Natural antioxidant vitamins: A review of their beneficial roles in management of diabetes mellitus and its complications

Diabetes mellitus is a complex and progressive metabolic disease which is associated with multiple complications. Chronic  hyperglycaemia is the defining characteristic of diabetes mellitus. Hyperglycaemia leads to generation of free radicals and  induces oxidative stress, which has become the chief factor that leads to diabetic complications. This review supports the use of antioxidant vitamins as therapeutic agents in the management of diabetes mellitus and its complications, and also provides an insight into the potential pharmacological effects of natural antioxidant vitamins in diabetic conditions. These antioxidant  vitamins can be used as safe supplements to manage the occurrence and complications of the disease. Selected studies have  reported on the beneficial effects of antioxidant vitamins in experimental models. The involvement of oxidative stress in diabetes and its complications has made the use of natural antioxidant vitamins (free radical scavengers) from plants inevitable as they may be very effective and safer in the management of diabetes. Keywords : Antioxidant, Oxidative stress, Vitamins, Diabetes mellitus


INTRODUCTION
Diabetes mellitus (DM) is a complex disease with multiple etiologies characterized by hyperglycaemia [1]. In DM, lack of biologically active insulin results in the impairment of uptake and storage of glucose and reduces usage of glucose for energy purposes [2]. Deficiency of insulin leads to derangement in carbohydrate metabolism and reduces the activities of a number of key enzymes, including glucokinase, phosphofructokinase, and pyruvate kinase [3,4]. It has been reported that more than 347 million people worldwide have diabetes [5] and the metabolic disease has been projected to become the 7th leading cause of death in 2030 [6].
DM is usually categorised into two major types i.e. type 1 (insulin-dependent diabetes mellitus, IDDM) and type 2 (non-insulin dependent diabetes mellitus, NIDDM) [7,8]. Type 1 diabetes is caused by the autoimmune destruction of insulin-producing beta cells in the pancreas. Type 2 diabetes arises because the cells become resistant to the action of insulin or the body cannot make enough insulin. The most frequent and key symptoms of DM are hyperphagia, polyuria, polydipsia and reduced body weight [9,10]. Diabetic condition is chronic and requires constant supervision, education and monitoring [11].
Despite tremendous efforts in the control the prevalence of DM, its manifestations results in human suffering and high economic cost [12]. Oxidative stress, which is caused as a result of excessive production of reactive oxygen species (ROS) is increased in DM [13] and leads to oxidative damage of biomolecules i.e. lipids, proteins and DNA [14]. Antioxidant vitamins such as vitamin A (i.e. beta carotene), C and E are part of the physiological non-enzymatic defense against oxidative stress [15]. This review covers the potential roles of natural antioxidant vitamins in the management of diabetes and its complications. Diabetes is known to be also associated with oxidative stress. Hyperglycaemia results to the production of free radicals by auto-oxidation of glucose, non-enzymatic glycosylation and augmented polyol pathway [20-23]. Oxidative stress plays a pivotal role in diabetes-induced metabolic abnormalities [8,24]. Increased oxidative stress activates the nuclear redoxsensitive transcription factor κB that upregulates genes such as cytokines, adhesion molecules, endothelium-1, and procoagulant tissue factor which trigger the development of chronic diabetic complications [25,26]

OVERVIEW OF ANTIOXIDANT VITAMINS
Vitamins (combination of two words: vital amines) are complex organic substances that are needed by the body in small quantities. These are found in minute quantities in food, in some cases are produced by the body, and are also produced synthetically. Vitamins are divided into two major groups: the fat-soluble vitamins (vitamin A, vitamin D, vitamin E, and vitamin K) and the water-soluble vitamins which include vitamin C and the group of molecules referred to as the vitamin B complex. Each of them has its own special role in the development of human body.
Among the different classes of vitamins, vitamins A, C and E are referred to as antioxidant vitamins. Vitamins A, C, and E are derived from diets which detoxify free radicals directly and also interact in recycling processes to create reduced forms of the vitamins [47].
Vitamin A, a lipid-soluble vitamin is an isoprenoid compound with a 6-membered ring and an 11carbon side chain and is found in plants as a provitamin called β-carotene ( Figure 1, the most abundant carotenoid which can be converted to vitamin A by an oxygenase present in the intestine [33]. β-carotene has antioxidant properties that can help neutralize free radicals [34]. It remains the major source of vitamin A in the body and plays a significant role in maintaining the health of cells. Vitamin A is an essential nutrient needed for normal growth, reproduction, embryonic development, vision and immune function [35]. β-carotene can be found in food sources such as carrots, sweet potatoes and apricots. Vitamin A deficiency can lead to two major disorders like: night blindness and drying of the skin.    (Figure 2), also known as ascorbic acid, is a water soluble vitamin and is not easily stored in the body. It is needed for the growth and repair of tissues in all parts of the body and also helps the body make collagen, an important protein used to make skin, cartilage, tendons, ligaments, and blood vessels. It is a well-known antioxidant that efficiently scavenges free oxygen radicals [36]. The presence of an enediol group in the structure of vitamin C allows electron availability and makes it a member of an oxidation-reduction system with electrondonating or accepting potential [37]. The richest natural sources of vitamin C are fruits and vegetables. Vitamin C deficiency symptoms include scurvy, decreased wound-healing rate, nosebleeds and a reduced ability to fight infection. Vitamin E is a fat-soluble vitamin which include four tocopherols (α, β, δ, γ) and four tocotrienols (α, β, δ, γ) [38]. It helps in the prevention of oxidation and formation of red blood cells in the body. It also assist in the protection of the lungs from becoming damaged by polluted air. This vitamin can be found in whole grains (such as wheat and oat), wheat germ, leafy green vegetables, sardines, egg yolks, nuts, bread, cereals and seeds. The deficiency of this vitamin can cause many diseases like cancer, diabetes, heart disease, and Alzheimer's disease. Both tocopherols ( Figure 3) and tocotrienols ( Figure 4) are important components of biological membranes having both antioxidant and nonantioxidant effects [39]. It is essential for the inhibition of oxidation in body tissues, formation of red blood cells and prevention of the breakdown of body tissues. Vitamin E has proved to be effective in preventing lipid peroxidation and other radical driven oxidative events [38]. In the membrane-water interphase, the reaction between vitamin E and lipid radical takes place and vitamin E donates a hydrogen ion to lipid radical resulting in tocopheroxy radical formation which is regenerated back to its reduced form by vitamin C, reduced glutathione and coenzyme Q [39]. The cells alleviate the effects of oxidative stress through different means by eitherrepairing the damage (damaged nucleotides and lipid peroxidation by-products) or directly reducing the pro-oxidative state via enzymatic and non-enzymatic antioxidants [40].

ANTIOXIDANT VITAMINS AND DIABETES
The fight against free radicals in the body is mediated by the actions of antioxidants [41] andmuch interest on the use of natural antioxidants as a means to prevent oxidative damage in diabetes has also developed [42]. Though, there are not much studies from available literature on the efficacy of antioxidant vitamins on people with diabetes however, some researchers have shown their beneficial effects on diabetes clinical trials. On the other hand, many studies using animal models have shown the potency of antioxidant vitamins to combat diabetes and its complications. The combination of Vitamin A and insulin could protect the heart against the damaging effects of diabetic-induced pre-oxidative stress [43]. It has been shown that vitamin A supplementation could improve wound healing even in the absence of insulin and this indicates that vitamin A may be useful in wound management of insulin-resistant diabetic patients [44].
Treatment with β-carotene (a precursor of vitamin A) distinctly led to the prevention of thermal hyperalgesia and cold allodynia in streptozotocin induced diabetic rats (45) and had ameliorating effects on oxidative stress and nephropathy in diabetic rats [46]. The treatment with β-carotene increased hepatic glutathione levels and also reversed the increased cardiac and renal levels of lipid peroxidation in diabetic rats [47]. It has also been reported that dietary supplementation with β-carotene could reduce plasma triglycerides and other indices of diabetic risk which may in turn, reduce the occurrence of diabetic vascular complications by normalizing lipid metabolism in diabetic patients [48].
Vitamin C was found to significantly reduce the increased levels of blood hydroperoxide, glucose, cholesterol, triglycerides and lowdensity lipoprotein (LDL) as well as restoring and reconstituting polyfunctional, long-lived T cells in diabetic rats [49]. In another study, the administration of vitamin C to diabetic rats resulted in the restoration of basal metabolic rate and improvement of lipid profile, a risk factor for cardiovascular diseases [50]. However, some clinical studies conducted using human subjects showed that consumption of vitamin C decreased blood glucose and lipids in patients with type 2 diabetes and hence, could help to reduce the risk of complications [51,52]. Similarly, oral supplementation of vitamin C with metformin has been shown to decrease fasting blood sugar, post meal blood sugar and improved glycosylated haemoglobin in diabetic patients [53]. Also, vitamin C as add on therapy to oral hypoglycemic agent was shown to improve lipid profile to the desirable levels and hence, could help to reduce the risk of diabetic complications [54]. The direct inhibition of aldose reductase in human erythrocytes by vitamin C has also been established and this provides a rationale for the use of oral vitamin C supplements in diabetes [55]. Vitamin C supplementation has been shown to recover apoptotic rates in the prostate of diabetic rats [1]. Supplementation with vitamin C has been shown to improved erythrocyte deformabilty in diabetic rats [56]. In another study, vitamin C was able to reduce the number of abnormal sperm and increased testosterone and LH levels as well as seminiferous tubular diameter in the epidiymis of diabetic rats [32].
Vitamin E reduced systolic and diastolic pressure probably by interfering with some pathways that contribute to the occurrence of hypertension in diabetic conditions [57]. Vitamin E has been reported to improve beta cell function and insulin resistance in tissues as well as reducing blood glucose and glycated haemoglobin levels [58]. Apart from the reduction of blood glucose and glycated haemoglobin, tocotrienols also reduced plasma LDL-cholesterol and triglycerides and increased HDL-cholesterol [59]. The long term administration of vitamin E has been reported to improve insulin sensitivity and may improve endothelial function [60]. Vitamin E supplementation has also been shown to provide significant cardio protective effects against cardiac dysfunction and concomitant myocardial oxidative stress induced by type 1 diabetes [31].
Vitamin E has been shown to reduce ROS generation and damaging oxidative substances and maintain membrane fluidity in the brain of diabetic rats [61]. In another study, it has been suggested that the antioxidant potential of both the isomers of vitamin E may be responsible for the protection against intra-cerebroventricular STZ -induced oxidative stress by possibly increasing the endogenous defensive capacity of the brain [62].
Tocotrienols exhibit antioxidant activities and it activities are mediated through the induction of antioxidant enzymes such as SOD, NADPH: quinine oxidoreductase and glutathione peroxidase which quench free radicals such as superoxide ions [59]. Vitamin E supplementation was shown to prevent glucose-induced lipid peroxidation in rat mesangial cells and hence, could limit the development of glomerulosclerosis in diabetic nephropathy [63]. Favourable effect of vitamin E on oxidative stress in the renal cortex of diabetic rats has been shown [64].
Vitamin E supplementation has also been shown to significantly lower lipid peroxidation and lipid levels in the blood of diabetic patients [65]. It has been reported that the preventive effect of vitamin E supplementation in diabetic complications is possibly through a decrease in lipid peroxidation [66]. Vitamin E supplementation reduced glycaemia and glycated haemoglobin levels significantly and had a neuro-protective effect on the total myenteric population, without affecting intestinal area or thickness of the intestinal wall or muscular tunic [27]. High dose of vitamin-E supplementation in diabetic rats improved motor and sensory conduction velocity in tibial and sural nerves by 50 % [67]. Vitamin E has been shown to reverse the pathological changes in diabetic neuropathy and thereby serves as a safe and inexpensive supplement that can be used for prevention/treatment of diabetic neuropathy [11]. Vitamin E has been shown to favourably decrease microalbuminemia in diabetic subjects, hence showing nephroprotective activity [68]. Vitamin E can also help in the reduction peripheral neuropathic pain in diabetes [69] and its consumption has also been able to attenuate elevated plasma lipid profile and reduce plasma levels of C-reactive protein (CRP) and oxidizedlow-density lipoproteins (Ox-LDL) in diabetic rats [70], hence could be helpful in the management of cardiovascular disease, a diabetic complication. In other words, in diabetic subjects, the administration of vitamin E produced no effect on cardiovascular disease outcomes or nephropathy [71]. The modes of action of these vitamins are summarized in Table 1.
The treatment of diabetic rats with vitamin C and vitamin E singly ameliorated thermal hyperalgesia and cold allodynia [45] and also improved oxidative damage and nephropathy in diabetic rats [46]. Combined treatment with vitamins E and C in pregnant diabetic rats decreased fetal malformation rate and tissue damage caused by oxidative stress [72]. In another study, vitamins C and E significantly reduced the urinary albumin excretion rate (UAER) and glycosylated haemoglobin in patients with diabetic nephropathy [29]. Vitamin C and E have been helpful in alleviating renal degeneration by protecting the glomerular structures from oxidative injury [73] and also decreased lipid peroxidation and improved the activities of antioxidant enzymes in the kidneys [28,74], liver [75,76], brain, lens, and testes [76] of diabetic rats. Both vitamins C and E have been helpful in the decrease of kidney weight and glomerular basement membrane (GBM) thickness. This shows the potentials of antioxidant vitamins in the protection against the development of diabetic nephropathy [74].

CONCLUSION
Active reactive oxygen species are produced as a result of high glucose (hyperglycaemia) levels in the body. Indeed, diabetes constitutes a multiple source of free radicals due to prolonged exposure to hyperglycermia and reduction in the capacities of antioxidant defense systems. Body systems are negatively affected as a result of prolong hyperglycaemia oxidative stress which in turn leads to diabetic complications. As evident from literature, exploration of the potentials of natural antioxidants such as vitamins A, C and E have been helpful in the negation of excess ROS production and acts as counteractive agents against hyperglycaemia-induced oxidative damage in the body. Further studies are needed to establish the various mechanisms by which these vitamins produce their effects on diabetic conditions. In addition, since there are few studies on the antioxidant potentials of antioxidant vitamins using human subjects from available literature, more clinical studies are needed to support the claims from animal studies.

ACKNOWLEDGEMENT
We would like to thank the North-West University and National Research Foundation (NRF) of South Africa for providing funding for this work through Prof Emmanuel Mukwevho. We also appreciate Cape Peninsula University of Technology, South Africa for funding through Prof Oluwafemi Oguntibeju and Dr Nicole Brooks.

Conflict of Interest
No conflict of interest associated with this work.