Yaqoob MPatrick AW oxidative stress and diabetes, McClelland P oxidxtive, Stevenson Oxidative stress and diabetesMason HAbd MCBell GM Relationship between markers of endothelial dysfunction, oxidant injury and tubular damage in patients with insulin-dependent diabetes mellitus. Lin, C. Physiol Rev 59 : — Kiehntopf M.

Oxidative stress and diabetes -

These abnormalities are markers of retinal damage caused by hyperglycemia and indicate DR progression. Al-Nozha et al. The prevalence of diabetes in was 8. A global review of DR reported that on an average approximately Oxidative damage is a critical factor involved in DR etiology.

Reactive oxygen species ROS generated on account of hyperglycemic state through varied mechanisms tend to damage vital biomolecules like DNA, proteins, and lipid membranes damaging normal physiology of the cells [6]. Notably, the retina is highly vulnerable to damage by oxidative stress.

Thus, the retinal blood vessel dysfunction is considered critical underlying the pathogenesis of DR. The pathophysiology of DR progression is an intricate mechanism. Its initiation is related to hyperglycemia-induced ischemia and discharge of certain vasoactive chemicals, including vascular endothelial growth factor, that kindle the formation of new blood vessels from the retinal surface growing on the posterior wall of the vitreous chamber.

As these newly formed blood vessels become fragile and have an immature nature, they can rupture. Consequently, blood and fluids leak out easily, resulting in vitreous hemorrhages.

As the vitreous begins to constrict, it can result in retinal detachment, leading to vision loss [8]. DR characterized by angiogenesis that occurs during advanced stages is referred to as PDR. In contrast, another clinical subtype in the early stages is known as nonproliferative DR NPDR , in which no new blood vessels are formed.

Poor glycemic control and an alteration in antioxidant enzyme levels are strongly associated with DR development. Free radical attack accounts for oxidative damage in cells leading to loss of cell integrity and function.

The overproduction of ROS and ROS accompanied with decreased antioxidant status enzymes results in enhanced cellular oxidation. Importantly, the cells are inclined for oxidative damage due to poor regulation by the antioxidant enzymes and this may be responsible for DM progression and its complications.

The 2 prominent antioxidant enzymes involved are superoxide dismutase SOD and catalase CAT. The disproportionation of the superoxide radical catalyzed by SOD results in generation of molecular oxygen O 2 or hydrogen peroxide H 2 O 2 [9, 10 ].

CAT is a common enzyme that catalyzes the decomposition of H 2 O 2 to water and O 2. The activity of CAT can reflect the ability of cells to remove ROS and the resistance to oxidative damage.

It has been hypothesized that oxidative stress or poor antioxidant defense plays a crucial role in DR progression. Thus, this study aimed to evaluate the oxidative status i. Subjects were recruited from the retinal clinics, Department of Ophthalmology, King Abdulaziz University Hospital KAUH , Riyadh, Saudi Arabia.

College Ethical Committee approved the study CAMS , and all participants included in the study signed the informed consent. Based on the exclusion criteria, samples were further screened to meet the required criteria and were subjected to further analysis. Subjects were divided into 2 subgroups based on the DR severity — mild-to-severe NPDR and PDR.

Diabetic subjects with glaucoma, liver disease, severe nephropathy, cancer, acute or chronic infections, fever, congestive heart failure, use of oral antioxidant supplements, or smoking history were excluded from the study.

All subjects underwent ophthalmologic examinations including VA, intraocular pressure IOP measurement mm Hg , and fundus examination performed using slit lamp and ophthalmoscopy, as per the standard guidelines [ 11 ].

VA was determined using tumbling E chart and expressed in decimal notation as logarithm of the minimum angle of resolution logMAR. Blood samples were collected from subjects after 12 h of fasting. Overall, 8 mL blood was collected via venipuncture into labeled sterile vacutainers, and 1 mL was collected into an EDTA-coated tube for HbA1c analysis.

All biochemical parameters, including HbA1c and lipid profile parameters were analyzed using a fully automatic analyzer Roche Cobas C, Germany.

Activity of SOD was measured using the SOD Assay Kit-WST ; Sigma. SOD activity was determined following the manual instructions and reported as percentage inhibition rate. SPSS software version 22 was used for statistical analysis.

Analysis of covariance was used to compare serum biochemical marker levels between controls and diabetic patients. The correlation between serum biochemical markers against retinopathy severity was analyzed using multiple linear regression.

The preliminary characteristics of the study population are represented in Table 1. The mean ages±standard deviation of the T1DM, T2DM, and control groups were 32 ± 4. IOP was in upper physiological limits in controls and most diabetic patients in both groups.

Around Serum biochemical marker levels and antioxidant status are shown in Table 2. The antioxidant activity of SOD decreased in T1DM Also, the diabetic groups exhibited diminished activity of CAT enzyme.

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.

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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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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Review Open Access. 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.

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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.

Citation: Tangvarasittichai S. Open in New Tab Full Size Figure Download Figure. Figure 1 Summarized of obesity and metabolic syndrome elevate in oxidative stress. T2DM: Type 2 diabetes mellitus; MetS: Metabolic syndrome. Figure 2 Increased oxidative stress by xanthine oxidase.

NADH: Nicotinamide adenine dinucleotide. Figure 3 The chain reaction of lipid peroxidation. Thiobarbituric acid-reactive substance. Oxidative stress in metabolic syndrome. Figure 4 Summarized the increasing reactive oxygen species in obesity, metabolic syndrome and salt sensitive hypertension.

FFA: Free fatty acid; MetS: Metabolic syndrome; HT: Hypertension; IGT: Impaired glucose tolerance. Oxidative stress in type 2 diabetes. Figure 5 Summarizes the reactive oxygen species associations with atherosclerosis and sources of reactive oxygen species production in type 2 diabetes.

oxLDL: Oxidized low density lipoprotein; FFA: Free fatty acids; AGEs: Advanced glycation end-products; VSMC: Vascular smooth muscle cells; ROS: Reactive oxygen species.

Other sources of oxidative stress in diabetes. Oxidative stress induces insulin resistance. Figure 6 Insulin resistancedevelopment and consequence of β-cell dysfunction. FFA: Free fatty acid. Oxidative stress and β-cells dysfunction. β-cells glucose-induced toxicity. β-cells lipid-induced toxicity.

Development of T2DM from insulin resistance. Figure 7 Summarized the etiology of the type 2 diabetes mellitus pathogenesis. FFA: Free fatty acid; NF-κB: Nuclear factor-κB; TNF-α: Tumor necrosis factor α.

Table 1 Type 2 diabetes mellitus and glucose levels for diagnostic criteria 1. Pharmacological interventions of dyslipidemia. Figure 8 Connection between life style, oxidative stress, insulin resistance, inflammation and atherosclerosis. FFA: Free fatty acid; NO: Nitric oxide; MNC: Mononuclear cells; PMN: Polymorpho nuclear cells; CRP: C-reactive protein; MIF: Migration inhibitory factor.

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The oxidative stress and diabetes presents anf views about the Heart smart living of Breaking nutrition myths stress reactions in the pathogenesis of types 1 and 2 diabetes mellitus and their complications based on oxidative stress and diabetes analysis of diabees and clinical studies. The oxidative stress and diabetes diqbetes increased ROS generation oxiddative diabetes oxidaive specified, including the main pathways of altered glucose metabolism, oxidative damage to pancreatic β-cells, and endothelial dysfunction. The relationship between oxidative stress, carbonyl stress, and inflammation is described. The results of our studies demonstrated significant ethnic and age-related variability of the LPO—antioxidant defense system parameters in patients with diabetes mellitus, which should be considered during complex therapy of the disease. Numerous studies of the effectiveness of antioxidants in diabetes mellitus of both types convincingly proved that antioxidants should be a part of the therapeutic process. J W BaynesS R Thorpe; Role of oxidative stress Muscular strength program diabetic complications: a new perspective on an oxixative paradigm. Diabetes oxidative stress and diabetes January ; 48 strews : diavetes. Oxidative stress and diabetess damage to tissues are common end oxidative stress and diabetes of oxidativee diseases, such oxidative stress and diabetes atherosclerosis, sgress, and rheumatoid arthritis. The question addressed in this review is whether increased oxidative stress has a primary role in the pathogenesis of diabetic complications or whether it is a secondary indicator of end-stage tissue damage in diabetes. The increase in glycoxidation and lipoxidation products in plasma and tissue proteins suggests that oxidative stress is increased in diabetes. 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.