**1. Introduction**

Diabetes mellitus is a group of disorders of multiple aetiologies resulting from a defect in insulin secretion, insulin action, or both. Insulin deficiency in turn leads to chronic hypergly‐ cemia (very high blood glucose levels) with disturbances in carbohydrate, fat and protein metabolism [1]. The two major types of diabetes mellitus (DM) are insulin dependent (IDDM) - type 1 and non -insulin dependent (NIDDM) -type 2. Type 1 DM is characterized by a specific destruction of the pancreatic β cells commonly associated with immune-mediated damage [2]. Individuals with type 2 DM display a gradual change in glucose homeostasis due to insulin resistance and/or decreased insulin secretion [3].

Sustained hyperglycemia leads to the progressive development of long-term microvascular and macrovascular complications which causes morbidity and mortality among those affected [4, 5]. Although glycemic control has long been the mainstay for preventing the progression of diabetic complications, there is far less evidence that these interventions reverse diabetic complications [6]. Also, limitations in intensive glycemic treatment such as difficulty in achieving and/or maintaining tight glycemic control [7], incidence of hypoglycemia and increased mortality [8, 9] suggest an urgent need for alternative and/or complementary therapies to this disorder.

Hyperglycemia-induced oxidative stress is now recognized as the driving force for the development of diabetic complications [10]. Oxidative stress in diabetes results in stimulation of the polyol pathway, formation of advanced glycation end products (AGE), activation of

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protein kinase C (PKC) and subsequent formation of reactive oxygen radicals [11, 12]. Hyperglycemia, not only generates more reactive oxygen species (ROS), but also attenuates antioxidative mechanisms by scavenging enzymes and substances [13].

Both type I and type II diabetes are powerful and independent risk factors for coronary artery disease (CAD), stroke, and peripheral arterial disease [25, 26, 27]. Diabetics have a 2- to 4-fold higher risk for cardiovascular events [28] and nearly 80% of diabetes-associated deaths are caused by cardiovascular disease (CVD) [29]. Atherosclerosis, (excessive accumulation of lipids, cholesterol, inflammatory cells, and connective tissue in the vessel wall) accounts for more than 80% of the CVD-associated death and disability [30, 31]. Formation of atherosclerotic plaques can result in occlusion of vessel lumen and a rapid cessation in blood flow to target tissue [32]. Hyperglycemia, increased free fatty acids, and insulin resistance induce a large number of alterations at the cellular level that contribute to vascular dysfunction and accelerate the atherosclerotic process. These include increased oxidative stress, decreased bioavailability of NO, disturbances of intracellular signal transduction and increased production of several

Oxidative Stress and Diabetic Complications: The Role of Antioxidant Vitamins and Flavonoids

http://dx.doi.org/10.5772/57282

27

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the terms collectively describing free radicals and other non-radical reactive derivatives also called oxidants. Biological free radicals are highly unstable molecules which are products of normal cellular metabolism. They have electrons available to react with various organic substrates such as lipids, proteins and deoxyribonucleic acid (DNA). Free radicals are well recognized for playing a dual role as both deleterious and beneficial species, since they can be either harmful or beneficial to living systems [34]. At low or moderate levels free radicals (ROS and RNS) exerts beneficial effects such as defence against infectious agents, induction of a mitogenic response and the maturation process of cellular structures [35-37]. ROS include superoxide anion

OH), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) while RNS

) [38, 39]. High

NO), nitrogen dioxide (NO2 .-) and peroxynitrite (OONO<sup>−</sup>

concentrations of free radicals on the other hand result in deleterious processes that can

Free radicals produced under physiological conditions are maintained at steady state levels by endogenous or exogenous antioxidants (externally supplied through foods or supple‐ ments) which act as free radical scavengers. However, oxidative stress occurs when the production of free radicals overwhelms the detoxification capacity of cellular antioxidant system causing biological damage [42-44]. The endogenous antioxidants (Table 1) com‐ prise of the enzymatic antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and non-enzymatic antioxi‐ dants including glutathione (GSH), α lipoic acid, vitamins C and E [39, 45, 46]. On the other hand, the exogenous antioxidants include micronutrients and other exogenously adminis‐ tered compounds such as vitamin E, vitamin C, trace metals (selenium, manganese, zinc),

prothrombotic factors [32, 33].

(O2 .-), hydroxyl (.

include nitric oxide (.

**3. Role of oxidative stress in diabetic complications**

damage cell structures due to oxidative stress [40, 41].

carotenoids and flavonoids [39, 44, 47].
