**2. Hyperglycemia and oxidative stress**

A relationship has been established between hyperglycemia, oxidative stress and numerous pathways which can lead to the development of diabetic complications. Four of these pathways are very important: activation of protein kinase C isoforms, increased hexosamine pathway flux, increased advanced glycation end-product (AGE) formation [8-9], and increased aldosereductase pathway flux [10]. Oxidative stress has been implicated to play a central role in these pathways. Oxidative stress occurs as a result of excessive formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) collectively described as free radicals. Free radicals are highly unstable and have the ability to attract electrons from macromolecules such as carbohydrates, protein, lipid and DNA [11]. Excessive ROS can cause structural deterioration and instability of the macromolecules, consequently affecting proper cellular signaling pathways, gene regulation and function [12]. Although, the human system has check-in mechanisms to deal with oxidative damage and free radical formation through endogenous and exogenous antioxidants, however, when the rate of formation of ROS overwhelms the detoxifying ability of the antioxidants, oxidative stress can occur [11, 13-14].

According to Lobo *et al.* [33], the first line of defense is the preventive antioxidants, which suppress the formation of free radicals. Although the precise mechanism and site of radical formation in vivo are not well elucidated yet, the metal-induced decompositions of hydro‐ peroxides and hydrogen peroxide must be one of the important sources. To suppress such reactions, some antioxidants reduce hydroperoxides and hydrogen peroxide beforehand to alcohols and water, respectively, without generation of free radicals and some proteins sequester metal ions. Glutathione peroxidase, glutathione-s-transferase, phospholipid hydroperoxide glutathione peroxidase (PHGPX), and peroxidase are known to decompose lipid hydroperoxides to corresponding alcohols. PHGPX is unique in that it can reduce hydroperoxides of phospholipids integrated into biomembranes. Glutathione peroxidase and

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The second line of defense is the antioxidants that scavenge the active radicals to suppress chain initiation and/or break the chain propagation reactions. Various endogenous radicalscavenging antioxidants are known: some are hydrophilic and others are lipophilic. Vitamin C, uric acid, bilirubin, albumin, and thiols are hydrophilic, radical-scavenging antioxidants, while vitamin E and ubiquinol are lipophilic radical-scavenging antioxidants. Vitamin E is

The third line of defense is the repair and de novo antioxidants. The proteolytic enzymes, proteinases, proteases, and peptidases, present in the cytosol and in the mitochondria of mammalian cells, recognize, degrade, and remove oxidatively modified proteins and prevent

The DNA repair systems also play an important role in the total defense system against oxidative damage. Various kinds of enzymes such as glycosylases and nucleases, which repair

There is another important function called adaptation where the signal for the production and reactions of free radicals induces formation and transport of the appropriate antioxidant to the

The human system employs the use of endogenous enzymatic and non-enzymatic antioxi‐ dant defense systems against the onslaught of free radicals and oxidative stress [35-36]. Enzymatic antioxidants include superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase. Non-enzymatic antioxidants include vitamins A, C, and E, gluta‐ thione, alpha-lipoic acid, carotenoids, and coenzyme Q. Other antioxidants include biflavo‐ noids, minerals (copper, zinc, manganese, and selenium), and cofactors (folic acid, vitamins B1, B2, B6 and B12). These antioxidants work synergistically with each other using different mechanisms against different free radicals and stages of oxidative stress [37]. Hyperglycemia has been reported to impairthe endogenous antioxidant defense systems in many ways during diabetes in addition to generating free radicals [18, 38]. The involvement of hyperglycemiamediated oxidative damage in diabetes mellitus has led to the hypothesis that drugs that

accepted as the most potent radical-scavenging lipophilic antioxidant.

**4. Antioxidants and diabetes mellitus treatment**

catalase reduce hydrogen peroxide to water.

the accumulation of oxidized proteins.

the damaged DNA, are known [33].

right site [34].

The increase in oxidative stress in diabetes mellitus could be attributed to elevated blood glucose levels, which upon auto-oxidation generates free radicals and damages the cell membrane through peroxidation of membrane lipids [15] and protein glycation [16]. Chronic hyperglycemia results in oxidative stress via auto-oxidation of glucose in the presence of transition metals [17]; decreased activities of antioxidant enzymes such as superoxide dismu‐ tase (SOD) and glutathione peroxidase [18]; increased oxidative phosphorylation [19], glycosylation of proteins [17]; and activation of the hexosamine pathway [20]. Hyperglycemiainduced oxidative stress has been demonstrated to result in beta cell dysfunction and death [21-22], as well as in fibrosis of pancreatic islets [23-24]. It has also been established that hyperglycemia increases mitochondrial ROS production, which could represent a key event in the development of diabetic complications [19, 25].

Hyperglycemia has been reported to induce oxidative insult and apoptosis in diabetic liver and renal tubular cells [26-27]. Hyperglycemia leads to increased levels of ROS and D-glucose which has been shown to be capable of inducing apoptosis through the activation of Baxcaspase pathway [28]. Caspases are a family of cysteine proteases known to be the effectors of apoptosis. Upon activation of Bax by free radicals, caspases are activated, which alter mito‐ chondrial function by reducing the electrochemical gradient across the mitochondrial mem‐ brane leading to the release of mitochondrial cytochrome C into cytoplasm [28-29]. Studies had shown that movement of Bax into the mitochondrial membrane is accompanied by a significant increase in the activities of caspase-3 and caspase-9 [30-32].
