review summarises recent data from in vitro and in vivo studies that have been performed both to understand this aspect of the pathophysiology of diabetic neuropathy and to develop therapeutic modalities for its prevention or treatment. Extensive animal studies have demonstrated that oxidative stress may be a final common pathway in the development of diabetic neuropathy, and that antioxidants can prevent or reverse hyperglycaemia-induced nerve dysfunction. Most probably, the effects of antioxidants are mediated by correction of nutritive blood flow, although direct effects on endoneurial oxidative state are not excluded. In a limited number of clinical studies, antioxidant drugs including alpha-lipoic acid and vitamin E were found to reduce neuropathic symptoms or to correct nerve conduction velocity. These data are promising, and additional larger studies with alpha-lipoic acid are currently being performed.

Publication Types:

• Review

How does glucose generate oxidative stress in peripheral nerve?

Int Rev Neurobiol. 2002;50:3-35

Obrosova IG.

Diabetes-associated oxidative stress is clearly manifest in peripheral nerve, dorsal root, and sympathetic ganglia of the peripheral nervous system and endothelial cells and is implicated in nerve blood flow and conduction deficits, impaired neurotrophic support, changes in signal transduction and metabolism, and morphological abnormalities characteristic of peripheral diabetic neuropathy (diabetic peripheral neuropathy). Hyperglycemia has a key role in oxidative stress in diabetic nerve, whereas the contribution of other factors, such as endoneurial hypoxia, transition metal imbalance, and hyperlipidemia, has not been rigorously proven. It has been suggested that oxidative stress, particularly mitochondrial superoxide production, is responsible for sorbitol pathway hyperactivity, nonenzymatic glycation/glycooxidation, and activation of protein kinase C. However, this concept is not supported by in vivo studies demonstrating the lack of any inhibition of the sorbitol pathway activity in peripheral nerve, retina, and lens by antioxidants, including potent superoxide scavengers. Its has been also hypothesized that aldose reductase (AR) detoxifies lipid peroxidation products, and therefore, the enzyme inhibition in diabetes is detrimental rather than benefical. However, the role for AR in lipid peroxdation product metabolism has never been demonstrated in vivo, and the effects of aldose reductase inhibitors and antioxidants on diabetic peripheral neuropathy are unidirectional, i.e., both classes of agents prevent and correct functional, metabolic, neurotrophic, and morphological changes in diabetic nerve. Growing evidence indicates that AR has a key role in oxidative stress in the peripheral nerve and contributes to superoxide production by the vascular endothelium. The potential mechanisms of this phenonmenon are discussed.

Publication Types:

• Review

Short-term hyperglycemia produces oxidative damage and apoptosis in neurons

FASEB J. 2005 Apr;19(6):638-40. Epub 2005 Jan 27

Vincent AM, McLean LL, Backus C, Feldman EL.

Dorsal root ganglia neurons in culture die through programmed cell death when exposed to elevated glucose, providing an in vitro model system for the investigation of the mechanisms leading to diabetic neuropathy. This study examines the time course of programmed cell death induction, regulation of cellular antioxidant capacity, and the protective effects of antioxidants in neurons exposed to hyperglycemia. We demonstrate that the first 2 h of hyperglycemia are sufficient to induce oxidative stress and programmed cell death. Using fluorimetric analysis of reactive oxygen species (ROS) production, in vitro assays of antioxidant enzymes, and immunocytochemical assays of cell death, we demonstrate superoxide formation, inhibition of aconitase, and lipid peroxidation within 1 h of hyperglycemia. These are followed by caspase-3 activation and DNA fragmentation. Antioxidant potential increases by 3-6 h but is insufficient to protect these neurons. Application of the antioxidant alpha-lipoic acid potently prevents glucose-induced oxidative stress and cell death. This study identifies cellular therapeutic targets to prevent diabetic neuropathy. Since oxidative stress is a common feature of the micro- and macrovascular complications of diabetes, the present findings have broad application to the treatment of diabetic patients.

Publication Types:

• Review

Oxidative stress and antioxidant defense in relation to the severity of diabetic polyneuropathy and cardiovascular autonomic neuropathy

Diabetes Care. 2004 Sep;27(9):2178-83

Ziegler D, Sohr CG, Nourooz-Zadeh J.

OBJECTIVE: Oxidative stress resulting from enhanced free-radical formation and/or a defect in antioxidant defenses has been implicated in the pathogenesis of experimental diabetic neuropathy. The objective of this study was to evaluate plasma levels of various biomarkers of oxidative stress in diabetic subjects in relation to the presence or absence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN). RESEARCH DESIGN AND METHODS: Plasma 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)), superoxide anion (O(2)(.-)) generation, lag phase to peroxidation by peroxynitrite (ONOO(-)), vitamin E-to-lipid ratio, and vitamin C were measured in nonsmoking diabetic patients without PN and CAN (PN(-)/CAN(-) group; n = 62), in a group with PN but without CAN (PN(+)/CAN(-) group; n = 105), in those with both PN and CAN (PN(+)/CAN(+) group; n = 22), and in healthy control subjects (n = 85). RESULTS: All three markers of oxidative stress were significantly increased, and both markers of antioxidant defense were decreased in the PN(+)/CAN(-) group compared with the control group (all P < 0.05). PN(-)/CAN(-) subjects showed a significant increase compared with control subjects for 8-iso-PGF(2alpha), O(2)(.-), and ONOO(-) and a decrease for the vitamin E-to-lipid ratio (all P < 0.05). In the PN(+)/CAN(-) group, a significant increase compared with the PN(-)/CAN(-) group was noted for O(2)(.-), whereas the vitamin E-to-lipid ratio and vitamin C were reduced (all P < 0.05). No significant differences were noted between the PN(+)/CAN(-) and PN(+)/CAN(+) groups for each of the five markers of oxidative stress. In multivariate models, O(2)(.-) and ONOO(-) were independently associated with neuropathic deficits, but diabetes duration and triglyceride levels were also independent determinants. CONCLUSIONS: Oxidative stress is enhanced in diabetic patients before the development of PN but to an even higher degree in those with PN, without further significant increase in relation to superimposed autonomic neuropathy. However, apart from oxidative stress, diabetes duration and triglyceride levels are also related to the severity of PN.

Oxidative stress in the pathogenesis of diabetic neuropathy

Endocr Rev. 2004 Aug;25(4):612-28

Vincent AM, Russell JW, Low P, Feldman EL.

Oxidative stress results from a cell or tissue failing to detoxify the free radicals that are produced during metabolic activity. Diabetes is characterized by chronic hyperglycemia that produces dysregulation of cellular metabolism. This review explores the concept that diabetes overloads glucose metabolic pathways, resulting in excess free radical production and oxidative stress. Evidence is presented to support the idea that both chronic and acute hyperglycemia cause oxidative stress in the peripheral nervous system that can promote the development of diabetic neuropathy. Proteins that are damaged by oxidative stress have decreased biological activity leading to loss of energy metabolism, cell signaling, transport, and, ultimately, to cell death. Examination of the data from animal and cell culture models of diabetes, as well as clinical trials of antioxidants, strongly implicates hyperglycemia-induced oxidative stress in diabetic neuropathy. We conclude that striving for superior antioxidative therapies remains essential for the prevention of neuropathy in diabetic patients.

Publication Types:

• Review

Diabetic neuropathy and oxidative stress

Diabetes Metab Res Rev. 2006 Jul-Aug;22(4):257-73

Pop-Busui R, Sima A, Stevens M.

This review will focus on the impact of hyperglycemia-induced oxidative stress in the development of diabetes-related neural dysfunction. Oxidative stress occurs when the balance between the production of reactive oxygen species (ROS) and the ability of cells or tissues to detoxify the free radicals produced during metabolic activity is tilted in the favor of the former. Although hyperglycemia plays a key role in inducing oxidative stress in the diabetic nerve, the contribution of other factors, such as endoneurial hypoxia, transition metal imbalances, and hyperlipidemia have been also suggested. The possible sources for the overproduction of ROS in diabetes are widespread and include enzymatic pathways, auto-oxidation of glucose, and mitochondrial superoxide production. Increase in oxidative stress has clearly been shown to contribute to the pathology of neural and vascular dysfunction in diabetes. Potential therapies for preventing increased oxidative stress in diabetic nerve dysfunction will be discussed.

Publication Types:

• Review

Oxidative stress and diabetic neuropathy: a new understanding of an old problem

J. Clin. Invest. 111:431-433 (2003). doi:10.1172/JCI200317863

Eva L. Feldman

Diabetes has reached epidemic proportions in the Western world. In the United States, 17 million individuals have diabetes, greater than 6% of the population (1). The morbidity and mortality of diabetes is due to the development of both macrovascular and microvascular complications (2). Macrovascular complications including myocardial infarction, stroke, and large vessel peripheral vascular disease are 2 to 4 times more prevalent in individuals with diabetes. The underlying common factor in macrovascular complications is the ability of the diabetic condition to accelerate atherogenesis. Atherogenesis is a multifactorial response of vessels to injury; both insulin resistance and elevated lipid levels, common in diabetes, are primary triggers of atherogenic injury (3). The endothelium in diabetic arteries is also more prone to atherogenic injury, likely due to decreased production of endothelial nitric oxide, known to be antiatherogenic, and increased production of plasminogen activator inhibitor-1 (PAI-1) (4). While macro-vascular complications are common among diabetics, diabetes-specific microvascular complications will eventually affect nearly all individuals with diabetes. Diabetic retinopathy is the most common cause of adult blindness in the United States. Ninety percent of diabetics present evidence of retinopathy within 15 years of disease onset and approximately 25,000 new cases of diabetes-related blindness are reported per year (5). Diabetes is also the leading cause of renal failure in the United States, accounting for 40% of new cases each year (6). Greater than half of all patients with diabetes develop neuropathy, a progressive deterioration of nerves resulting in peripheral and autonomic nerve dysfunction. As a result, diabetic neuropathy is the most common cause of nontraumatic amputations and autonomic failure (7, 8). In his or her lifetime, a diabetic patient with neuropathy has a 15% chance of undergoing one or more amputations (9).

Publication Types:

• Review

Publication Types:

• Review