Dossier: Antioxidants in the prevention of human diseases
A review on the role of antioxidants in the management of diabetes and its complications

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Abstract

Diabetes is a prevalent systemic disease affecting a significant proportion of the population worldwide. The effects of diabetes are devastating and well documented. There is increasing evidence that in certain pathologic states, especially chronic diseases, the increased production and/or ineffective scavenging of reactive oxygen species (ROS) may play a critical role. High reactivity of ROS determines chemical changes in virtually all cellular components, leading to lipid peroxidation. Production of ROS and disturbed capacity of antioxidant defense in diabetic subjects have been reported. It has been suggested that enhanced production of free radicals and oxidative stress is central event to the development of diabetic complications. This suggestion has been supported by demonstration of increased levels of indicators of oxidative stress in diabetic individuals suffering from complications. Therefore, it seems reasonable that antioxidants can play an important role in the improvement of diabetes. There are many reports on effects of antioxidants in the management of diabetes. In this paper, after complete bibliography and criticizing all relevant articles, the relationships between diabetes and oxidative stress and use of antioxidants in the management of diabetes and its complications have been well reviewed. This review well indicates that oxidative stress is involved in the pathogenesis of diabetes and its complications. Use of antioxidants reduces oxidative stress and alleviates diabetic complications.

Introduction

Diabetes is a chronic metabolic disorder that continues to present a major worldwide health problem. It is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action associated with chronic hyperglycemia and disturbances of carbohydrate, lipid, and protein metabolism. As a consequence of the metabolic derangements in diabetes, various complications develop including both macro- and micro-vascular dysfunctions [1].

It is accepted that oxidative stress results from an imbalance between the generation of oxygen derived radicals and the organism's antioxidant potential [2]. Various studies have shown that diabetes mellitus is associated with increased formation of free radicals and decrease in antioxidant potential. Due to these events, the balance normally present in cells between radical formation and protection against them is disturbed. This leads to oxidative damage of cell components such as proteins, lipids, and nucleic acids. In both insulin dependent (type 1) and non-insulin-dependent diabetes (type 2) there is increased oxidative stress [3].

Conflicting results have been reported for the role of oxidative stress in diabetes. F2-isoprostanes are prostaglandin-like compounds formed in-vivo from free radical catalyzed peroxidation of arachidonic acid and have emerged as novel and direct measures of oxidative stress. F2-isoprostane levels have been reported to be increased in the plasma of type 2 diabetes mellitus and in the urine of type 2 and type 1 diabetic subjects [4], [5]. A correlation between impaired glycemic control and enhanced lipid peroxidation has been reported [5]. However, lack of correlation between glycemic control and levels of 8-iso-PGF2α or MDA has been shown in another astudy [6]. It was shown that oxidative stress exists in diabetic patients as evidenced by increased total antioxidant capacity in saliva and blood of patients [7].

Oxidative stress is increased in diabetes because of multiple factors. Dominant among these factors is glucose autoxidation leading to the production of free radicals. Other factors include cellular oxidation/reduction imbalances and reduction in antioxidant defenses (including decreased cellular antioxidant levels and a reduction in the activity of enzymes that dispose of free radicals). In addition, levels of some pro-oxidants such as ferritin and homocysteine are elevated in diabetes. Another important factor is the interaction of advanced glycation end products (AGEs) with specific cellular receptors called AGE receptors (RAGE). Elevated levels of AGE are formed under hyperglycemic conditions. Their formation is initiated when glucose interacts with specific aminoacids on proteins forming a compound that then undergoes further chemical reactions. Glycation of protein alters protein and cellular function, and binding of AGEs to their receptors can lead to modification in cell signaling and further production of free radicals [8].

Oxidative stress has been suggested to be a common pathway linking diverse mechanisms for the pathogenesis of complications in diabetes [9].

One of the major complications of diabetes is cardiovascular disease. The incidence of cardiovascular disease in people with diabetes mellitus is three to four times of that in non-diabetic individuals. Furthermore, established risk factors such as dyslipidemia, hypertension, and smoking cannot explain this increased prevalence of macrovascular disease in diabetes. Thus, the diabetic state itself is an independent risk factor for premature atherosclerosis. One of the potential mechanisms that could mediate the premature atherosclerosis in diabetes is oxidative stress. Oxidative stress plays a crucial role in atherogenesis and cause to oxidation of low density lipoprotein. While some studies have not found increased susceptibility of LDL to oxidation in diabetic subjects, evidence for increased LDL oxidizability in diabetic subjects has been shown in at least five studies. Increased concentrations of autoantibodies to both oxidized and glycated LDL and glyco-Ox-LDL have been documented in diabetes suggesting that in type 2 diabetes enhanced oxidative stress occurs in-vivo and that LDL glycation may represent a predisposing event that facilitates subsequent oxidative modification. Several lines of evidence support a proatherogenic role for oxidized LDL (Ox-LDL) and its in vivo existence. Ox-LDL is not recognized by the LDL receptor but by the scavenger receptor pathway on macrophages, which results in unregulated cholesterol accumulation, leading to foam cell formation [10].

Diabetic nephropathy is one of the important microvascular complications of diabetes mellitus. It occurs in about one-third of patients with insulin-dependent diabetes [11] and is the single largest cause of end-stage renal disease requiring chronic dialysis or transplantation. The pathophysiology of diabetic nephropathy is not well defined. Recent studies have indicated that ROS play a key intermediate role in the development of diabetic nephropathy. High glucose directly increases hydrogen peroxide production by mesangial cells and lipid peroxidation of glomerular mesangial cells. Hyperglycemia-induced secondary mediators activation such as protein kinase C (PKC), mitogen-activated protein (MAP) kinases and cytokine production is also responsible for oxidative stress-induced renal injury in the diabetic condition [12].

Another complication of diabetes is neuropathy. Hyperglycemia plays a critical role in the development and progression of diabetic neuropathy. One of the mechanisms by which hyperglycemia causes neural degeneration is via the increased oxidative stress that accompanies diabetes. Metabolic and oxidative insults often cause rapid changes in glial cells. Key indicators of this response are increased synthesis of glial fibrillary acidic protein (GFAP) and S100B, both astrocytic markers [13].

Retinopathy is another complication of diabetes. In the pathogenesis of diabetic retinopathy, pericytes and endothelial cells are lost selectively before other histopathology is detectable. How these capillary cells die is unclear, but apoptosis is considered as one of the possible mechanisms in their death. Retinal capillary cell death precedes the development of other lesions characteristic of retinopathy in diabetes, and the frequency of early death of retinal capillaries can predict the development of histological lesions of retinopathy. A redox-sensitive nuclear transcriptional factor, NF-κB, is an important regulator of antioxidant enzymes. Activation of NF-κB is considered a key-signaling pathway by which high glucose induces apoptosis in endothelial cells. In the retina, NF-κB is localized in sub-retinal membranes and in microvessels, and is activated very early in the course of development of retinopathy in diabetes. Activated NF-κB binds to nuclear DNA and modulates the expression of several genes, and this amplification cascade in turn, results in increased free radical production eventually leading to the cell death. Recent studies have shown that NF-κB activation in retinal pericytes is responsible for the hyperglycemia-induced accelerated loss of pericytes observed in diabetic retinopathy [14].

Diabetic cataract is a major complication of diabetes mellitus, and is primarily caused by polyol accumulation and glycation within lens fibers and the epithelium. Blood sugar can passively diffuse into lens tissue insulin independently and then be converted by aldose reductase to polyols, which cannot diffuse passively out of the lens, and thus they accumulate. This accumulation of polyols causes osmotic changes, which lead to lens hydration and swelling that are followed by biochemical and physiological damage to cell membranes. In addition, oxidative stress could also contribute to diabetic cataract formation, and diabetic human lenses have been found to be more susceptible to protein oxidation. More recent studies indicate that the polyol pathway is a likely major contributor to oxidative stress, at least, in the lenses and nerves of diabetic mice and it was reported that aldose reductase inhibitor reduced oxidative stress enhancement in sugar cataract. The polyol pathway may be related to hyperglycemia-induced oxidative stress, and there may be a metabolic connection between the polyol pathway and oxidative stress [15].

Erectile dysfunction is commonly associated with diabetes and occurs at an earlier age in such patients than in the general population. The pathogenesis of erectile dysfunction as a diabetic complication remains incompletely understood. Diabetes has a known pathologic effect on peripheral tissue innervation and vascularization, both of which are critical for erectile function. Oxidative stress to cavernous tissue may be an important contributory factor to erectile dysfunction in diabetics [16].

Section snippets

General

Antioxidants counter the action of free radicals by several mechanisms. These mechanisms include: (1) enzymes that degrade free radicals, (2) proteins such as transferrin that can bind metals which stimulate the production of free radicals, and (3) antioxidants such as vitamins C and E that act as free radical scavengers [8].

In an study, the total antioxidant capacity in plasma of type 1 diabetics was shown to be 16% lower than that of normal subjects [6]. Decreased activities of antioxidant

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