Oxidative Stress in Diabetes Mellitus

Abstract

Oxidative stress is the outcome of an imbalance between the production and neutralization of reactive oxygen and nitrogen species (RONS) such that the antioxidant capacity of cell is overwhelmed. The present review briefly summarized the underlying role of overwhelming levels of RONS in the pathophysiology of diabetes mellitus (DM). The primary causative factor of oxidative stress in DM is hyperglycemia, which operates via several mechanisms. However, the individual contribution of other intermediary factors to hyperoxidative stress remains undefined, in terms of the dose response relationship between hyperglycemia and overall oxidative stress in DM. Intuitively, the inhibition and/or scavenging of intracellular free radical formation provide a therapeutic strategy to prevent oxidative stress and ensuing pathologic conditions. Therefore, the integration of antioxidants formulations into conventional therapeutic interventions, either by ingestion of natural antioxidants or through dietary supplementation, should be encouraged for a holistic approach to the management and prevention of DM and the complications associated with the pathology. Introduction Oxidative stress is the outcome of an imbalance between the production and neutralization of reactive oxygen and nitrogen species (RONS) such that the antioxidant capacity of cell is overwhelmed [1-4]. Ordinarily, the peculiar molecular configuration of oxygen (O2) confers a very slow reactivity between O2 and biomolecules. Two main factors make O2 kinetically insert; the spin restriction imposed by its triplet state, and the negative standard potential for one electron reduction of O2 to superoxide radical (O2 •−). However, O2 possesses the attributes of free radicals in that it has two unpaired electrons with parallel spin in different π-anti-bonding orbitals that is responsible for its paramagnetic properties and relative stability [4,5]. Spin restriction can be overcome by single electron exchange that converts it to strong oxidizing agent [6,7]. Therefore, the activation of O2 by specific enzymes is achieved by the presence, at the active site, of either flavins or reduced transition metals such as iron (Fe2+) and copper (Cu2+), which donates single electron to O2 [6]. In the case of metalloproteins, a varying degree of electron transfer from the metallic moiety to O2 is possible. On this basis, metalloproteins can behave either as O2 carriers (hemoglobin, hemocyanin, hemerythrin, myoglobin), where reversible interaction with O2 occurs, or as O2 reductants. Studies showed that autoxidation of oxy-hemoglobin elicit the generation of free radicals [8]. Free radical production and oxidative stress Electron transfer to O2 is catalyzed by oxidases for production of chemical energy or oxidation of substrates. These enzymes, located in different subcellular compartments (mitochondria, endoplasmic reticulum, peroxisomes) are potential sources of partially reduced Cu2+ derivatives in biological milieu. Cytosolic enzymes {xanthine oxidase, NADPH oxidases, lipoxygenase, cyclooxygenase (COX), cytochrome P450 enzymes and aldehyde oxidase}, uncoupled endothelial nitric oxide synthase (eNOS), and other hemoproteins also produce O2 •− during catalysis [2,9,10]. The mitochondrial electron transport chain reduces O2 to O2 •− at ubiquinone and NADH dehydrogenase sites whereas; microsomal cytochrome P450 and its reductases produce O2 •− during xenobiotic biotransformation [11-14]. The “leaky” inner mitochondrial membrane electron transport chain reacts with O2 directly to generate O2 •−, which dismutates to form hydrogen peroxide (H2O2), which can further react to form the hydroxyl radical ( •−OH) [2,5,10]. Additionally, the mitochondrial outer membrane enzyme monoamine oxidase catalyzes the oxidative deamination of biogenic amines and is a quantitatively large source of H2O2 that contributes to increase in the steady state concentrations of reactive species within both the mitochondrial matrix and cytosol [15]. Specifically, O2 •− is the primary radical formed by the reduction of O2 leading to secondary radicals or reactive oxygen species (ROS) such as H2O2 and •−OH in the mitochondria [2,5]. Although the cause-effect relationship remains tentative, there appears to be a strong association between mitochondrial dysfunction and chronic metabolic diseases such as Type II diabetes mellitus (T2DM) and obesity [10]. The origin, enzymatic pathways of ROS and their oxidized products, as well as their enzymatic inactivation pathways in T2DM have previously been summarized [16]. RONS have been implicated in the pathophysiology of various disease states, including diabetes mellitus (DM) and long-term development of associated complications [10,12,14,16,17]. Oxidative tissue damage is mediated byactivating a number of cellular stresssensitive pathways, which include nuclear factor-ĸB (NFĸB), p38 Correspondence to: Paul C. Chikezie, Department of Biochemistry, Imo State University, PMB 2000,Owerri, Imo State, Nigeria, Tel: +2348038935327; E-mail: p_chikezie@yahoo.com