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filter your search All Content All Journals Diabetes. Advanced Search. User Tools Dropdown. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume 48, Issue 1. Next Article. Article Navigation. Abstract January 01 Role of oxidative stress in diabetic complications: a new perspective on an old paradigm.

J W Baynes ; J W Baynes. Department of Chemistry and Biochemistry, University of South Carolina, Columbia , USA. baynes psc. This Site. Google Scholar. S R Thorpe S R Thorpe. Obrosova I, Fathallah L, Greene D: Early changes in lipid peroxidation and antioxidative defense in rat retina.

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Download references. This work was supported by grants from NIH HL , American Heart Association Scientist Development Grant and American Diabetes Association to Adviye Ergul and an AHA Southeast Affiliate Predoctoral Fellowship Award to Alex K.

University of Georgia College of Pharmacy, Athens, Georgia, USA. Medical College of Georgia Vascular Biology Center, Augusta, Georgia, USA.

You can also search for this author in PubMed Google Scholar. Correspondence to Adviye Ergul. AKH and JSJ contribute equally to writing the evidence-based sections and drafting of this review. DR was responsible for critical revision and formatting.

AE participated in all aspects and areas of this review. Open Access This article is published under license to BioMed Central Ltd. Reprints and permissions. Johansen, J. et al. Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical practice.

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View archived comments 1. Skip to main content. Search all BMC articles Search. Download PDF. Download ePub. Abstract Cardiovascular complications, characterized by endothelial dysfunction and accelerated atherosclerosis, are the leading cause of morbidity and mortality associated with diabetes.

Introduction It is a well-established fact that diabetes is a risk factor for cardiovascular disease [ 1 , 2 ]. What is oxidative stress? Figure 1. Full size image. Figure 2. References Pyorala K, Laakso M, Uusitupa M: Diabetes and atherosclerosis: an epidemiologic view. Article CAS PubMed Google Scholar Laakso M: Hyperglycemia and cardiovascular disease in type 2 diabetes.

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However, some of these products, such as 3-deoxyglucosone adducts to lysine and arginine residues, are formed independent of oxidation chemistry.

Elevated levels of oxidizable substrates may also explain the increase in glycoxidation and lipoxidation products in tissue proteins, without the necessity of invoking an increase in oxidative stress. Further, age-adjusted levels of oxidized amino acids, a more direct indicator of oxidative stress, are not increased in skin collagen in diabetes.

We propose that the increased chemical modification of proteins by carbohydrates and lipids in diabetes is the result of overload on metabolic pathways involved in detoxification of reactive carbonyl species, leading to a general increase in steady-state levels of reactive carbonyl compounds formed by both oxidative and nonoxidative reactions.

The increase in glycoxidation and lipoxidation of tissue proteins in diabetes may therefore be viewed as the result of increased carbonyl stress. The distinction between oxidative and carbonyl stress is discussed along with the therapeutic implications of this difference. Sign In or Create an Account.

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Many research studies demonstrated the association of oxidative stress and the pathogenesis of insulin resistance via insulin signals inhibition and adipocytokines dysregulation[ 8 , 9 ].

The lipid peroxidation contributes to the pathogenesis of atherosclerosis. It is occurred in the blood vessel walls and does not occur from low density lipoproteins LDL in circulation[ 87 , 88 ]. LDL can enter to the blood vessel walls. The modified LDL oxidized LDL may escape from the scavenger recognition receptors and back to the circulation.

Therefore, this circulating LDL peroxidation is a potentially useful biomarker of lipid peroxidation in circulation. Indeed, this assay is used for the demonstration of in vivo antioxidants inhibit the effects of lipid peroxidation[ 89 , 90 ].

MDA from the oxidative polyunsaturated fatty acids PUFA degradation is determined by the reaction of thiobarbituric acid TBA with MDA to generate the stable end product of MDA-TBA adduct[ 91 - 95 ]. Serum MDA levels have been used as the lipid peroxidation biomarker and indicator of free radical damage[ 37 , 83 , ].

MDA, the three-carbon dialdehyde, can exist in many forms in the aqueous circulation. This method was used the reaction of MDA with TBA and heated under acidic conditions but the TBA can react with many chemical species such as proteins, phospholipids, aldehydes, amino acid and nucleic acids[ , ].

One MDA molecule reacts with TBA two molecules to form a stable pink to red chromophore that absorbs maximally at nm[ ] or fluorescence detection. This chromophore is termed thiobarbituric acid reacting substances. Elevated MDA levels in T2DM patients are associated with cardiovascular disease risk[ 83 ].

The most valuable of lipid peroxidation biomarker in the biological system is the isoprostanes, elevated from the PUFA peroxidation[ - ].

Isoprostanes identified as free form and the most are esterified to lipids in circulation. Isoprostanes can be analyzed by mass spectrometry techniques, so that can easily be detected in human body fluids[ , , , ]. Isoprostanes appear to turn over rapidly in metabolized and excreted[ , ].

Isoprostanes and their metabolites detection in urine may be the useful biomarker for lipid peroxidation[ ]. Isoprostanes assay have focused on the F 2 -isoprostanes measurement, which elevate from the arachidonic acid peroxidation[ ].

Elevation of F 2 -isoprostanes levels have been shown in conditions of the cardiovascular disease, diabetes development[ , ], cigarette smoking[ , , ], hyperhomocysteinaemia[ ] and hypercholesterolaemia[ , ]. F 2 -isoprostane levels have also been shown to decrease by antioxidants supplementation both in animal models and humans subjects[ - ].

The components of metabolic syndrome consist with abdominal obesity, dyslipidemia, hypertension and diabetes[ , ].

It is the major modern lifestyle complication cause from physical inactivity and overeating and associated with the increased risk of cardiovascular diseases, hypertension and T2DM that summarized in Figure 4.

Over nutrition and oxidative stress: In metabolism of glucose through glycolysis and tricarboxylic acid TCA cycle to generate nicotinamide adenine dinucleotide NADH and flavin adenine dinucleotide FADH 2 as the electron donors.

In over nutrition, the excessive glucose occur and a large amount of glucose is oxidized in the glycolysis and TCA cycle to increase NADH and FADH 2 generation in electron transport chain of mitochondrial and increased superoxide generation[ ].

The excessive of free fatty acids FFAs leads to increase FFA-oxidation and acetyl coenzyme A CoA oxidation in TCA cycle generate the NADH and FADH 2 electron donors as glucose oxidation results in mitochondrial ROS overproduction[ ]. Furthermore, NADPH oxidase in the plasma membrane can convert oxygen molecule to superoxide radical and involve in ROS nutrient-based generation.

In adipocytes, ROS is generated by in fused with FFAs, treatment with NADPH oxidase inhibitor can block this ROS generation. This indicates that NADPH oxidase involves in fatty acids ROS generation[ 8 ]. Palmitate can activate diacylglycerol synthesis and protein kinase C PKC leading to activate NADPH oxidase[ ].

Thus, over accumulated fat result in the increased fatty acids oxidation and lead to activate NADPH oxidase in local or remotely cells to cause ROS over production in over nutrition or obesity Figure 4.

Conversely, calorie restriction may be associated with normal physiological system[ ] and may involve in normal cellular redox state[ ]. In aged animals models treated with antioxidant agents or hypocaloric diets led to ameliorate in oxidative stress status and tissue function[ , ].

Treatment with resveratrol, a polyphenol reduced atherosclerosis and diabetes development[ ]. These studies demonstrate that nutrition is associated with increased or decreased redox status and over nutrition result to increase oxidative stress to contribute pathogenesis of atherosclerosis, cancer and other diseases.

Oxidative stress in adipose tissue: Increased fat accumulation in human has been associated with oxidative stress biomarkers[ ]. Similarly, obese mice were significantly higher oxidative stress levels in circulation[ 8 ].

Moreover, lipid peroxidation and H 2 O 2 levels were increased in adipose tissue[ 8 ]. These mean that adipose tissue may the major source of ROS production and can be released to the circulation potentially affecting various distance organs functions and damage Figure 4.

Increased NADPH oxidase expression in adipose tissue associated with increased oxidative stress levels. Increased mRNA expression was found in adipose tissue of obese mice[ 8 ]. Increased ROS generation in lipid accumulation and further elevating ROS generation with FFA treatment were found in 3T3-L1 adipocytes cultured[ 8 ].

These ROS generation processes can be blocked by NADPH oxidase inhibitors, apocynin or diphenyleneiodonium. Many studies suggest that NADPH oxidase induces adipocytes ROS production[ 8 ].

Moreover, obese mice ameliorated hyperinsulinemia, hypertriglyceridemia, hyperglycemia and hepatic steatosis by supplementation with apocynin[ 8 ].

These data demonstrate that NADPH oxidase increase ROS production in obesity and metabolic syndrome may play the important roles in the atherosclerosis, T2DM and cancer pathogenesis. Adipose tissue tries to increase antioxidant enzymes levels to against ROS over production. However, these antioxidant enzymes activity and expression are decreased in adipose tissue[ 8 , - ].

Then, increased ROS-production enzymes and decreased antioxidant enzymes may cause oxidative stress in obese and metabolic syndrome. Oxidative stress and salt-sensitive hypertension: As in mention above, ROS levels are increased in obesity and can be ameliorated by weight loss[ 7 ].

Obese rats induced by refined sugar or high fat diet leading to ROS overproduction and increase oxidative stress[ 6 , ]. Many research evidences suggest that metabolic syndrome was associated with the salt-sensitive hypertension.

ROS play the roles as mechanical link of metabolic syndrome and salt-sensitive hypertension[ , ], which itself leads to ROS overproduction[ - ].

Salt restriction in hypertensive obesity was more effective reduction in blood pressure than in hypertensive non-obesity patients, and weight loss in obesity and salt sensitive hypertensive patients caused the successful of blood pressure reduction[ ].

Salt-sensitive hypertensive patients were significantly more prevalent in metabolic syndrome patients than without metabolic syndrome[ ]. Oxidative stress in abdominal adipocytes due to increase adipocytokines secretion such as TNF-α, angiotensinogen, non-esterified fatty acids[ ].

Interestingly, infused Ang II-rats disturbed sodium balance to cause ROS overproduction in salt-sensitive rats[ - ]. Moreover, in salt-sensitive hypertensive patients are also increased 8-isoprostane levels[ ].

Thus, ROS may the underling pathogenesis of diseases in metabolic syndrome, obese and non-obese intake excessive salt as the salt-sensitive hypertensive patients. In high-renin patients non-modulating salt sensitive hypertension had elevated the homeostasis model assessment of insulin resistance HOMA-IR levels[ ].

Insalt-sensitive hypertensive non-obesity patients had significantly lower insulin sensitivity than in non-salt-sensitive hypertensive patients[ ]. Increased renal ROS overproduction may increase the salt sensitive hypertension[ ]. Then, increased renal oxidative stress may contribute to cause salt-sensitive hypertension development.

Moreover, ROS overproduction in vascular endothelial cells suppresses the NO-dependent vasodilation[ ] and may play the role in the salt-sensitive hypertension development. Many research studies demonstrated that T2DM patients have increased ROS production-induced higher oxidative damage in the circulation and also have reduced antioxidant defenses mechanisms[ - ].

Elevated free fatty acids, leptin and other circulating factors in T2DM patients may also contribute to cause ROS overproduction. Figure 5 demonstrates the association of increased ROS production with atherosclerosis and sources of ROS generations in T2DM patients.

Hyperglycemia due to cause increased glucose metabolism leading to increase NADH and FADH 2 overproduction, which are used by the electron transport chain of mitochondria to generate ATP[ ].

NADH overproduction can cause the higher proton gradient production in mitochondria. These electrons are transferred to oxygen to produce higher superoxide[ ]. Oxidative stress increased in circulation of T2DM patients from the polyol pathway.

ROS was generated by two enzymes: 1 Aldose reductase in the reaction use NADPH to change glucose to sorbitol. Sorbitol production is a minor reaction in normal physiological conditions.

In the condition of sorbitol overproduction, the availability of NADPH is reduced this reflect to reduce glutathione regeneration and NOS synthase activity to cause increased oxidative stress[ ]; and 2 Sorbitol dehydrogenase in the second step oxidizes sorbitol to fructose concomitant with NADH overproduction.

Increased NADH may be used by NADH oxidases to increase superoxide production[ ] include in mitochondrial over superoxide production. Glycation end-product is the binding of ketone or aldehyde groups of glucose with the free amino groups of proteins leading Schiff bases formation without enzymes, then to form the Amadori product and rearrangements of the structure to the irreversible AGEs in the final[ , ].

AGEs has been demonstrated in atherosclerotic lesions and their tissue of T2DM patients and increased AGEs levels associated with severity of the diseases[ ]. Moreover, binding of AGEs to specific cell surface receptor for AGE can activate intracellular redox signaling and subsequent to activate the expression of redox-sensitive transcription factors and inflammatory mediator[ - ].

Oxidative stress is the major factor underlying in the CVD, insulin resistance and T2DM pathogenesis. These may explain by the presence of the inflammation conditions.

Now, inflammation recognized as the one manifestation of oxidative stress[ ] and can be generate the inflammatory mediators including adhesion molecules and interleukins to induce oxidative stress[ ].

The concept of atherosclerosis is an inflammatory disease now well established. This chronic inflammation may be involved in the insulin resistance and T2DM pathogenesis[ ]. Recent clinical research indicates that sub-clinical inflammation may impact in the development and progression of diabetic complications[ , ].

Moreover, excessive FFA and glucose induce inflammation effect through oxidative stress and reduced antioxidants[ ]. Interestingly, the subclinical pro-inflammatory state observed in many pathogenesis conditions such as atherosclerosis, aging, T2DM and cancer, is caused from mitochondrial ROS overgeneration[ ].

Non-esterified FFAs are elevated in T2DM patients[ ]. These excessive FFAs enter the citric acid cycle to generate acetyl-CoA to receive NADH overproduction to cause mitochondrial superoxide over production.

In humans, infused FFA has been shown increased lipid peroxidation by elevated isoprostanes marker levels[ , ]. Adipocytokine, leptin is secreted from the adipocytes to act on the central nervous system to decrease food intake.

It reflects all effects on the vascular smooth muscle cells, endothelial cells, macrophages and monocytes[ ]. Leptin levels are increased and associated with cardiovascular disease in T2DM patients[ - ].

In culture of endothelial cells incubated with leptin to cause ROS production[ , ]. Superoxide is converted by SOD to H 2 O 2 and O 2 molecule. Catalase, the heme metalloenzyme is expressed in peroxisomes, mitochondria, cytoplasm and nucleus.

H 2 O 2 is catalyzed by catalase to oxygen and water[ ]. While glutathione peroxidase the selenoprotein, was found in both intracellular and extracellular. Glutathione peroxidase has a highly sensitive function for lipid peroxides degradation, converses H 2 O 2 to water by using the thiol group of glutathione[ ].

Their H 2 O 2 detoxification plays the important roles to prevent lipid peroxidation production and regulation of the cellular redox status[ ]. For example, the expressed transcription factor NF-E2 related factor in the cytosolic is interrupted binding with Keap-1 as the responsible to increase oxidative stress and translocate to the nucleus for initiation of the transcription of the various antioxidant enzymes[ ] as the strategy to develop many class of antioxidant, anti-inflammatory, and anticancer agents.

Reduction in non-enzymatic antioxidants, thiol glutathione and thioredoxin are the major dysregulation of the cellular redox status[ ]. The cellular redox status is reflected by the reduction of glutathione GSH , oxidized glutathione GSSG ratio or GSH:GSSG ratio , ascorbic acid, tocopherols and methionine and cysteine amino acids.

Exogenous herbal antioxidants compounds in dietary foods include flavanoids, anthocyanins and polyphenolics act as ROS scavenging[ , ].

The direct interaction of ROS with non-enzymatic antioxidants is based on chemical structure properties. In free radicals participate in 1e- oxidation while non-radical species was 2e- oxidation.

H 2 O 2 and the non-radical may react with thiols and methionine, and the OONO - discriminate to react with thiols, ascorbic acid, tocopherols and methionine[ ]. Oxidative stress plays the major role in the association with the insulin resistance pathogenesis by insulin signals disruption and adipocytokines dysregulation[ 8 , 9 ].

In rat models, oxidative stress enhances insulin resistance. The evidence suggested that Ang II infused rats required the increased glucose infusion to maintain euglycemia during hyperinsulinemic clamp to stimulate ROS production[ 10 ]. For this example, Ang II-infused rats were caused insulin resistance from the suppression on insulin-induced glucose uptake in skeletal muscle and increased in oxidative stress biomarkers in this animal experiment.

In experimental model, superoxide dismutase and tempol can reduce the insulin resistance. Many evidences indicated that ROS overproduction may induce insulin resistance and confirmed by the supplementation of antioxidant tempol to cause insulin resistance amelioration in Ren-2 transgenic rats[ ].

Insulin-target organs of the obese and diabetic KKAy mice were stimulated and caused ROS over production skeletal muscle, liver and adipose tissue [ 8 ] and to cause insulin resistance in these organs.

High fat-fed mice found ROS overproduction in liver and adipose tissue of these obese mices to induce insulin resistance[ ]. Many research studies suggested that antioxidant agents decreased plasma insulin, glucose, triglycerides levels and ameliorate insulin resistance in KKAy mice with no weight loss[ 8 ].

As mention above, in over nutrition, the excessive glucose occur and a large amount of glucose is metabolized in the glycolysis and TCA cycle leading to increased NADH and FADH 2 production in electron transport chain of mitochondrial and increased superoxide production[ ].

In general population, insulin resistance precede in many years before onset of T2DM and it is also multifactorial[ 11 , 12 ] such as genetic component[ 11 , 13 ]. Insulin resistance and reduction in insulin production are the major characteristics of the T2DM pathogenesis[ 11 , 12 , 14 - 16 ].

Modern lifestyle, physical inactivity, abdominal obesity and excessive of adipokines can cause insulin resistance[ 11 , 15 ].

In early stage, normal glucose tolerance is preserved by compensation hyperinsulinemia. Increased glucose, FFA and insulin levels lead to ROS overproduction, increased oxidative stress and activate stress transduction factor pathways. This can cause insulin activity inhibition and secretion to accelerate the onset of T2DM as shown in Figure 6.

Oxidative stress has been demonstrated the implication and association in the late complications of diabetes mellitus[ 17 , 18 ] as in the schematic of Figure 5. Many studies have demonstrated ROS overproduction and increased oxidative stress to insulin resistance[ - ]. Both in vitro studies and in animal models demonstrated that α-lipoic acid LA , antioxidant agent increase insulin sensitivity[ - ].

In clinical trials, supplementation with vitamin C, vitamin E, glutathione increases insulin sensitivity in both insulin-resistance and T2DM patients[ , ]. Oral supplementation with LA formulation for 6 wk decreased circulating fructosamine levels[ ] and increase insulin sensitivity[ ] in T2DM patients and the other studies have confirmed 2.

Because insulin resistance occurred before chronic hyperglycemia development[ 12 ], that difference from insulin resistance in the pre-diabetic state result from oxidative stress activation by increased glucose levels. However, obesity demonstrated the strong association with insulin resistance.

In this regard, the mediator of oxidative stress-induced insulin resistance of the pre-diabetic state might be from the adipocyte-derived factor such as TNF-α[ ], leptin[ ], FFAs[ - ] and resistin[ ].

However, the FFAs elevations are associated with insulin resistance and obesity[ , , ]. Many studies found that increased FFA levels decrease insulin sensitivity, as in the Randle hypothesis[ ] and insulin-signaling inhibition[ ]. Elevated FFA concentrations cause mitochondrial dysfunction such as uncouplers of oxidative phosphorylation in mitochondria[ ] and increased superoxide production[ ].

These caused the exacerbated situation from FFAs induce oxidative stress and reduce intracellular glutathione caused impaired endogenous antioxidant defenses[ , , ]. Supplementation with glutathione improves insulin sensitivity and β-cell function by the restoration of redox status in T2DM patients and healthy subjects[ ].

FFA mediated the nuclear factor-κB NF-κB activation, as the consequence of FFAs increased ROS overproduction and glutathione reduction[ , - ] and also linked to FFA-activated PKC-θ [ ] to caused NF-κB activation[ ]. Vitamin E supplementation inhibits the FFA-induced NF-κB activation[ ] indicated that FFAs act as pro-inflammatory agent effects the alteration of the cellular redox status.

The HOMA-IR was proposed by Matthews et al [ ] that can be used to estimate insulin resistance and insulin sensitivity in individuals. HOMA-IR is easy to calculate and no more laborious technique.

HOMA-IR method derives from the mathematic calculation from fasting plasma insulin and glucose concentrations. Increased circulating glucose levels stimulate the β-Cells function by sensing and secreting of insulin in appropriate amount[ ] and as the target of oxidative stress.

The processes are complex and depend on many factors[ 16 ]. The critical glucose metabolism in mitochondrial is the importance linking stimulus the insulin secretion[ - ]. Therefore, mitochondria damage and markedly blunt insulin secretion is also occur by the ability of oxidative stress H 2 O 2 [ ].

Because β-Cells are lower in antioxidant enzymes levels superoxide dismutase, catalase and glutathione peroxidase and higher sensitive to oxidative stress[ ]. Oxidative stress exposure to β-cells activated the increased p21 cyclin-dependent kinase inhibitor production, decreased insulin mRNA, ATP and calcium flux reductions in mitochondria and cytosol to cause apoptosis[ ].

The results indicate that mitochondria in β-cells involved in the processes of glucose induced insulin secretion are affected by increased oxidative stress. Lipid peroxidation, oxidative stress products exposed to islets, inhibited insulin secretion and also caused glucose oxidation[ ].

Conversely, antioxidants can protect β-cell against the toxicity of oxidative stress, AGEs production and inhibit NF-κB activation[ - ]. These antioxidants are N-acetyl cysteine NAC , α-phenyl-tert butylnitrone, aminoguanidine and zinc.

Recent research study evaluated β-cells function after over expression of glutamine. Hexosamine over production resulted from the deterioration of insulin signaling of glucose-stimulated insulin secretion.

Fructosephosphate amidotransferase is the rate-limiting enzyme increase in hexosamine pathway[ ], coincident with increased H 2 O 2 production[ ] that can ameliorate by NAC supplementation. West[ 19 ] demonstrated that insulin secretion in T2DM patients improved by the reduction of hyperglycemia with diet, insulin or sulfonylureas.

On the other hand, in healthy normal, high glucose infused as a clamp reduces insulin secretion[ ]. Thus, glucose toxicity, the concept of the condition of hyperglycaemia itself can decrease insulin secretion which implies the irreversible damage to cellular components of β-cells[ ].

Generally in β-cells, excessive glucose oxidation and metabolism will always cause to ROS over production. Superoxide dismutase and catalase are normally as the detoxified antioxidant enzymes.

β-Cells are low amount of these antioxidant enzymes and also low in glutathione peroxidase, a redox-regulating enzyme[ ]. Then, hyperglycaemia condition leads to increase ROS production and accumulation in β-cells and subsequent of cellular components damage.

Pancreas duodenum homeobox-1 is an insulin promoter activity regulator was loss leading to β-cell dysfunction[ ]. Lipotoxicity to β-cells concept, elevation of non-esterified fatty acids concentrations in diabetic and non-diabetic obese patients, result of the enhanced adipocyte lipolysis.

In the presence of the excessive fatty acid oxidation in β-cells is caused increased long-chain acyl CoA accumulation leading to inhibite β-cells function[ ]. This process is as an integral part of the normal insulin secretory function. Thus, impaired insulin secretion and β-cell dysfunction strongly associated with the FFA-stimulated ROS overproduction[ ].

Elevation of glucose and FFA levels are the major characteristic of T2DM patients. This combination is the major β-cells toxicity and require the maximize protection. In culture cells of islets or HIT cells were exposed to high concentrations of glucose and FFA levels.

There was decrease in insulin-gene activity and insulin mRNA[ ]. In the study of islets co-culture with high glucose and palmitate levels caused impaired insulin signaling of the glucose-stimulated insulin secretion[ ]. Recent studies have confirmed that β-cells lipotoxicity is the concurrent status as the amplifying effect mediated by glucose toxicity in hyperglycemia condition[ , ].

Insulin resistance and T2DM are characterized by dyslipidemia one major risk factor for cardiovascular disease. Lipid triad is the complex metabolic milieu associated with dyslipidaemia[ ] comprise with hypertriglyceridemia, low levels of high-density lipoprotein cholesterol HDL-C and the appearance of small, dense, LDL sdLDL - and caused excessive post prandial lipemia[ , ].

Diabetic dyslipidemia caused from the disturbance of lipid metabolism, an early event cardiovascular complications development and was preceded in T2DM patients by several years[ - ].

Indeed, insulin resistance status in both with and without T2DM patients was display qualitatively similar lipid abnormalities[ ]. The different components of diabetic dyslipidemia are closely linked to each other metabolically[ - ] and are initiated by the elevation of triglyceriderich very LDL VLDL from hepatic over production[ , ].

It is the key importance mechanisms to elucidate the over production of VLDL involved in diabetic dyslipidemia[ ]. In insulin resistance state, decrease insulin function and lack of insulin inhibits lipolysis leads to increase FFAs generation of and lower lipoprotein lipase activity.

This occurs after meal consumption, generates a chylomicron remnant rich in TG[ ], caused elevated hepatic FFAs and VLDL TG-rich particles secretion. These processes affects HDL-C metabolism through the interchange with TG-rich lipoproteins via cholesteryl ester transfer protein to produce HDL particles containing high TG concentrations.

These HDL-TG particles were hydrolyzed with hepatic lipase to TG and HDL. This HDL becomes smaller and less antiatherogenic activity, easily to remove from the circulation by the kidneys. Moreover, insulin resistance in T2DM patients associated with endothelial dysfunction led to increase risk of CVD[ ].

The most atherogenic subfractions of sdLDL are elevated in circulation of obesity individuals, as a key feature in association with elevated triglyceride and low HDL cholesterol. Elevated sdLDL concentrations are also founded in abdominal obesity subjects and demonstrated greater myocardial risk.

The mechanisms are related to excess accumulation of abdominal adipose tissues, elevated total cholesterol and LDL-C and related to high saturated-fat consumption, weight gain and obesity. Dyslipidemia is commonly occurred in T2DM patients and might play the major role in accelerated macrovascular atherosclerotic disease and increased CVD risk in T2DM patients[ ].

Dyslipidemia in T2DM patients as lipids triad is characterized by increased insulin levels, hypertriglyceridemia, low HDL-C levels and increased sdLDL-particles independent of LDL-cholesterol and increased TG-rich remnant lipoprotein TGRLs concentrations[ , ].

In this manner, low HDL-C levels associated with hyperinsulinemia or insulin resistance and insulin signaling for insulin-mediated glucose disposal[ ] characterized by higher fasting plasma glucose and insulin levels. Then, these major changes associated with the insulin resistance syndrome are increased TGRLs and decreased HDL-C levels.

Thus, in dyslipidemia, using the lipoprotein concentration ratios are associated with insulin resistance and increased CVD risk conditions. Lipoprotein ratios might be useful to identify insulin resistance individuals even different in fasting glucose or insulin levels.

Lipoprotein ratios: In description above, the major change is increased TGRLs and decreased HDL-C levels are associated with insulin resistance syndrome.

Insulin plays the important role in TG metabolism, in normal condition TGRLs particles reduces synthesis by the distinct pathways when compared with VLDL particles synthesis[ , ].

Insulin fails to suppress VLDL particles synthesis[ ]. Insulin resistance is significantly associated with increased lipid synthesis in the liver, increased FFAs flow to the liver and decreased VLDL particles clearance resulting in increased VLDL levels in the circulation[ ].

Thus, dyslipidemia as lipoprotein ratios may associate with insulin resistance and increased CVD risk. On this basis, waist circumference, LDL-C, TG levels, insulin resistance and the CVD risk are estimated[ ].

The major features of dyslipidemia are determined by hypertriglyceridemia, low HDL-C levels and slightly high or normal LDL-C levels with altered composition.

Hypertriglyceridemia is indicate as elevated atherogenic chylomicron and VLDL remnant and associated with increased CVD risk[ , ]. These phenomenons demonstrated the problems of VLDL and HDL levels but not the LDL levels and concurrent with increased insulin levels.

All of these features are associated with coronary heart disease risk in obesity, metabolic syndrome and T2DM patients. The cut-off value of these ratios in Tangvarasittichai et al [ ] study was lower than the results from Western populations[ - ]. Then, insulin resistance was significantly predicted by these markers.

For atherosclerotic risk assessment in obesity, metabolic syndrome and T2DM patients requires more attention to lipid screening. Insulin resistance often occurs with T2DM but is insufficient for the T2DM development. β-cells dysfunction are important event for the T2DM development and progression.

In early stage of insulin resistance, β-cells increase the secretory function try to compensate and control hyperglycemia. In Pima Indian population study caused acute insulin response dysfunction or decreased β-cell responses was found during the normal glucose tolerance state in individuals who eventually progressed from normal glucose tolerance to impaired glucose tolerance or T2DM when compared with individuals who persisted in the state of normal glucose tolerance[ ].

There was evidence of early defects in glucose disposal by decreased insulin sensitivity before the development of glucose intolerance state, although output of circulating glucose did not increase until the progression from impaired glucose tolerance to T2DM revealed. Interestingly, individuals who demonstrated transient glucose intolerance but were able to recover and to reach normal glucose tolerance and did not show the early secretory defect observed in progressed individuals[ ].

β-cells failure or dysfunction occurred as the results of the combination of increased oxidative stress, glucose and lipids accumulation to cause glucotoxicity and lipotoxicity to β-cells to progress increased apoptosis and loss of the insulin granule secretory components expression[ ].

The World Health Organization updated the prevalence of T2DM estimated by the year those By the year , those T2DM is associated with obesity, sedentary lifestyle and lack of exercise in the aging population. There are a number of gene abnormalities related to T2DM, that showed significant differences exist in the abnormalities gene associated with T2DM among the various ethnic populations, such as African Americans, Asians and Europids[ , ].

It is typically diagnosed in patients older than 30 years with overweight or obesity and positive in family history of T2DM. However, insulin resistance may occur and develop in many years before diagnosed as T2DM[ ]. Figure 7 summarized the etiology of the T2DM pathogenesis.

Patients are diagnosed as T2DM when plasma glucose levels reach at the diagnostic criteria Table 1. These T2DM patients are at high risk for microvascular complications e.

T2DM patients with good controlled plasma glucose levels demonstrated to delay the progression of microvascular and macrovascular complications[ , ]. Fasting serum lipids profile should be determined annually in T2DM patients as in the recommendation by the American Diabetes Association ADA [ ].

Lifestyle interventions: The American Diabetes Association and the American Heart Association recommend that increased physical activity and lifestyle modifications should be advised for all T2DM patients[ , ].

Combination with such interventions included nutrition therapy or supplementation, weight loss and non-smoking. These have been help T2DM patients to receive better controlled their lipid concentrations.

Glycemic control can also modify circulating triglycerides levels, especially in T2DM patients with hypertriglyceridemia and poor glycemic control[ ].

There are many pharmacological classes available for dyslipidemia treatment. Statins: Statins inhibit enzyme 3-hydroxymethylglutaryl CoA reductase suppress cholesterol synthesis and increase number and activity of LDL-receptor.

Statins are effective drug for lowering LDL-cholesterol, raising HDL-C and reducing TG levels. There are seven pharmaceutical forms of statins including lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin available in the market.

Statins also have the other pharmacodynamic actions such as vascular inflammation reduction, immune suppression, improved endothelial function, platelet aggregability, enhanced fibrinolysis, antithrombotic action, increase neovascularization in ischemic tissue and stabilization of atherosclerotic plaques[ ].

Fibrates control the lipid metabolism by mediated through peroxisome proliferator-activated receptors-α activation, stimulation of β-oxidation of fatty acids in peroxisomes and mitochondria to cause lowering fatty acid and triglycerides levels in circulation.

The first drug of this class is Clofibrate. Eventually, the revolution in lipid-lowering drugs research discover of many other fibrate drugs such as fenofibrate, bezafibrate, gemfibrozil and ciprofibrate.

These drugs demonstrated the adverse effect to cause hepatomegaly and tumor formation in the liver of rodents. Then, they had restricted for the widely use in humans. Gemfibrozil and fenofibrate are Food and Drug Administration FDA -approved for lipid lowering drugs due to milder effect on peroxisome proliferation.

Long term study of the coronary drug project demonstrated that niacin is the effective drug to increase HDL-C levels and reduced CVD events[ ] in a non-diabetic subjects. Niacin cause adverse effects on the glycemic control levels in T2DM patients.

In high doses treatment with niacin may increase blood glucose levels. However, there is no evidence for the CVD outcomes reduction with niacin supplementation in T2DM patients. Antihyperglycemic drugs: The standard care for T2DM patients is mainly in controlled blood glucose levels by using glycemic lowering drugs and concomitant with controlled diet and increased physical activity.

With proper controlled and managed these contributors such as circulating glucose levels, hemoglobin A1c, lifestyle modifications, these can be effectively controlled and reduced the progression and complications disease. There are many reasons for poor control of T2DM including medication efficacy, adverse effects, access to medications and health care education, poor adherence, lack of lifestyle changes and no physical activity.

Now a day, more pharmacologicals for T2DM treatment have been approved for use. There are 12 classes of antihyperglycemic drugs FDA-approved in the United States[ ] such as sulfonylureas, meglitinides, thiazolidinediones, dipeptidyl peptidase-4 DPP-4 inhibitors, biguanides, sodium glucose transporter 2 inhibitors, α-glucosidase inhibitors, amylin analogues and glucagon-like peptide-1 GLP-1 receptor agonists.

These are insulin analogues. Metformin is one of the most commonly prescribed medications for T2DM management. Metformin treatment ameliorate the insulin resistance especially in liver and skeletal muscle but less effect in adipose tissue[ , ], decreased inflammatory response, improved glycemic control[ , ] and enhance β-cell function in T2DM patients by increased insulin sensitivity and glucotoxicity reduction[ ].

Metformin reduces fatty acid oxidation in adipose tissue[ ], increased GLUT4 translocation in muscle and adipose tissues by activated enzyme adenosine monophosphate kinase and reduced gluconeogenesis in liver[ - ]. There are many developed non-conventional drugs to improve glycemic control such as Cycloset is used together with diet and exercise to treat type 2 diabetes.

Cycloset is not for treating type 1 diabetes. Welchol is a non-absorbed, polymeric form, lipid-lowering and glucose-lowering agent for oral administration.

Welchol is a high-capacity bile acid-binding molecule. Afrezza Inhalation Powder is the FDA approved the inhalation form of insulin. The new drug is not a substitute for long-acting insulin and use as the combination with conventional long-acting insulin drug for both types of diabetes and many drugs are in the late clinical trials state.

There are new medications and treatments were identified from the FDA, they are in the clinical trials or waiting for approval treatment in dyslipidemia, obesity and T2DM[ ]. Recent research study reports that metformin treatment cause metabolic effects to increase GLP-1 concentration in the circulation[ , ].

GLP-1 is an incretin generated from the transcription product of the proglucagon gene. Incretin is a signaling polypeptide contained with amino acid. GLP-1 secretion by ileal L-cells is not depend on the presence of nutrients in the small intestine and responsible for stimulated insulin secretion to limit glucose elevations with the higher efficacy at high glucose levels[ , ].

Elevated GLP-1 secretion might possibly cause increased glucose absorption in the distal segments of small intestine. Incretins are the gastrointestinal hormone secreted from the intestine and stomach responsible for oral food intake and stimulated the secretion of insulin during meals in healthy peoples[ ].

Two major incretin molecules are 1 GLP-1; and 2 Glucose-dependent insulinotopic peptide knows as gastric inhibitory polypeptide GIP and to neutralize stomach acid to protect the small intestine and no therapeutic efficacy in T2DM. GLP-1 has lower glucose levels by stimulated insulinproduction and increased glucose metabolism in adipose tissue and muscle.

GLP-1 promote the pancreatic β-cells proliferation, reduce apoptosis, increase cardiac chronotropic, inotropic activity, decreases glucagon secretion, reduces glucose production, increase appetite suppression for food intake reduction and slow gastric emptying[ , , ]. GLP-1 is degraded by enzyme DPP-4 and this enzyme does not inhibit by metformin[ ].

The prevention of GLP-1degradation by DPP-4 is one method to increase the effects of GLP DPP-4 inhibitor drugs inhibit the glucagon secretion which in turn increases secretion of insulin to decrease blood glucose levels and decreases gastric emptying.

The FDA-approved the DPP-4 inhibitor drugs including sitagliptin Januvia , alogliptin Nesina , saxagliptin Onglyza , linagliptin Tradjenta , anagliptin, vildagliptin, teneligliptin, gemigliptin and dutogliptin.

The adverse effects are dose-dependent to cause headache, vomiting, nausea, nasopharyngitis, hypersensitivity and other conditions. Other side effects of exenatide GLP-1 agonist note for abdominal pain, acid stomach, diarrhea, altered renal function, weight loss, dysgeusia, belching and cause pruritus, urticaria and rash reactions at the injection site.

In this present review has described the detrimental effects from chemicals and biochemicals reaction, metals, medications, over nutrition, obesity and diseases in oxidative stress, insulin resistance development and the progression of T2DM and the progression of diabetic complications and organ dysfunctions.

Oxidative stress played underling associated with the pathogenesis of diseases, leading to increases risk of insulin resistance, dyslipidemia, elevated blood pressure, metabolic syndrome, inflammation and endothelial dysfunction.

This reviewed support the oxidative stress contribution of the multifactorial etiology of oxidative stress and insulin resistance in the whole body.

ROS act as the signal transduction factor and plays the important role in oxidative stress-mediated downstream signaling pathways and enhances the cell death. These diseases may be substantially reduced by dietary modifications, increased physical activity and antioxidant drugs ameliorated oxidative stress.

The therapeutic approaches target on oxidative stress may delay or prevent the progression and onset of diseases. Then, antioxidants supplementation may curtail the progression and onset of the metabolic disease complications. Antioxidant interventions, an importance goal of future clinical investigations should be implementation and to improve oral bioavailability targeted to the oxidant overproduction site.

Lifestyle change remains the best prevention and therapeutic approach to oppose the increasing epidemic of cardiovascular diseases, obesity, hypertension, dyslipidemia and T2DM. Finally, the connection between oxidative stress, insulin resistance, dyslipidemia, inflammation, life style, atherosclerosis and diabetes as demonstrated in the schematic in Figure 8.

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Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes ; 6 3 : [PMID: DOI: Corresponding Author of This Article. Surapon Tangvarasittichai, Associate Professor, Chronic Disease Research Unit, Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, 99 Moo 9 Tambon Tha Pho, Muang, Phitsanulok , Thailand.

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Copyright ©The Author s Published by Baishideng Publishing Group Inc. All rights reserved. World J Diabetes. Apr 15, ; 6 3 : Published online Apr 15, doi: Surapon Tangvarasittichai.

Surapon Tangvarasittichai, Chronic Disease Research Unit, Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok , Thailand. Open-Access : This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers.

Correspondence to : Dr. Received: September 3, Peer-review started : September 4, First decision : November 14, Revised: December 25, Accepted: January 9, Article in press : January 12, Published online: April 15, Key Words: Insulin resistance , Dyslipidemia , Type 2 diabetes mellitus , Oxidative stress.

However, these differences in activity and level were not significant. The comparison of the SOD and CAT levels in the studied groups is illustrated in Figure 1.

The correlations between antioxidant levels and severity of DR in the diabetic group were investigated and showed no significant correlation between antioxidant level SOD and CAT and severity of DR Fig.

The correlation between HbA1c and severity of DR is depicted in Figure 3. Table 4 shows the differences in the antioxidant enzymes among the diabetic group with or without retinopathic changes. Increased levels of HbA1c were significantly associated with decreased SOD in both the groups.

However, CAT levels varied insignificantly to HbA1c in diabetic patients with and without retinopathic changes. Serum antioxidant enzyme levels in the 3 groups.

SOD, superoxide dismutase; CAT, catalase; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. Correlation between DR severity and antioxidant enzymes. DR, diabetic retinopathy; SOD, superoxide dismutase; CAT, catalase.

Diabetic groups were subdivided into NPDR and PDR based on the grades of DR severity. Serum levels of HbA1c, SOD, and CAT in the subgroups are depicted in Figure 4. Regression graph showing the correlation between severity of DR and antioxidant enzymes in the NPDR and PDR subgroups is represented in Figure 5.

Furthermore, the Kruskal-Wallis test performed to analyze NPDR and PDR subgroups yielded informative results. Status of biochemical markers in DR subgroups — NPDR and PDR. DR, diabetic retinopathy; NPDR, nonproliferative DR; PDR, proliferative DR; HbA1c, glycated hemoglobin; SOD, superoxide dismutase; CAT, catalase; HbA1c, glycated hemoglobin.

Regression graph showing the correlation between DR severity and antioxidant enzymes in the NPDR and PDR subgroups. DR, diabetic retinopathy; NPDR, nonproliferative DR; PDR, proliferative DR; SOD, superoxide dismutase; CAT, catalase.

Oxidative stress can contribute to the pathogenesis of DR. Interestingly, we observed reduced antioxidant activity in DR patients compared to healthy nondiabetic subjects. Increased HbA1c, TG, and LDL-C levels were found in subjects with both DM types compared to nondiabetic control.

Hyperglycemia-induced oxidative stress is considered an important factor that contributes to DR. Schematic diagram of role of oxidative stress in retinopathy is depicted in Figure 6.

Oxidative damage, as introduced earlier, is the result of free radical attack that leads to a loss of structure and function of cells and their components [ 13 ].

Numerous mechanisms are considered to play a crucial role in etiology underlying DR viz synthesis of advanced glycation end products, linked with the overproduction of ROS [ 14 ]. Increased free radical or ROS levels because of an imbalance in the oxidation-reduction cycles in the biological system eventually lead to the destruction of the antioxidant system composed of prominent antioxidant enzymes.

Antioxidant enzyme levels critically affect the susceptibility of cells to oxidative stress and may also be linked to the progress of diabetes-related complications including retinopathy. Additionally, the hyperglycemic state can exacerbate the effects of oxidative damage and lead to DR.

SOD is the major scavenger of ROS, which are associated with diabetic complications. It is catalytically involved in the production of the H 2 O 2 and O 2 from superoxide anions. CAT regulates H 2 O 2 metabolism, and diminished CAT levels can have deleterious effects on cellular components.

Under CAT-deficient conditions, enhanced oxidation in pancreatic beta cells could lead to beta-cell dysfunction and eventually to diabetes [ 15 ].

Parallel to present study, Pan et al. The observations in the current study, hyperglycemia with poor antioxidant enzymes in T2 diabetic patients are similar to as reported earlier [ 17, 18 ].

Similarly, Alghazeer et al. It is speculated that the increase in enzymatic glycation due to glucose overload may account for diminished CAT activity in diabetic patients. DR progression to PDR was correlated with increased oxidative damage and decreased antioxidant activity in previous reports [ 20 ].

The nonsignificant decrease in SOD levels in the diabetic group is in accordance to the results reported by Gurler et al. There was no correlation between antioxidant markers and severity of DR in either type of diabetic patients.

Exploring the role of antioxidant enzymes, the diabetic groups were divided into 2 subgroups, NPDR and PDR, based on the severity of DR. The comparison of HbA1c, SOD, and CAT levels between the 2 subgroups NPDR and PDR is depicted in Figure 4. These findings are in agreement with earlier reports [ 22 ].

Certainly, activities of these 2 antioxidant enzymes — SOD and CAT — were found to be involved in DR progression.

Increased HbA1c thus reflected the cause of oxidative damage by altering SOD and CAT distinctly and mediating the subsequent progression of NPDR to PDR. Thus, the role of antioxidant enzymes in DR progression was conspicuous in our study. The results obtained in the present study revealed the relative role of these enzymes in the onset of diabetes and to subsequent stages of DR.

It is noteworthy that serum SOD and CAT activity might be a biomarker for DR screening and evaluation of the clinical severity of DR in T2 diabetic patients. However, further elaborative investigations are needed to explicitly understand such associations.

The main study finding was increased HbA1c levels, poor antioxidant status along with diminished VA in diabetic patients. Approximately The diabetic group exhibited higher IOP than controls in the upper physiological limit.

Presumably, elevated IOP could lead to the death of ganglion cells in the retina which has been documented in previous reports [ 23, 24 ].

Furthermore, raised IOP levels can lead to the inception of optic neuropathy, which gradually destroys the optic nerve head by mechanical compression. Ultimately, progressive loss of optic nerve fibers manifested by vision loss can be caused by such compression. In conclusion, the present findings support the hypothesis that oxidative stress and decreased antioxidant defenses are associated with DR progression to PDR.

The major findings and strength of the current study were the role of the antioxidant enzymes in progression of DR; NPDR to PDR was evident.

HbA1c as a predisposing factor in progression of DR following generation of imbalance of the oxidant-antioxidant system reflected by altered SOD and CAT added to a better understanding of the etiopathological mechanism underlying DR.

However, the study has some limitations. First, although the association of oxidative stress in diabetic progression to DR is confirmed, the evaluation of oxidative stress markers as a comparative study from other ocular diseases would have added additional information to the outcome of the present investigation.

Second, study reports association on a small sample size, and hence, larger studies investigating a large number samples are needed. The authors are thankful to the Research Support and Services Unit, King Saud University, for technical support.

The study was approved by the Ethics Committee Approval No. CAMS , King Saud University. All participants included in the study signed the informed consent. Conceived and designed the experiments: Kholoud Bokhary and Manal Abudawood; performed the experiments: Afnan Bakhsh, Shatha I.

Alhammad, and Rawan Aleyadhi; literature search: Hajera Tabassum and Feda Aljaser; data analysis: Kholoud Bokhary; statistical analysis: Hajera Tabassum; manuscript preparation: Kholoud Bokhary and Hajera Tabassum; manuscript editing and manuscript review: Feda Aljaser, Faisal Almajed, and Roua Alsubki.

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