At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.

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Increased oxidative stress in obesity and its impact on metabolic syndrome

Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. These consequences of oxidative stress can promote the development of complications of diabetes mellitus. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes, and their consequences, are discussed in this review. In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed. There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.

Diabetes, oxidative stress, and antioxidants: a review

Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although prospective randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between diabetic hyperglycemia and the development of secondary complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that the generation of reactive oxygen species (oxidative stress) may play an important role in the etiology of diabetic complications. This hypothesis is supported by evidence that many biochemical pathways strictly associated with hyperglycemia (glucose autoxidation, polyol pathway, prostanoid synthesis, protein glycation) can increase the production of free radicals. Furthermore, exposure of endothelial cells to high glucose leads to augmented production of superoxide anion, which may quench nitric oxide, a potent endothelium-derived vasodilator that participates in the general homeostasis of the vasculature. In further support of the consequential injurious role of oxidative stress, many of the adverse effects of high glucose on endothelial functions, such as reduced endothelial-dependent relaxation and delayed cell replication, are reversed by antioxidants. A rational extension of this proposed role for oxidative stress is the suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status.

Oxidative Stress and Diabetic Vascular Complications

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

Mechanisms of Diabetic Complications

Diabetes mellitus is a major cause of peripheral neuropathy, commonly manifested as distal symmetrical polyneuropathy. This review examines evidence for the importance of vascular factors and their metabolic substrate from human and animal studies. Diabetic neuropathy is associated with risk factors for macrovascular disease and with other microvascular complications such as poor metabolic control, dyslipidaemia, body mass index, smoking, microalbuminuria and retinopathy. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. Investigations on biopsy material from patients with mild to severe neuropathy show graded structural changes in nerve microvasculature including basement membrane thickening, pericyte degeneration and endothelial cell hyperplasia. Arterio-venous shunting also contributes to reduced endoneurial perfusion. These vascular changes strongly correlate with clinical defects and nerve pathology. Vasodilator treatment in patients and animals improves nerve function. Early vasa nervorum functional changes are caused by the metabolic insults of diabetes, the balance between vasodilation and vasoconstriction is altered. Vascular endothelium is particularly vulnerable, with deficits in the major endothelial vasodilators, nitric oxide, endothelium-derived hyperpolarising factor and prostacyclin. Hyperglycaemia and dyslipidaemia driven oxidative stress is a major contributor, enhanced by advanced glycation end product formation and polyol pathway activation. These are coupled to protein kinase C activation and omega-6 essential fatty acid dysmetabolism. Together, this complex of interacting metabolic factors accounts for endothelial dysfunction, reduced nerve perfusion and function. Thus, the evidence emphasises the importance of vascular dysfunction, driven by metabolic change, as a cause of diabetic neuropathy, and highlights potential therapeutic approaches.

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Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy

Reduced nerve perfusion is an important factor in the etiology of diabetic neuropathy. Studies in streptozotocin-induced diabetic rats show that nerve conduction velocity (NCV) and blood flow deficits are corrected by treatment with vasodilator drugs, with angiotensin II and endothelin-1 antagonists being particularly important. The AT 1 antagonist ZD7155 also prevents diabetic deficits in regeneration following nerve damage, indicating that hypoperfusion is an important limitation for nerve repair. Metabolic changes include high polyol pathway flux, increased advanced glycosylation, elevated oxidative stress, and impaired ω-6 essential fatty acid metabolism. Aldose reductase inhibitors (ARIs) restore NCV via their effects on perfusion. ARI action probably depends on blocking the conversion of glucose to sorbitol, thus preventing depletion of vasa nervorum glutathione, an important endogenous free radical scavenger. Free radicals cause vascular endothelium damage and reduced nitric oxide vasodilation. Inhibition of advanced glycosylation and autoxidation (autoxidative glycosylation), major sources of free radicals, by aminoguanidine or transition metal chelators, corrects neurovascular dysfunction. Evening primrose oil supplies γ-linolenic acid (GLA) to improve vasodilator eicosanoid synthesis in diabetes, correcting nerve blood flow and NCV deficits. Interactions between some of these mechanisms have therapeutic implications. Thus, combined ARI and evening primrose oil treatment produced a 10-fold amplification of NCV and blood flow responses. Similarly, GLA effects are markedly enhanced when given in combination with ascorbate as ascorbyl-GLA. Thus, metabolic abnormalities combine to produce deleterious changes in nerve perfusion that make a major contribution to the etiology of diabetic neuropathy. The potential importance of multi-action therapy is stressed.

Metabolic and Vascular Factors in the Pathogenesis of Diabetic Neuropathy

A reduction in nerve blood flow in chronic experimental diabetes has been linked to impaired conduction. Recently, there have been reports that this is preceded by a period of functional hyperemia. The present investigation explored early changes in sciatic nerve endoneurial blood flow and function in streptozocin-treated rats with durations of diabetes from 1 wk to 4 mo. Blood flow was monitored by microelectrode polarography and hydrogen clearance in thiobutabarbital (Inactin)-anesthetized animals. It was reduced by 41% as early as 1 wk after diabetes induction. There was no evidence of an early functional hyperemia, flow remaining 44% depressed up to 4 mo. In another investigation, similar reductions in blood flow were acutely induced in normal rats rendered hyperglycemic by glucose infusion. In diabetic animals, conduction velocity in sciatic branches supplying gastrocnemius and tibialis anterior muscles was correlated with blood flow. The link was further tested using a group of 2-mo diabetic rats treated with guanethidine. Treatment caused a functional adrenergic sympathectomy, and blood flow increased to within the normal range. Conduction velocity, depressed by 26% with diabetes, was normalized by treatment. These observations support the hypothesis that hyperglycemia-induced blood flow reductions and resultant endoneurial hypoxia are important factors underlying nerve conduction deficits early in the development of diabetic neuropathy.

Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/dmr.5610100302

The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications

Increased oxygen free radical activity, coupled with reduced protection against oxidative stress, could play a role in the aetiology of neurovascu-lar abnormalities in experimental diabetes mellitus. To test this hypothesis, non-diabetic and streptozotocin-diabetic rats were treated with the anti-oxidant probu-col or the pro-oxidant primaquine. One-month diabetes caused 21.4% and 13.6% reduction in sciatic motor and saphenous sensory conduction velocity (p >0.001). These deficits were prevented by probucol treatment (p>0.001). After 1-month untreated diabetes, conduction velocity deficits were reversed by a further month of probucol treatment (p >0.001). For non-diabetic rats, primaquine treatment caused a 12.9% reduction in motor conduction velocity (p >0.001), which was prevented by probucol treatment (p >0.001). Primaquine treatment did not affect diabetic rats. Sciatic nerve nutritive endoneurial blood flow, measured using microelectrode polarography and hydrogen clearance, was 48.0% reduced by 2-month diabetes (p > 0.001). This was completely prevented by probucol treatment (p > 0.001). Primaquine treatment did not affect blood flow in diabetic rats. However, in non-diabetic rats it caused a 30.0 % reduction (p > 0.01) which was prevented by probucol treatment (p > 0.05). Sciatic endoneurial oxygen tensions were also measured by microelectrode polarography. Mean tension was 38.8 % reduced by diabetes (p > 0.001). This was prevented by probucol treatment. Non-diabetic rats given primaquine treatment showed a 21.7% reduction in endoneurial oxygen tension (p > 0.01). The data suggest that vascular-mediated nerve dysfunction in diabetes depends on oxidative stress, and that similar effects in non-diabetic rats may be produced by pro-oxidant treatment. This provides evidence for the potentially important role of oxygen free radical activity in diabetic neuropathy.

https://link.springer.com/content/pdf/10.1007/s001250050131.pdf

Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats

Mary A. Cotter

Papers

Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy

Metabolic and Vascular Factors in the Pathogenesis of Diabetic Neuropathy

Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits.

The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications

Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats