**4. Antioxidants and diabetes mellitus treatment**

**2. Hyperglycemia and oxidative stress**

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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

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

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

The antioxidants acting in the defense systems act at different levels such as preventive, radical

scavenging, repair and de novo, and the fourth line of defense, i.e., the adaptation.

detoxifying ability of the antioxidants, oxidative stress can occur [11, 13-14].

in the development of diabetic complications [19, 25].

**3. Levels of antioxidant action**

significant increase in the activities of caspase-3 and caspase-9 [30-32].

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 improve glycemic index and/or oxidative stress will be beneficial in the treatment of diabetes mellitus and its complications.

Majority of the drugs currently used in the treatment of diabetes mellitus have antioxidant activities in addition to their primary pharmacological activity. For example, aminoguanidine has been shown to exhibit free radical scavenging properties and inhibit lipid peroxidation [39-43] although clinical trials were discontinued in Europe and in the United States due to its long term toxicity. Troglitazone lowered hydroperoxides and decreased SOD activity in type 2 diabetic rats [44]. Glibenclamide, a sulphonylureas in addition to its glucose lowering effect possesses antioxidant properties due to its ability to restore liver catalase and superoxide dismutase in diabetic rats [45]. Also, repaglinide used in the treatment of type 2 diabetes mellitus exhibited antioxidant properties and inhibited protein peroxidation by upregulating glutathione reductase and glutathione levels in diabetic rabbits in addition to its insulin releasing effects [46].

**Figure 1.** The chemical structure of quercetin.

and decrease the intestinal maltose activity [27].

Quercetin reduces intestinal glucose absorption by inhibiting GLUT 2 in CaCo-2 intestinal cells [73-74]. Quercetin has been extensively investigated in diabetic rat models in recent times. It decreases the fasting blood glucose and improves glucose tolerance [75]; protects against oxidative damage and preserves pancreatic beta cell integrity [76]. Kobori *et al.* [77] reported that quercetin alleviated diabetic symptoms and liver injury in diabetic patients. Quercetin blocks tyrosine kinase thereby interfering with insulin signaling and the propagation of the biological actions of the hormone [78-79]. Quercetin elevated insulin secretion in insulinsecreting cell line induced by glucose and glibenclamide [80] by mediating ERK1/2 pathway [81]. Insulin resistance was improved in genetically obese Zucker rats upon administration of quercetin [82]. Quercetin also reduced maltose-induced postprandial hyperglycemia in type 2 diabetic patients by inhibiting intestinal alpha glucosidase activity [83]. Several mechanisms of action of quercetin in diabetes have been postulated and those included: decreases lipid peroxidation, increases antioxidant enzymes activity like superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase [76]. Other mechanisms are inhibition of insulindependent activation of phosphoinositol-3 kinase (PI-3K) [84], increase adiponectin levels [85],

Antioxidant -Rich Natural Products and Diabetes Mellitus

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**Figure 2.** Proposed mechanisms for anti-diabetic effects of Quercetin. Reproduced from Portillo *et al.,* (2011).

Several *in vivo* studies have been carried out to ascertain the effects of antioxidants on exper‐ imental diabetic models [47-53]. Most of these studies reported the beneficial role of antioxi‐ dants against specific biomarkers of oxidative stress and provided the foundation for clinical trials embarked on later [54-60]. Majority of the studies were not designed specifically to assess the effects of antioxidant use in diabetic patients and none has been carried out yet on antioxidant-rich plant products despite the large evidence supporting its use. Medicinal plants and antioxidant-rich plant products definitely hold promise in this area in the near future.
