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Oxidative stress in diabetes mellitus

Paul C. Chikezie

Department of Biochemistry, Imo State University, Owerri, Nigeria

E-mail :

Okey A. Ojiako

Department of Biochemistry, Federal University of Technology, Owerri, Nigeria

Agomuo C. Ogbuji

Department of Food Science and Technology, Abia State Polytechnic, Aba, Nigeria

DOI: 10.15761/IOD.1000116

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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.

Key words

antioxidants, diabetes mellitus, hyperglycemia, oxidative stress, radicals


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 stress-sensitive pathways, which include nuclear factor-ĸB (NF- ĸB), p38 mitogen-activated protein kinase, NH2-terminal Jun kinases/stress-activated protein kinases and hexosamines [18]. Consequently, imbalance between cellular generation and scavenging capacity of free radicals elicits tissue damage associated with DM pathology [2,14,19]. Also, incidents of oxidative stress-induced neurological disorders mediated by inhibition of enzymatic activities connected with neurotransmission have been reported in experimental diabetic rats [20-22]. As a follow up to these findings, it is obvious that understanding the relationship between oxidative stress and DM pathology has the potentials to expand the therapeutic intervention options against the pathogenesis and progression of the disease. Therefore, the present review briefly summarized the underlying role of overwhelming levels of RONS in the pathophysiology of DM.

Oxidative damage and modification of macromolecules

The radicals (O2•−, •−OH, NO¯, 1O2, RO¯2, ¯ONOO) and pro-radicals (H2O2, HOCl, RS, and O3) are extremely reactive molecules. In biological systems, RONS cause substantial damage/modification to functional and structural macromolecules (lipids, nucleic acids, and proteins), as well as modulation of activity of antioxidant enzymes [4]. Oxidative attack of polyunsaturated fatty acids (PUFAs) gives rise to peroxided molecules, which subsequently breakdown to form reactive metabolites. For the fact that lipids are the major components of biological membranes, fluidity and permeability of these supra-molecules are severely affected, together with membrane protein functionality [4]. The reactive aldehydes are cytotoxic products of lipid peroxidation. Specifically, 4-hydroxynonenal (HNE) causes long-lasting biological consequences by covalent modification of macromolecules, whereas at physiological levels, HNE is considered as second messengers of free radicals and signaling molecules. Report showed that HNE and related reactive aldehydes may play critical roles in the pathophysiology of DM, in terms of the pathogenesis, progression and complications of the disease [23].

Base modification, scission of deoxyribose rings, strand breaks and ultimately, chromosomal aberration are outcomes of oxidative damage to nucleic acids. Oxidative challenge on proteins leads to the modification of amino acids side chains with the introduction of carbonyl groups, or oxidation of sulphydryl groups with consequent cross linking and aggregation of protein molecules. The presence of oxidative modifications ultimately results in increased susceptibility of modified proteins to specific proteases, enzyme deactivation, or conversely, unwarranted activation of enzymes [4,11].

There appears to be a direct mechanistic link between oxidative stress and the etiology of DM through the accumulation of oxidative damage to critical macromolecules. Several studies have established an association between increased carbonylation and nitrosylation of proteins in insulin-sensitive tissues and T2DM [24-26]. In another study, evidence showed that oxidation of specific proteins compromised their function in vitro [27,28] and there is a correlation between increasing oxidative stress and diminished protein folding and function in different animal models [29,30].

Oxidative stress is as a result of free radicals generated during autoxidation of glucose in DM [18,31]. Overall, DM is characterized by raised level of oxidative stress with associated increased generation of glycoxidation products, notably, HbA1c above the benchmark plasma value <7% [12,16,32]. The presence of hyperglycemia promotes increase in intracellular levels of advanced glycation end products (AGEs) [33-35].  Furthermore, auto-oxidation of glucose generates ROS, such as O2•−, H2O2 and •−OH [8,14], which in turn, accelerate lipid peroxidation with corresponding accumulation of advanced lipoxidation end products (ALEs) and more free radicals [23,36]. Increased levels of ROS in T2DM also contribute to a hypercoagulable state and evidence suggests that accumulation of oxidation products occur prior to the development of DM [37]. 

Antioxidants such as the flavonoids prevent the formation of AGEs by impeding the glucose dependent formation of Amadori, Schiff bases or Milliard products, which are intermediary products leading to the formation of AGEs [35,38]. Likewise, disruptions of AGEs cross linkages by drugs such as alagebrium or inhibition of AGE signal transduction pathway can substantially prevent the accumulation and formation of AGEs respectively [39]. The option of shielding or obliteration of AGEs’ receptor (RAGE), expression of RAGE antisense cDNA or anti-RAGE ribozyme may reverse atherosclerosis in experimental animals [17,40]. Also, notable inhibitors (amino guanidine and pyridoxamine) of AGEs formation exhibit reno-protective effects in diabetic animals [39,41].

Mechanisms of hyperglycemia induced production of oxygen free radicals

Hyperglycemia is known to cause elevation in plasma free radical concentrations [42,43]. The production of free radicals is engendered by uncontrolled hyperglycemia, which may occur via several routes [14,17,36]: i) increased glycolysis [44]; ii) intercellular activation of sorbitol (polyol) pathway [34,45]; iii) autoxidation of glucose [46], iv) protein kinase C (PKC) dependent activation of NAD(P)H oxidase [47], v) increased hexosamine pathway flux [36], vi) increased intracellular formation of AGEs [17], vii) increased expression of receptor for AGEs and its activating ligands [17] and viii) non-enzymatic protein glycation [48]. The overall rate of formation of oxidative products leading to oxidative tissue damage is summarized in Figure 1.

Figure 1. Relationship between rates of oxidant generation, antioxidant activity, oxidative stress, and oxidative damage in diabetes [31]; RAGE: receptor for AGEs.

Hyperglycemia appears to enhance non-oxidative catabolism of glucose to lactate, which is associated with increase in NADH/NAD+ ratio [44,45]. Under the condition of accelerated glycolysis, oxidation of glyceraldehyde 3-phosphate (GAP) to 1, 3-biphosphoglycerate (1, 3-DPG) by glyceraldehyde 3-phosphate dehydrogenase is coupled to reduction of NAD+ to NADH, and appears to become the rate limiting step in glycolysis [49]. In the cytosol, NADH is oxidized to NAD+ by lactate dehydrogenase (LDH) with concomitant reduction of pyruvate to lactate.

Thus, increase in the ratio of NADH/NAD+ reflects increased lactate/pyruvate ratio [45]. The mechanism by which increased rate of glycolysis increases free cytosolic NADH/NAD+ ratio (redox imbalance) suggest disequilibrium between the rate of oxidation of GAP to 1, 3-DPG and the rate of reduction of pyruvate to lactate [49]. Thus, enhanced glycolysis as a result of hyperglycemia is associated with increase in NADH/NAD+ ratio due to impaired oxidation of NADH to NAD+.

The increase in glucose flux via sorbitol pathway (a pathway of a minor significant under normal glycemic condition) elicits one of the major metabolic disturbances associated with diabetic hyperglycemia [50]. In this pathway, glucose is reduced to sorbitol by aldose reductase (AR) coupled with oxidation of NADH/NAD+ [51]. Subsequently, sorbitol is oxidized to fructose by NADH dependent sorbitol dehydrogenase (SDH) [17,52]. Previous studies have suggested several hypotheses for tissue injury engendered by increased sorbitol pathway activity, thus:

The decreased availability of NADPH, which is required for maintenance of reduced glutathione (GSH), is oxidized to NADP+ by the reduction of glucose to sorbitol by AR pathway [53]. Furthermore, the competition between AR and glutathione reductase (GSH-R) for NADPH cofactor further depletes intracellular GSH [50]. Attention has been focused on GSH depletion, because it dictates levels of cellular ROS production and accumulation, which in turn have a bearing on extent of oxidative tissue damage in DM [54]. Increased ratio of NADH/NAD+ is connected with accelerated oxidation of sorbitol to fructose by NADH dependent SDH [55,56]. Consequently, NADH molecules generated in the cytosol by oxidation of sorbitol to fructose are eventually conveyed to the mitochondria and oxidized by respiratory chain reaction that result in production of O2•− and other ROS [45,57]. Thus, an increase in the cytosolic NADH may be accompanied by increased load of mitochondrial NADH, which in turn, leads to increased ROS generation.

In a cell-free system under physiological conditions, glucose can be auto-oxidized to H2O2, throughenediol tautomer formation, which elicits the accumulation of reactive intermediate such as •−OHandO2•−, and ketoaldehydes [58,59]. Transition metals such as Fe2+ promote auto-oxidation of glucose and therefore, are crucial in these reaction cascades [59]. Several studies have equally shown that auto-oxidation of glucose in this manner are responsible for increased levels of ROS in DM [60,61].

Non-enzymatic glycation is a spontaneous reaction between glucose and amino groups of proteins in which reversible Shift bases and more stable Amadori products are formed [31]. The AGEs are produced by auto-oxidation of Amadori product [36,38,62]. Glucotoxicity is elicited through the binding of AGEs to RAGEs, which have been identified in endothelial cells, monocots/macrophages, mesangial cells, neurons and smooth muscle cells [12,16,31,47,63]. The presence of AGEs elicits poor matrix protein flexibility as a result of formation of cross-links among extracellular matrix proteins, which leads to abnormal interactions with other matrix components [63]. Additionally, the interaction of AGEs with endothelial surface RAGEs promote intracellular oxidative stress via the activation of AR of polyol-sorbitol pathways, activation of PKC isoforms and transforming growth factor-β (TGF-β) as well as activation of nuclear factor (NF-κB) [18,31]. The activation of NF-κB promotes increase in expression of a variety of cytokines such as tumor necrosis factors (TNF-α and TNF-β), interleukins (IL) 1, 6, 8 and 18 and interferon-γ, even in the presence of intact antioxidant mechanisms, which may engender overt diabetic nephropathy with associated glomerulosclerosis [2,12,16,31,47,64,65].

Also, increased cellular uptake of glucose stimulates PKC activity [66] which, amongst other effects, activates peroxidase enzymes and the COX pathway [66-68], with resultant overproduction of RONS. The process leading to this pathology is further enhanced and amplified when antioxidant defense mechanisms are compromised [69].

Mechanisms of hyperinsulinemia induced production of oxygen free radicals

Decline in physical fitness, increase in body fatness and upper body fat distribution are frequently associated with hyperinsulinemia and insulin resistance [70]. Several lines of evidence indicated that hyperinsulinemia promoted the generation of free radicals by NAD(P)H-dependent mechanism, which involved the activation of phosphatidylinositol 3'-kinase and stimulation of proliferative extracellular signal-regulated kinases (ERK-1- and ERK-2)-dependent pathways [71]. Furthermore, Krieger-Brauer and Kather, [72] reported that prolong exposure of human adipocytes to insulin caused a time- and dose-dependent accumulation of H2O2 in vitro. This effect, which has been linked to the presence of a membrane-bound NADPH oxidase, was observed to persist after cell disruption and devoid of ATP utilization; an indication that the receptor-kinase activity step was bypassed. In addition, increased insulin concentration in rats following intra-peritoneal injection of dextrose has been reported to be associated with increased free radical production [73].

Fasting hyperinsulinemia is considered to be a hallmark of insulin resistance [70] and there is a relationship between insulin resistance and plasma free radical concentration [74,75]. Factors that contribute to the elevation of free radicals and pathogenesis of insulin resistant DM are as follows:

  1. Hyperinsulinemiaoverdrive of the sympathetic nervous system [76]. Specifically, catecholamine increases free radical production through induction of metabolic rate and auto-oxidation pathway in DM [77].
  2. Insulin resistance is associated with elevated fasting plasma non-esterified fatty acid (NEFA) concentration [70,78]. 

Toborek and Henning, [79] showed that NEFA caused raised levels of oxidative stress in cultured endothelial cells following initial decreased level of GSH after 6h of incubation.

It is worthwhile to note that the complexity of these multitudes of findings suggests that the generation of free radicals may represent a potential mechanism by which chronic hyperinsulinemia activates proliferative events and down-regulates metabolic signals [71].

Oxidative stress induced lipid peroxidation in diabetes mellitus

Lipid peroxidation has been implicated in the pathogenesis of many degenerative disorders [80] including naturally occurring and chemically induced DM [81-83]. Lipid peroxidation is the primary cellular damage resulting from free radical reactivity, of which cellular lipid structures are mostly affected [62,84]. Oxidative deterioration of PUFAs of cellular membrane phospholipids, via intermediate radical reactions involves the production of hydroperoxides [85,86]. The chain reactions are associated with the generation of highly toxic peroxyl radicals (RO¯2) in a cycle of reactions that generate new lipid hydroperoxides (LHP) because of the proximity of PUFAs in biomembranes [19,87].

Also, both radical and non-radical oxidants can induce lipid peroxidation in lipoproteins, particularly those that contain PUFAs. For instance, peroxynitrite (¯ONOO) is particularly a powerful oxidant of low-density lipoproteins (LDL) [88]. Similarly, in vitro studies have revealed the presence of oxidized LDL (ox-LDL) fractions with identifiable auto-antibodies against ox-LDL in plasma of Type I DM (T1DM) patients, which suggest that the oxidation LDL can as well occurs in DM in vivo [89]. Accordingly, Maejima et al., [90] noted raised levels of ¯ONOO in T2DM patients. Additionally, LDL receptor does not recognize ox-LDL and are subsequently taken up by scavenger receptors in macrophages to form foam cells, which leads to atherosclerotic plaques [31,91].

Early evidence that suggested lipid peroxidation in DM was reported by Sato et al., [92], in which they noted that the levels of lipid peroxides in plasma of DM patients were significantly higher than that of normal subjects. Likewise, levels of plasma lipid peroxides of DM patients with angiopathy were relatively higher than that of DM patients. They further inferred that raised level of lipid peroxides was among other several factors that initiates atherosclerosis in DM. In another study, Davison et al., [93] used electron spin resonance (ESR) spectroscopy in conjunction with alpha-phenyl-tert-butylnitrone spin trapping to measure pre- and post-exercise free radical concentration in the venous blood of young male patients suffering from T1DM in order to ascertain their susceptibility to rest and exercise-induced oxidative stress. They suggested that greater concentration of oxidants and LHP were as a result of glucose auto-oxidation couple with lower rate of exercise-induced oxidation of major lipid soluble antioxidant; α-tocopherol in DM. Furthermore, they noted that ESR-detected radicals, in the course of the investigation, were secondary species derived from decomposition of LHP, which were major initial reaction products following free radical attack on biomembranes.

The underlying mechanisms of the formation of LHP and biologically active metabolites, together with their effect on cellular structure and function are becoming of increasing importance in understanding the pathogenesis and management of DM [94]. For instance, lipoxygenase products, especially 12(S)-HETE and 15(S)-HETE, are involved in the pathogenesis of several diseases including DM [14]. The LHPs are produced from a variety of PUFAs precursors via intermediate radical reactions involving O2 and metal cations (Fe2+ and Cu2+). The reactions generate highly reactive and cytotoxic lipid radicals. Extracellular LHP are transported in the systemic circulation by low- and high-density lipoproteins [82]. When released locally, LHP elicits structural damage to variety of biomolecules. For instance, the formation of LHP and their metabolites are important in ophthalmic medicine in that the retinal portion of eye is particularly sensitive to oxidative stress. Additionally, a steady irreversible decline in electroretinogram is observed in streptozotocin (STZ)-induced diabetic rats [95] when synthetic LHP was injected into the vitreous chamber of experimental animals [80]. Fortunately, LHP induced oxidative damage to biomolecules is ameliorated by lipid and water-soluble antioxidants, as well as by specific antioxidant enzymes.

Oxidative stress indicators in diabetes mellitus

The concept of raised level of oxidative stress (increased generation of free radicals) in DM was derived principally from in vitro experiments [12,96,97]. One of such investigations involved the use of cultured human umbilical vein endothelial cells incubated in variable glucose concentrations followed by monitoring the generation of ROS by a measure of cellular level of nitrotyrosine [12,98].

Early observations have focused attention in understanding underlying mechanisms that may be relevant to atherogenesis in patients suffering from T2DM and in obesity. Persons suffering from T2DM and/or obese individual exhibit raised level of oxidative stress and inflammatory response[10,99], which from reports have been linked to increased cellular levels of inflammatory cytokines, TGF-β and insulin-like growth factor binding protein (IGFBP)-3 [12,14,99]. Raised level of oxidative stress in T2DM is indicated by an increase in ROS generation by circulating mononuclear cells, increased lipid peroxidation [82] protein carbonylation [100], nitro-tyrosine formation [101], and DNA damage [1,2,,32,102]. Importantly, even pre-DM individuals showed elevated 8-hydroxyguanosine, which suggested that oxidative damage to DNA is present even before the clinical development of DM [2]. Recently, raised level of oxidative stress was also demonstrated in the obese as reflected in increased lipid peroxidation, protein carbonylation, and ortho-tyrosine and meta-tyrosine formation in DM individuals [2,38,43,103,104]. However, the levels of these oxidative stress indicators, as well as generation of ROS by leucocytes, were reversed following restriction to 1,000 calories/day for 4 weeks [105].

The primary causative factor of oxidative stress in DM is hyperglycemia, which operates via several mechanisms (Figure 2). 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.

Figure 2. Pathogenesis of hyperoxidative stress in non-insulin dependent diabetes. In boxes are shown mechanisms that are directly related to hyperglycemia. In circles are some mechanisms that result from the reaction of free radicals e.g. superoxide (O2•−) with lipoproteins (e.g. small, dense low- density lipoprotein) and nitric oxide (NO¯), oxidized LDL (ox-LDL), peroxynitrite (¯ONOO). 

In the presence of elevated calcium levels in endothelial cell, hyperglycemia stimulates the synthesis of NO¯ [106,107], in which in the presence of O2•−, NO¯ is converted to highly potent oxidant ¯ONOO that promotes endothelial cell damage and endothelial dysfunction [108,109]. Hyperglycemia causes paradoxical increase in the generation of NO¯ but low availability of NO¯ [12,110], which appears to activate NF- κB, and thereby engendering increased expression of inducible nitric oxide synthase (iNOS) [111]. However, Santilli et al., [110] noted that low availability of NO¯ is attributable to uncoupling of receptor-mediated signal transduction [112] and is the primary causative factor of endothelial dysfunction and diabetic angiopathy. In addition, overwhelming levels of O2•− directly inactivates two critical anti-atherosclerotic enzymes (eNOS and prostacyclin synthase) and consequently, precipitate defective angiogenesis [17].

Although there are extreme difficulties in measuring free radicals in vivo, some evidence in support of the notion of raised level of oxidative stress in DM and its association with poor metabolic control and coronary heart disease has been derived from observations in patients with DM [113]. Raised level of oxidative stress may provide a plausible pathophysiologic basis for the direct link between hyperglycemia and increased cardiovascular risk in DM [114]. There is persuasive evidence and definitive clinical proof that oxidative stress is associated with the pathogenesis and progression of atherosclerosis in both diabetic and non-diabetic subjects [31]. Insulin resistance and raised level of oxidative stress have been observed in obese T2DM patients [115].

There is a relationship between plasma malondialdehyde (MDA) concentration and hyperglycemia [16,116]. Earlier reports by Sato et al., [92] noted increased level of TBARS in blood samples of patients with poorly controlled DM and diabetic angiopathy. The elevation in TBARS concentration is considered to be an indicator of marked organ or tissue degeneration [112]. Also, elevation of TBARS concentration provides an indirect measurement of level of lipid peroxidation and alterations in erythrocyte antioxidant enzyme activities in diabetic patients [117,118] as observed in heart, pancreas and blood of STZ-induced diabetic rats [119]. In another instance, TBARS is considered as an indicator of free radical production. An increase in TBARS level in liver may therefore be due to raised level of oxidative stress that might promote DNA and protein alterations [46] including changes in the enzyme activities implicated in lipid metabolism and free radicals scavenging process [120].

Raised level of oxidative stress accounts for low erythrocytes count because of low levels of erythrocyte GSH coupled with increased utilization of GSH, in efforts to ameliorate oxidative stress associated with diabetic erythrocytes [121]. Consequently, pathophysiology of DM promotes oxidative damages of phospholipids and associated biomolecules of erythrocyte membrane. This is supported by the fact that erythrocytes of diabetic patients are more susceptible to lipid peroxidation when treated with H2O2 in vitro [122,123]. In addition, low hematocrit (PCV) percentage may be attributed to the reduction in the total red blood cell count due to failure in blood osmoregulation and elevation of plasma osmolality [124].

Diabetes mellitus induced alterations in antioxidant enzymes activities

Several studies on tissue levels of activity of enzymatic antioxidant systems are characterized with divergent results. For instance, studies using STZ-treated diabetic rats close to three decades ago showed that increase in pancreatic superoxide dismutase (SOD) activity might be an adaptive response to low pancreatic SOD level, whereas reduction in SOD activity in liver and kidney has direct linkage with the damaging effect of free radicals on the enzyme [125]. In another report, Piper et al., [126] demonstrated that in experimental DM, the activity of CAT was elevated in vascular tissues, whereas no significant alterations in the activity of other major antioxidant enzymes {SOD and glutathione peroxidase (GSH-Px)} were noted. Ojiakoet al., [127] reported that levels of renal and hepatocyte antioxidant enzymes (GPOx, SOD, CAT) and low molecular weight antioxidant (LMWA) (GSH/GSSG ratio) were altered in alloxan-induced hyperglycemic rats. In addition, Wohaieb and Godin, [125] reported increased CAT and SOD activities in pancreatic tissues of DM rats, whereas the hepatocytes showed generalized low CAT, SOD and GSH-Px activities. They noted that increase in both CAT and SOD activities occurred in tissues with the lowest antioxidant enzymatic activities (pancreas) before onset of DM. Thus, suggesting a compensatory response to an increase in endogenous oxidant radicals in the pancreas of DM rats. Decreased tissue concentrations of antioxidants, such as vitamin E, SOD and CAT, have also been demonstrated in vitro [125].

Low levels of GSH in erythrocytes of DM subjects is as a result of low activities of the enzymes involved in GSH synthesis (γ-glutamylcysteinsynthetase) and/or in the export of oxidized glutathione (GSSG) out of the cell [128] as well as enhanced sorbitol pathway [50]. In addition, low activity of GSSG-R, which acts to reduce GSSG to GSH, has also been reported in DM [129]. Kazuhiro et al., [130] and Matkovics et al., [131] reported low level of activity of GSSG-R in erythrocyte haemolysate of STZ-induced DM rats, which they attributed to be the effect of enzyme glycation in uncontrolled hyperglycemia [121]. Also, earlier reports showed significant reduction in the level of activity of erythrocyte GSH-Px in diabetic children and adolescents when compared with that of the control subjects [132,133]. These previous reports attributed low level of activity of erythrocyte GSH-Px to low blood GSH content in DM subjects, since GSH is a substrate and cofactor for GSH-Px activity. Therefore, low GSH content resulted in corresponding low GSH-Px activity and propensity to elicit oxidative stress. Accordingly, enzyme inactivation either through glycation process [117] or under conditions of increased oxidative stress also contribute to low GSH-Px activity [134].

Antioxidant defenses mechanisms are often impaired in DM with corresponding hyperoxidative stress [14,36]. Furthermore, there is evidence to suggest that DM induces alterations in the activities of antioxidant enzymes in various tissues [127,135]. Theoretically, alterations in antioxidant enzyme activity are consequences of oxidative stress, glycation of antioxidant enzymes/proteins and disturbances in micronutrient status in DM [136-138].


The critical roles of overwhelming cellular levels of RONS play in the pathophysiology of DM have been incontrovertibly established. Intuitively, the inhibition and/or scavenging of intracellular free radical formation provide a therapeutic strategy to ameliorate oxidative stress and prevent ensuing pathologic complications associated with DM. Therefore, the integration of antioxidants formulations into conventional therapeutic interventions, both by ingestion of natural antioxidants or through dietary supplementation, should be encouraged for a holistic approach to the management and prevention of DM and associated complications. However, despite the obvious usefulness and potential merit/advantages of antioxidant pharmacotherapy, there is still the need to investigate and evaluate the efficacy and safety scores of this therapeutic strategy. Moreover, previous studies on the effect of certain LMWAs on endothelial dysfunction in T2DM revealed contradictory results [139]. Besides, the query of whether antioxidants could have beneficial effect by reducing the risks associated with DM, especially cardiovascular disease, has remained unresolved and inconclusive [14].

Finally, another novel approach to DM therapy is to provoke over-expression of antioxidant enzymes in a tissue-specific manner, as exemplified in genetic mutant mice model, to serve as control measure against the development of metabolic diseases associated with oxidative stress [2]. This proposed DM therapy shared similar concepts with the reports of Alfadda and Sallam, [10], in which they noted that activation of transcription nuclear factor, nuclear factor-erythroid 2-related factor 2 (Nrf2) induced several antioxidant and detoxification genes in patients with lung cancer. Unfortunately, the metabolic fallouts and effect of this proposed therapeutic approach on general haemostasis of DM individuals is yet to be elucidated.


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Editorial Information


Masayoshi Yamaguchi
Emory University School of Medicine

Article Type

Review Article

Publication history

Received: April 21, 2015
Accepted: May 25, 2015
Published: May 27, 2015


©2015 Chikezie PC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Chikezie PC, Ojiako OA, Ogbuji AC (2015) Oxidative stress in diabetes mellitus. Integr Obesity Diabetes . 1: doi: 10.15761/IOD.1000116

Corresponding author

Paul C. Chikezie

Department of Biochemistry, Imo State University, PMB 2000,Owerri, Imo State, Nigeria, Tel: +2348038935327.

E-mail :

Figure 1. Relationship between rates of oxidant generation, antioxidant activity, oxidative stress, and oxidative damage in diabetes [31]; RAGE: receptor for AGEs.

Figure 2. Pathogenesis of hyperoxidative stress in non-insulin dependent diabetes. In boxes are shown mechanisms that are directly related to hyperglycemia. In circles are some mechanisms that result from the reaction of free radicals e.g. superoxide (O2•−) with lipoproteins (e.g. small, dense low- density lipoprotein) and nitric oxide (NO¯), oxidized LDL (ox-LDL), peroxynitrite (¯ONOO).