Oxidative stress is a cytopathic consequence of excessive production of ROS and the suppression of ROS removal by antioxidant defense system is implicated in the development of many diseases, including Alzheimer’s disease, and diabetes and its complications.Oxidative stress again represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Retinopathy, a debilitating micro vascular complication of diabetes, is the leading cause of acquired blindness in developed countries (Reenu, 2007). Retinopathy is one of the most severe ocular complications of diabetes and is a leading cause of acquired blindness in young adults. The cellular components of the retina are highly coordinated but very susceptible to the hyperglycemic environment.
Figure 1 above shows, Glucose damages the retina via repeated acute and/or cumulative changes. Continued high circulating glucose in diabetes can damage retina via many acute and cumulative long-term changes that can cause tissue injury. Some acute insult, when repeated multiple times in this life-long disease, can result in cumulative changes in stable macromolecules.
Diabetes on the other hand is a disorder or a severe health problem that is currently on rapid increase, mostly in the developed countries. It is classified into two categories: type 1 diabetes also known as juvenile onset diabetes and type 2 diabetes, which is also called non-insulin dependent diabetes. Diabetes is characterized by very high levels of glucose in the body that results to deregulation of the metabolism. Diabetics’ bodies cannot control the amount of sugar in the blood. The developed countries such as the United States, China and India are the most affected by this disorder. In addition to this, oxidative stress leads to blindness if it merges with diabetes in patients.
Diabetes mellitus (DM) is a major medical problem throughout the world. Diabetes causes an array of long-term systemic complications which have a considerable impact on both the patient and the society, because it typically affects individuals in their most productive years. The ophthalmic complications of diabetes include corneal abnormalities, glaucoma, iris neo-vascularization, cataracts and neuropathies. However, the most common and the potentially most blinding of these complications is diabetic retinopathy (Yorio, 2007).
Diabetes mellitus is characterized by hyperglycaemia, together with the biochemical alteration of glucose and lipid peroxidation. DM is considered to be one of a rank of free radical diseases which propagate their complications with increased free radical formation. Oxidative stress is increased in DM, owing to an increase in the production of oxygen free radicals and a deficiency in the antioxidant defense mechanisms. The lipid per-oxidation of the cellular structures, a consequence of the increased oxygen free radicals, is thought to play an important role in the atherosclerosis and the micro-vascular complications.
Patients with long standing Type II DM have a higher prevalence ofsevere visual impairment that is usually associated with diabetic retinopathy. The incidence of retinopathy that increases with an increasing duration of diabetes and sustained hyperglycaemia has been identified as the major risk factor in the development of this micro-vascular complication. It is known that 20–50% of the long duration diabetes cases show proliferative diabetic retinopathy.
This type of retinopathy progresses from mild non-proliferative abnormalities to proliferative retinopathy which is characterized by the growth of new vessels on the retina and on the posterior surface of the vitreous. The exact biochemical mechanism that causes the initiation and progression of diabetic retinopathyhasbeen poorly understood. It has now been proved that the blood supply to the essential organs including the retina is reduced in long standing diabetes mellitus, owing to a failure in the auto-regulatory mechanisms. We assume that ischaemia in the inner retinal tissues produces some biochemical changes which are responsible for the morphological changes in the retina (Levin, 2008).
Oxidative stress is increased in diabetes mellitus, owing to an increased production of free radicals such as the super oxide radical, hydrogen peroxide and the hydroxide radical and free radical induced lipid per oxidation.
Taking into consideration the above facts, that chronic hyperglycaemia leads to the formation of free radicals and free radical induced lipid peroxidation, which cause microangiopathic changes like retinopathy in DM, we conducted this study with an objective to evaluate the role of oxidative stress and its correlation with hyperglycaemia in patients of Type II DM with and without retinopathy.
Type 1 Diabetes
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Patients with diabetes type 1 cannot produce insulin at all or do not produce enough insulin hence cannot control the glucose levels in the blood. This type of diabetes is mostly common in people below thirty years of age. To reduce its effects, it is required that the patient takes the right amounts of food as well as administration of insulin in the blood. Some of the symptoms of this illness are urination, hunger and thirst. To be able to sustain the patient’s life, it is paramount that the patient gets insulin treatment every day to supplement the missing amount (Standl et al., 2006).
Scientifically, Standl et al, in his research examined the nocturnal incident and control of glycemic through bedtime and morning-glargine-plus- glimepiride-insulin administration. In a 24-week period, an open randomize study was conducted for multinationals in which 625 patients were controlled poorly through oral therapy received either morning or bedtime glargine plus glimepiride of 2, 3, or 4 Mg doses titrated to target at a specified blood glucose. The results of the research showed that the two groups had the same results in terms of getting any better. For the incidence of nocturnal hypoglycemia, there was equivalence for the two groups while morning glargine was non-inferior to bedtime administration. As conclusion of the research neared, similar improvements in the control of glycemic control were recorded for morning administration as compared to bedtime. The meaning of the endpoint means that glargine dose was compared and significance difference in between-treatment period did not register in terms of body weight. Glargine administered daily with only one dose in a flexible bedtime or morning routines can be steered to achieve good control of glycemic without hypoglycemia differences (Standl et al., 2006). The significance of these routines of treatment and management of hypoglycemia is to set a foundation for assessing the magnitude of medical intervention when treating Diabetes alongside active role of oxidative stress.
Type 2 Diabetes
Type 2 Diabetes is not dependent to insulin, and only affects people of over the age of 40 years and runs through the family. When the pancreas secretes insulin, the phase is called type 2 diabetes. However, the produced insulin goes to waste as the body does not need it or the body is unable to use the insulin. Insulin resistant individuals develop type-2 diabetes if they are unable to produce insulin large enough to cater for body insulin demands. The treatment of this type of diabetes is through diet changes, exercises, and glycemic control of desirable margin. Physical and mental comfort for diabetes-type 2 patients is achieved if all diet changes are observed and adhered to. Type 2 diabetes requires oral medication or insulin (Farooqi, 2011).
Of late, type 2 diabetes has been associated with oxidative stress in terms of merging to affect the body even further. To result to oxidative stress, overproduction of reactive oxygen elements in the body had to be taking place. Oxidative stress has been in diabetes for as long as 27 years to date. There are different ways in which overproduction of reactive oxygen elements can result. For this reason, this paper will be analyzing the role played by oxidative stress in diabetes and diabetic retinopathy to be specific.
OVERVIEW OF DIABETES (TYPE 1&2) AND OXIDATIVE STRESS
Endogenous and exogenous are the free radicals that the human body is exposed to both externally and internally respectively. Amongst the factors that lead to the free radicals include cigarette, smog, consumption of large amount of alcohol, radiation from both mechanical machineries or from the sun, and breathing moisture from the air. At the same time, most of the factors that lead to the free radicals come from within the body. Oxygen is necessitated by the cells to produce enough energy needed to work efficiently. In this process, scientifically known as mitochondrial respiration, energy is taken in by the cells, it is burnt, and energy is released.
During the mitochondrial process, free radicals are produced. If the ability of the body to neutralize the free radicals is exceeded, then the body experiences the occurrence of oxidative stress. One of the following reasons result to this imbalance: a) when there is a reduction of antioxidants, or, b) when the production of the free radicals are produced in excess. Diabetes or the process of aging is responsible in some case for the overproduction of the endogenous free radicals and a reduction in the production of antioxidants. Oxidative stress is bi-functional in that it helps in the escalation and the development of diabetes and the associated complications. According to Ha et al, in his study, he argues that oxidative stress is significant in the mediation of vascular diabetes complications and nephropathy. Because of glucose auto-oxidation, glycosylation products development, and metabolism reactive oxygen species are produced by high glucose levels (Tsatsoulis 2009).
Gene expression through the pathway signaling of reactive oxygen species is because of modification of the reactive oxygen species-induced injury of the tissue concept as a new role. Although the transduction of the signal pathways linking high extracellular matrix protein synthesis in mesangial cells, protein kinase C, glucose, reactive oxygen species, and transcription factors have not yet received full clarification, the current data points out that reactive oxygen generated by the metabolism of glucose acts as integral signaling molecules in presence of high glucose like in other receptor signaling.
Hyperglycemia, Diabetes and Oxidative Stress
Diabetes and diabetic complications are connected by hyperglycemia (Preedy, 2007). Preedy et al, states that are four important mechanisms by molecules associated in the hyperglycemia-induced damage of tissues: protein kinase C isoforms activation via the synthesis of de novo of diacylglycerol as the second lipid messenger lead to an increase of hexosamine pathway flux, formation of glycation end-products at advanced levels, and polyol flux pathway increase.
Hyperglycemic damage results from the link provided by hyperglycemia-induced over production of superoxide for high glucose and the pathways. Impaired antioxidant defense mechanisms and increased generation of free radicals is responsible for diabetes and represents central contribution for reactive oxygen element initially with a definition for pathological diabetes’ consequences. Inspite of the direct link that oxidative stress has on diabetes in terms of progression and contribution to complications, evidence has shown that there are links between various mitochondrial and type 2 diabetes disturbances. Type 2 diabetes is caused by mitochondrial DNA mutations and decrease in mitochondrial DNA copy number (Preedy, 2007). In addition, the four molecular mechanisms responsible for the overproduction of superoxide by mitochondrial electron-transplant from the hyperglycemia-induction has been traced in glucose-mediated vascular damage. Oxidative stress has been found in diabetes at a higher rate for the last decade with women more affected than men have. The end result of this an increased rate of cardiovascular diseases for women.
Preedy, set to examine this phenomenon through 29 control subjects 30 patient without the diabetes type 1 complications. Following a 3 to 9-year period of observation, compared to the control subjects the patients with type 1 diabetes scored higher in terms of having low levels of plasma capacity of oxidants, lipid hydroperoxide level was higher as well as the conjugated diane levels. Comparing men to women, women scored higher for having lesser plasma capacities of oxidants and higher levels of lipid hydroperoxide. The findings of this research showed that the onset of increased oxidative stress and reduced antioxidant production came earlier for type 1 diabetic patients. The case for women was recorded to be higher and than that of men and this was considered a basis for explanation as to why more women are diagnosed with cardiovascular complication was draw.
Through the intake of less calories and a change of lifestyle through more physical activity is a considerable method of prevention for future diabetes cases. Some research showed that cardiovascular disease and all-cause mortality are rampant in men than they are to women due to the metabolic syndrome, even for cases with no cardiovascular disease and diabetes baseline. Timely diagnosis, management, and prevention of metabolic syndrome is a potential challenge for medical personnel majoring in this type of field in that confronting the issue of overweight and inactive lifestyle is not a thing they can control.
Oxidant defense for people with diabetes is minimal but on the contrary have bigger margin of damage caused by free radicals. For young type 1 diabetic patients, Martin et al, conducted a research in which he aimed to find out the potential role that oxidative stress played in the onset of pathophysiological related disease complications. Oxidant defense system changes, oxidation of proteins, and lipoperoxidation were the indicative parameters and were measure from samples of blood of 26 patients who had less than 6 months of diagnosis of microangiopathy (+DC), 28 complication free patients (-DC), and group of age-matched healthy controls. Glycated hemoglobin (HbA1c) and fructosamine values were similar for the toe groups. However, glutathione peroxidase activity , plasma beta-carotene, and glutathione to be ominously higher in control subjects as compared with the diabetic patients, but there was less noteworthy variances between –DC and +DC groups. Diabetic patients’ erythrocytes had a significant high level of antioxidant enzyme superoxide dismutase activity. This was independent of microvascular complications presence (H.-P, Hammes, 2010). However the plasma alpa-tocopheral to lipids ratio was surprisingly diminished for the case of +DC subjects as compared to their counterparts –DC. Indices measured in plasma for lipid peroxidation included lipoperoxides,malondialdehyde, and lipid hydroperoxides, happened to be expressively preeminent in patients with diabetes inspite of the presence of complications. Oxidative damage was evidently shown through plasma protein carbonyl levels quantification, that were high for both –DC and +DC groups compared with those of control subjects and quantification of protein-destined carbonyls through ammunoblot analysis (Poretsky, 2010).
Considered to be an oxidized albumin index, AOPP – advanced oxidation protein products’ assessment was used to mark an increase of protein oxidation for +DC patients; AOPP were lower for –DC than in +DC patients. These results have been formulated to show that oxidatively modified proteins as differential factors related to the pathogenesis of diabetic complications like the retinopathy.
Oxygen free radicals are formed in great sums when oxidative stress takes place through decreased oxygen. Surveys to determine the margin of stress had been conducted for type 1 and type 2 diabetes. One of the surveys conducted by a renowned writer focused on diabetic children with diabetes type 1. The survey showed that the children showed decreased levels of plasma antioxidant capacity, glutathioneperoxide, and an extensively increased malondialdehyde levels when compared with healthy children. The study further included the siblings of these children and findings were the same but with a varied degree. It is obvious in the same way that decreased anti-oxidative defense and concurrent free radical over-fabrication takes place in diabetic children. Their siblings, although not displaying the same tendency, their significance is not very important. The conclusive importance of the research was to show that it is necessary to reduce oxidative stress in diabetic children and preventing development of diseases for vulnerable relatives.
It was observed that production of free radicals increased in diabetic patents and had everything to do with complications for diabetic patients. To conduct the survey; a meal was given to patients and plasma malondialdehyhde alongside Vitamin C increased. On the other hand, uric acid, protein SH, vitamin E, and the parameter for plasma radical trapping decreased excessively in the diabetic subjects than the control subjects. To conclude the study, it was argued that the absorptive phase resulted to the production of free radicals for diabetic subjects. In diabetic patients, hyperglycemia plays an important role in the generation of postprandial oxidative stress since there is an extensive amount of plasma glucose in such patients (Cunha Vaz 2011).
Lipid Peroxidation and Diabetes
Through excessive urine and plasma in type 2 diabetes patients, indication of lipid peroxide was recorded. As an index of oxidative stress in vivo, a study showed that a specific nonezymatic peroxidation in plasma levels because of arachidonic acid and esterified epi-PGF2 alpha from non-insulin dependent and healthy individuals. It was also shown that increased plasma lipid peroxidation in non-insulin dependent diabetes mellitus patients. Another study showed that lasting platelet activation and improved peroxidation of lipids was associated with diabetes mellitus in vivo formation of F2-isoprostane, 8-isoprostaglandin F2 alpha, arachidonic acid peroxidation through the bioactivity contributed to improved levels in diabetes mellitus and the activation of platelets. 85 subjects of 85 years and below proved urine samples that were measured and tested through the vivo index of platelet activation. As a conclusion of this research, increased formation of F2-isoprostanes was associated with diabetes mellitus through the impairment of glycemic control and increased peroxidation of lipids. This means that there is a possible biochemical link between platelet activation and impaired glycemic control. From this study, dose-finding research can commence to find antioxidant in diabetes (Tombran-Tink, 2007).
Possible Diabetes Complications
Diabetic people are likely to suffer from complications like heart disease and stroke (Kamalesh, 2006; Asfandiyarova et al., 2006). Risk factors for diabetic patients have not yet been defined inspite of the seriousness of the complication; this is according to Asfandiyarova’s study of 2006. The aim for conducting this study was to determine the risk factors for people with type 2 diabetes mellitus (T2DM).
As an undertaking of the study, 200 T2DM patients were examined over a period of seven years. Investigation of the stroke incidence was carried out under the guidelines of lymphocyte proliferation in retort to insulin. Stroke incident of higher levels was found in subjects indirect cell mediated resistance to insulin using cimetidine to constrain cells with histamine receptors and indometacin to obstruct prostaglandin-synthesizing cells. Consequently, some risk factors associated with patients with diabetes mellitus type 2 is high activity of prostaglandin-synthesizing cells and cells containing histamine receptors. The above mentioned cells overwhelm mediated cell immunity to insulin and can also play a role in encouraging the development of insulin resistance (Asfandiyarova et al., 2006).
Kamalesh et al. carried a review on heart diseases where it was shown that diabetes amongst people with congestive heart disease (CHF) is on the increase. The m mortality rate of people with the congestive heart failure together with diabetes is high compared to those people without diabetes at all.
Numerous mechanisms are responsible for the development of CHF in diabetics, with the complication of the left ventricular dysfunction and ischemic heart disease being the major causes. It is therefore predicted that, in future physicians will have to deal with the increasing numbers of people suffering from heart failure, coronary diseases and diabetics.
Managing co-morbid conditions and diabetes plays a very important role in the prevention of the development of CHF in diabetics. Major clinical trials have been carried out in the recent past to help manage CHF and treat asymptomatic left ventricular dysfunction (Kamalesh, 2006).
Damages prompted by oxidative stress
Oxidative stress damages organs or tissues caused by free radicles (Hsieh et al., 2005). Hsieh et al in his study has shown the possibility of 8-hydroxy-2’-deoxyguanosine (8-OHdG) being a biomarker of Oxidative stress and oxidative DNA damage. Another cause of diabetes is the Reactive Oxygen Species (ROS), which is induced by chemicals in experimental animals like the Streptozotocin (STZ). It was examined in the study that oxidative DNA damage in several tissues in rats with induced diabetes from STZ through measuring 8-OHdG levels in the kidney, liver, heart, brain and pancreas. Levels of 8-OHdG in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) were determined in rats’ tissues treated with rice bran oil. The levels of mtDNA of the 8-OHdG were ten times higher than the ones for nDNA in multiple tissues.
Levels of 8-OHdG in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) were also determined in multiple tissues of rats treated with rice bran oil. Levels of mtDNA of 8-OHdG were 10 times higher than those of nDNA in multiple tissues were. Significant reductions in mtDNA 8-OHdG levels were seen in the liver, kidney, and pancreas of diabetic rats treated with rice bran oil compared with diabetic rats without intervention. The study demonstrated that oxidative mtDNA damage might occur in multiple tissues of STZ-induced diabetic rats and that intervention with rice bran oil treatment may reverse the increase in the frequency of 8- OHdG (Hsieh et al., 2005). In the study made by Molnar et al, angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is a well-known risk factor of hypertension, cardiovascular diseases and progression of diabetic nephropathy. In carriers of allele D, serum level of angiotensin-II is higher, which can be associated with increased oxidative stress and subsequent endothelial damage. Albuminuria is a sensitive marker of endothelial damage, while serum activity of the enzyme gamma-glutamyltransferase--that plays important role in the antioxidant defense--may refer to the level of oxidative stress. This research reports on a cross-sectional clinical study, where authors have examined on the relation between ACE gene insertion/deletion polymorphism and carbohydrate metabolism, hypertension as well as albuminuria in type 2 diabetics (n = 145). In patients carrying allele D, fructosamine levels were significantly higher (p = 0.007) than in carriers of allele I. Patients with II + ID genotypes and those who were treated with insulin took more antihypertensive drugs than the ones with II genotype or orally treated (p = 0.015). They found a significant association between genotype and fructosamine level (p = 0.023). Association between genotype or modality of treatment of diabetes (oral vs. insulin) and combined treatment of hypertension was of borderline significance. They found that fructosamin level of patients receiving ACE inhibitor was lower than that of patients not receiving ACE inhibitors. In patients with allele D, they have also found higher activity of gamma-GT and higher albuminuria. From this results and data of the literature the authors conclude that because of insulin resistance (in connection with the presence of allele D), these patients tend to have a worse metabolic state, more advanced glycation products, due to which oxidative stress and endothelial cell damage may develop. As albuminuria and activity of gamma-GT were both found higher in patients with allele D, and the patients did not suffer of any hepatic disease, authors take the consequence that gamma-GT is a marker of the oxidative stress caused by allele D. Endothelial damage may explain that these patients take a higher number of antihypertensive combination. Based on this, D allele may contribute-via increased glycation and oxidative stress-to the target organ damage in type 2 diabetes.
OXIDATIVE STRESS AND DIABETIC COMPLICATIONS
In Ceriello et al, study, Ceriello examines facts that involve hyperglycemia derived oxygen free radicals as mediators of diabetes-associated complications. Current studies have specified that a hyperglycemia-induced overproduction of superoxide appears to be the major event in the development of complications of diabetes.
Superoxide overproduction is associated with increased generation of nitric oxide and, as a result, formation of the strong oxidant peroxynitrite and by poly (adenosine diphosphate-ribose) polymerase activation, which in turn further initiates the pathways implicated in the development of diabetes-related complications. In addition, this procedure consequence in severe endothelial dysfunction and initiation of inflammation in blood vessels of individuals with diabetes, and these aspects contribute to the development of complications of diabetes. Furthermore, in vivo evidence supports the major contribution of hyperglycemia in producing oxidative stress and, eventually, severe endothelial dysfunction in blood vessels of individuals with diabetes (Ceriello, 2006). In diabetes mellitus, persistent hyperglycemia forms several biochemical sequela, and diabetes induced oxidative stress may possibly play an important role in the beginning and progression of the disease.
Insulin Treatment and Diabetes Complications
The overproduction of reactive oxygen species leads to oxidative stress, in which reactive oxygen species consist of oxygen free radicals and free radicals cause oxidative stress. Insulin treatment stops successfully the onset and reduces the development of lasting diabetic complications in insulin-dependent diabetes mellitus, but the clinical management which is accessible for keeping tight control of glucose homeostasis does not decreases their occurrence (Prasad, 2010). In the Diabetes Control and Complications Trial Research Group et al, it has been examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of complications. A total of 1441 patients with insulin-dependent diabetes mellitus (IDDM)--726 with no retinopathy at base line and 715 with mild retinopathy were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent, as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent and reduced the development of proliferative or severe non-proliferative retinopathy by 47 percent. In the two cohorts combined, intensive therapy reduced the occurrence of micro-albuminuria by 39, that of albuminuria by 54 percent, and that of clinical neuropathy by 60 percent. The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM (Semba, 2007).
Physiologic and Pathophysiologic Procedures
Varieties of physiologic and pathophysiologic procedures are believed that reactive oxygen species play an important part in which the expansion of oxidative stress may have a significant function in disease mechanisms. A common pathogenic method in quite a few complications of diabetes such as nephropathy, retinopathy, and atherosclerosis, is too much oxidative stress, which happens as a consequence of an imbalance at the cellular level involving production and abolition of reactive oxygen species (Voziyan and Hudson, 2005).
In the study of Voziyan, it was shown that vascular NAD (P) H oxidase-derived reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) have emerged as important molecules in the pathogenesis of atherosclerosis, hypertension, and diabetic vascular complications. In addition, myeloperoxidase (MPO), a transcytosableheme protein that is derived from leukocytes, is also believed to play important roles in the above-mentioned inflammatory vascular diseases. Previous studies have shown that MPO-induced vascular injury responses are H2O2 dependent. It is well known that MPO can use leukocyte-derived H2O2; however, it is unknown whether the vascular-bound MPO can use vascular non-leukocyte oxidase derived H2O2 to induce vascular injury. In the present study, ANG II was used to stimulate vascular NAD (P) H oxidase and increase their H2O2 production in the vascular wall, and vascular dysfunction was used as the vascular injury parameter. It was demonstrated that vascular-bound MPO has sustained activity in the vasculature. MPO could use the vascular NAD (P) H oxidase-derived H2O2 to produce hypochlorus acid (HOCl) and its chlorinating species. More importantly, MPO derived HOCl and chlorinating species amplified the H2O2-induced vascular injury by additional impairment of endothelium-dependent relaxation. HOCl-modified low-density lipoprotein protein (LDL), a specific biomarker for the MPO-HOCl-chlorinating species pathway, was expressed in LDL and MPO-bound vessels with vascular NAD (P) H oxidase-derived H2O2. MPO-vascular NAD (P)H oxidase-HOCl-chlorinating species may represent a common pathogenic pathway in vascular diseases and a new mechanism involved in exacerbation of vascular diseases under inflammatory conditions.
Function of Oxidative Stress
The function of oxidative stress in the progression of clinical complications in young patients with diabetes has been barely reported. In some research it was found that expanded levels of oxidative stress in children and adolescents that were diagnosed with diabetes with no complications proposed a high level of oxidant stress. In the research made by Dominguez et al, the persistence of hyperglycemia has been reported to cause increased production of oxygen free radicals through glucose auto oxidation and nonenzymaticglycation. Furthermore, the purpose of this study was to establish whether oxidative cellular damage takes place at the clinical onset of diabetes and in later stages of the disease in young patients such as children and adolescents (Duh, 2009).
Indicative parameters of lipoperoxidation, protein oxidation, and modifications in the status of antioxidant defense systems were estimated in single blood samples from 54 diabetic children, adolescents, and young adults and 60 healthy age- and sex-matched control subjects. Malondialdehyde and protein carbonyl group levels in plasma were increasingly higher in diabetic children and adolescents than in control subjects. In diabetic children at onset of clinical diabetes was found the highest erythrocyte superoxide dismutase activity and in adolescents, superoxide dismutase activity was higher comparative to the control subjects. In contrast, compared with control subjects, erythrocyte glutathione peroxidase was extensively lower in diabetic children and adolescents. At the current onset of diabetes, it was found a considerable decline in blood glutathione content. In addition, the results demonstrated progressive depletion during diabetes development. This study had shown that in diabetic patients that were examined the systematic oxidative stress was present on the early onset of type 1 diabetes and is higher in early adulthood. Decreased antioxidant defenses may increase the susceptibility of diabetic patients to oxidative injury. Appropriate support for enhancing antioxidant supply in these young diabetic patients may help prevent clinical complications during the course of the disease (Coulston, 2008).
Hyperglycemia and Oxidative Stress
Hyperglycemia leads to some important complications through oxidative stress in many cells. Free radicals make an important contribution in the development of diabetes complications (Hsu et al., 2006) such as changes in kidney, nerve, vascular tissue etc. In the research made by Hsu et al, parameters of lipid peroxidation, protein oxidation, and antioxidant defense systems were measured in blood samples from 47 children with type 1 diabetes mellitus and from 51 healthy controls, matched for age and sex. In the children with diabetes chemi-luminescent assay of plasma superoxide anion gave photoemissions, which were considerably higher than those in controls. In addition, plasma vitamin A levels in children with diabetes were also higher than those in controls. In a subgroup of 24 diabetic children with blood HbA1C levels >or=8.5%, plasma lipoperoxide and vitamin E levels were higher (p <0.05) than those in 23 diabetic children with blood HbA1C levels <8.5%. In a subgroup of 26 children with diabetes duration >or=5 yr., plasma lipoperoxide levels were higher (p <0.05) than those in 21 children with diabetes duration <5 yr. These results confirm the presence of oxidant stress in children with type 1 diabetes mellitus and prove that particular manifestations of oxidant stress are influenced by the duration of diabetes and by the efficiency of glycemic control. These remarks propose that supportive therapy intended at oxidative stress may help to prevent clinical complications in children with type 1 diabetes mellitus (Hsu et al., 2006).
Some of the diabetic complications that are going to be discussed are as follows: cardiovascular complications and (Haidara et al., 2006) and neuropathy complications (Martin et al., 2006) which includes the Alzheimer’s disease. In the review written by Haidara et al, it has been found that diabetes is an important risk factor for the development of cardiovascular problems such as coronary heart disease, peripheral arterial disease, hypertension, stroke, cardiomyopathy, nephropathy and retinopathy.
Furthermore, a linking element between all this complications could be the excess production of reactive oxygen species (Haidara et al., 2006). In the study of Martin et al, the objective was to evaluate the impact of prior intensive diabetes therapy on neuropathy among former Diabetes Control and Complications Trial (DCCT) participants. At the conclusion of the DCCT, subjects in the intensive group were encouraged to maintain intensive therapy, and subjects in the conventional group were encouraged to begin intensive therapy. Thereafter, we annually assessed neuropathy as part of the Epidemiology of Diabetes Intervention and Complications (EDIC) study. Neuropathy was defined using the Michigan Neuropathy Screening Instrument (MNSI). It was recorded potential adverse consequences of neuropathy. At the first EDIC examination, 1,257 subjects participated in the neuropathy assessment. Consistent with DCCT results, the former intensive group showed a lower prevalence of neuropathy than the conventional group based on positive questionnaire (1.8 vs. 4.7%; P = 0.003) or examination (17.8 vs. 28.0%; P < 0.0001) results. Despite similar levels of glycemic control, symptoms and signs of neuropathy remained less prevalent among the former intensive group compared with the conventional group. At the beginning of the EDIC study, prior intensive therapy reduced the odds of having symptoms and signs of neuropathy using MNSI criteria by 64% (P = 0.0044) and 45% (P < 0.0001), respectively, with similar odds reductions observed for both neuropathic symptoms (51%, P < 0.0001) and neuropathic signs (43%, P < 0.0001) across 8 years of EDIC follow-up.
The benefits of 6.5 years of intensive therapy on neuropathy status extended for at least 8 years beyond the end of the DCCT, similar to the findings described for diabetic retinopathy and nephropathy (Fox, 2006).
OXIDATIVE STRESS IN INSULIN RESISTANCE AND DIABETES
Insulin resistance takes place when the cells no longer respond well to insulin. A growing number of clinical and experimental studies have indicated a hyperglycemia yield in the generation of reactive oxygen species, in the end leading to increased oxidative stress in a variety of tissues. The cause of oxidative stress in diabetes has been, and continues to be, the object of considerable clinical investigation. It has been well established that oxidative stress in the cells of peripheral nerves lead to diabetic complications like neuropathy; plus the oxidative stress began long before the neuropathic symptoms of pain, burning, and numbness appear. More considerable is how oxidative stress has an effect on blood sugar concentration. It has been made known that oxidative stress has the ability to lower the insulin sensitivity and injure the insulin producing cells within the pancreas. Adipose tissue and muscle are the most significant tissues participating in the development of insulin resistance. Oxidative stress modifies the signaling pathway within a cell installing insulin resistance. In the review of Evans et al, in both type 1 and type 2 diabetes, diabetic complications in target organs arise from chronic elevations of glucose. The pathogenic effect of high glucose, possibly in concert with fatty acids, is mediated to a significant extent via increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent oxidative stress. ROS and RNS directly oxidize and damage DNA, proteins, and lipids. In addition to their ability to directly inflict damage on macromolecules, ROS and RNS indirectly induce damage to tissues by activating a number of cellular stress sensitive pathways. These pathways include nuclear factor-kappaB, p38 mitogen activated protein kinase, NH (2)-terminal Jun kinases/stress-activated protein kinases,
hexosamines, and others. In addition, there is evidence that in type 2 diabetes, the activation of these same pathways by elevations in glucose and free fatty acid (FFA) levels leads to both insulin resistance and impaired insulin secretion. Therefore, it is proposed that the hyperglycemia-induced, and possibly FFA-induced, activation of stress pathways plays a key role in the development of not only the late complications in type 1 and type 2 diabetes, but also the insulin resistance and impaired insulin secretion seen in type 2 diabetes (Joussen, 2007).
Oxidative Stress in Insulin Resistance Caused by Agents
The following agents cause insulin resistance: obesity, hormone excess, pregnancy and a life style that is not physically active. Oxidative stress participates in the progression of insulin resistance. In a certain review, in both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor kappa B, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions (Johnstone, 2005).
OXIDATIVE STRESS AND DIABETIC RETINOPATHY
Diabetic retinopathy is the most specific of all the diabetic micro-vascular complications. The prevalence of retinopathy is related tothe duration of diabetes. Diabetic retinopathy is the leading cause of new blindness in persons who are aged 25-74 years. The incidence of retinopathy is rarely detected in the first few years of diabetes, but the incidence increases to 50% by 10 years and to 90% by 25 years of having diabetes. The prevalence of diabetic retinopathy is increasing due to the prolonged survival of the diabetic patients. In south India, diabetic retinopathy was detected in 1.78% of the patients who were screened and it was projected to become a significant cause of blindness in the coming decades. Subjects with a duration of diabetes which was<5 years had 22.9% of diabetic retinopathy, while those with diabetes for >5 years had 33.5% of diabetic retinopathy. Younger subjects (<40 years) had 17.9% of diabetic retinopathy, while those who were >40 years of age had 36% of diabetic retinopathy. Subjects with HbA1c which was <7%had a 12.5% prevalence as compared to those with HbA1c which was > 7%, who had a prevalence of 40.5%.
The pathogenesis of DR has not been completely understood, but the established risk factors include poor glycaemic control, hypertension, increasing age and the duration of diabetes.
A study on the epidemiology of diabetes complications demonstrated that high triglyceride and high LDL levels at the baseline were associated with the subsequent progression of retinopathy over 2 years. It is found that a poor metabolic control which was demonstrated by high HbA1c levels was directly proportional to the prevalence of DR, which has been documented by Klein et al. in 1988. A longer duration of diabetes has been seen to have a stastically highly significant correlation with the prevalence of DR. Oxidative stress plays a major role in the onset of diabetes mellitus, as well as in the development of vascular and neurological complications of the disease. The source of the oxidative stress is a cascade of Reactive Oxygen species (ROS) which leak fromthe mitochondria. Hyperglycaemia contributes to micro-vascular complications. The prominent biochemical pathways which explain how diabetes causes damage to the micro-vasculature system include: (1) an increased polyolpathway flux (2) the production of advanced glycation end products (AGE) (3) the generation of reactive oxygen species (ROS) and (4) the activation of the diacylglycerol and the protein kinase C isoforms. AGEs are the products of glycation and oxidation and they are responsible for the liberation of superoxide radicals. Excess glucose enters the polyolpathway, resulting in excess sorbitol production, with a concomitant decrease in the NADPH levels. Low levels of NADPH can decrease nitric oxide production in the endothelial cells and can adversely affect the cellular redox balance, thereby resulting in deleterious metabolic consequences (Veves, 2007).
NADPH is required for regenerating the reduced glutathione and the consumption of NADPH could contribute to an intracellular increase in the formation of the reactive oxygen species, thus leading to oxidative stress and resultant diabetes related vascular damage. Therefore, an increased flux through the polyol pathway can lead to micro-vascular damage by contributing to AGE formation, specific protein kinase C activation and the generation of reactive oxygen species (ROS).
Oxidative stress in hyperglycaemia is amplified by the metabolicstress (Ford, 2006). In the present study, the production of the oxygen free radicals was directly related to hyperglycaemia and the duration of diabetes. The MDA levels acted as a marker for lipid peroxidation i.e. oxidative stress and it was significantly increased in the cases as compared to the controls (P<0.001). In a state of poor metabolic control, increased serum MDA levels are expected. A positive correlation was found between the mean serum MDA levels and the mean HbA1c levels in the diabetic patients. The longer the duration of the disease, the higher were the lipid peroxide levels.
This was in agreement with the findings of Gupta and Ambade. Thus, the increase in the lipid peroxides in blood, coupled with the weakness of the defense antioxidant system in diabetics with complications, probably served as a background for the pathogenesis of the endothelial dysfunction which was associated with diabetes.
The retina is highly susceptible to oxidative stress because of itshigh consumption of oxygen, its proportion of polyunsaturated fatty acids (PUFA) and its exposure to visible light. Studies have consistently shown that photochemical injury is attributable to oxidative stress and that the antioxidants, Vitamins A, E and C protect against this type of injury. The levels of Vitamin C, which is a measure of the antioxidant status, is significantly decreased in diabetic patients (P<0.05).
In the present study, HbA1c was significantly elevated in diabeticpatients, which indicated their glucose status for the past 3 months. There was a significant elevation of triglycerides in patients with complications, indicating dyslipidaemia. Thus, this study concluded that the poor glycaemic control, the long duration of diabetes and dyslipidaemia contributed to the increased oxidative stress. The increased oxidative stress and a decreased antioxidantstatus can predict the micro-vascular complications in diabetes mellitus. The raised MDA levels indicate the oxidative stress and the decreased Vitamin C levels indicate the reduced antioxidant status in diabetic retinopathy. Hence, for the early detection and prevention of diabetic retinopathy, it is advisable to estimate the oxidative stress markers. The diet of diabetic patients should contain a recommended dietary allowance of vitamins to allow the non-enzymatic as well as the enzymatic antioxidant systems to respond to oxidative stress, whichis observed among the diabetic changes (Browing, 2010).