Oxidative Damage In Diabetes Research Articles

A Systematic Review on Effect of Scoparia Dulcis on Alterations in Antioxidant Status, Oxidative Damage in Diabetes and Other Pharmacological Activities

Oxidative stress is implicated in the pathogenesis of diabetic complications. Diabetes mellitus is presently a burden not only on the individuals affected by the disease but also on society, particularly the national health system of all the countries. The war against diabetes through the development of new drugs is an ongoing continuous process. Despite many advances in the development of oral hypoglycemic agents, an ideal drug for treating diabetes mellitus is still a distant reality. As pointed out by World Health Organisation (WHO), prevention of diabetes and its complications is not only a major challenge for the future, but essential if health for all is to be attainable target. WHO study groups emphasize strongly in this regard the optimal, rational uses of traditional and natural indigenous medicine. The study of such medicinal plants might offer a natural key to unlock diabetologists pharmacy for the future. Indian traditional medicines have a long history to treat diabetic mellitus (DM) by the herbs and herbal extracts. Scoparia dulcis, also known as sweet broom weed, is a perennial herb which is commonly found in tropical and subtropical regions. In these regions, the fresh or dried plant has traditionally been used as one of remedies for diabetes and various diseases. The plant is abundantly found in many countries and can be easily grown and cultivated, should there be a need for mass production. The whole plant is used for ailments like diarrhea, stomach-ache, kidney stones, kidney problems, and fever. S. dulcis is a rich source of flavones, terpenes and steroids S. dulcis is one of the traditional antidiabetic herbs. There were so many research work done on its antidiabetic properties. S. dulcis has been used by human for centuries as a medicinal herb. S. dulcis has also been shown to exhibit analgesic, antimalarial, hepatoprotective, sedative, hypnotic, antiulcer, antisickling, and antimicrobial activities. Given this evidence, it may be concluded that S. dulcis could be promoted among the masses as an alternative and complementary therapy for diabetes, provided further scientific studies on the toxicological and pharmacological aspects are carried out through either in vivo or clinical means.

Autophagy Induced by ROS Aggravates Testis Oxidative Damage in Diabetes via Breaking the Feedforward Loop Linking p62 and Nrf2.

Testicular dysfunction due to hyperglycemia is the main cause of infertility in diabetic men. Over the years, in order to solve this growing problem, a lot of research has been done and a variety of treatments have been created, but so far, there is no safe, effective, and practical method to prevent male infertility caused by diabetes. In this review, we emphasize the male infertility mechanism caused by diabetes from the effects of oxidative stress and autophagy on the function of testes via the PI3K/Akt/mTOR signaling pathway, and we highlight that oxidative stress-induced autophagy breaks the feedforward loop linking Nrf2 and p62 and promotes oxidative damage in diabetic testes.

FDG uptake tracks the oxidative damage in diabetic skeletal muscle: An experimental study

ObjectivesThe present study aims to verify the relationship between glucose consumption and uptake of 18F-2-deoxy-glucose (FDG) in the skeletal muscle (SM) of experimental models of streptozotocin-induced diabetes mellitus (STZ-DM). MethodsThe study included 36 Balb/c mice. Two weeks after intraperitoneal administration of saline (control group, n = 18) or 150 mg streptozotocin (STZ-DM group, n = 18), the two cohorts were submitted to an oral glucose tolerance test and were further subdivided into three groups (n = 6 each): untreated and treated with metformin (MTF) at low or high doses (10 or 750 mg/kg daily, respectively). Two weeks thereafter, all mice were submitted to dynamic micro–positron emission tomography (PET) imaging after prolonged fasting. After sacrifice, enzymatic pathways and response to oxidative stress were evaluated in harvested SM. ResultsOn PET imaging, the FDG uptake rate in hindlimb SM was significantly lower in nondiabetic mice as compared with STZ-DM–untreated mice. MTF had no significant effect on SM FDG uptake in untreated mice; however, its high dose induced a significant decrease in STZ-DM animals. Upon conventional analysis, the SM standard uptake value was higher in STZ-DM mice, while MTF was virtually ineffective in either control or STZ-DM models. This metabolic reprogramming was not explained by any change in cytosolic glucose metabolism. By contrast, it closely agreed with the catalytic function of hexose-6P-dehydrogenase (H6PD; i.e., the trigger of a specific pentose phosphate pathway selectively located within the endoplasmic reticulum). In agreement with this role, the H6PD enzymatic response to both STZ-DM and MTF matched the activation of the NADPH-dependent antioxidant responses to the increased generation of reactive oxygen species caused by chronic hyperglycemia. Ex vivo analysis of tracer kinetics confirmed that the enhanced SM avidity for FDG occurred despite a significant reduction in glucose consumption, while it was associated with increased radioactivity transfer to the endoplasmic reticulum. ConclusionsThese data challenge the current dogma linking FDG uptake to the glycolytic rate. They instead introduce a new model considering a strict link between the uptake of this glucose analog, H6PD reticular activity, and oxidative damage in diabetes, at least under fasting condition.

The mitochondrial antioxidant SS-31 increases SIRT1 levels and ameliorates inflammation, oxidative stress and leukocyte-endothelium interactions in type 2 diabetes

There is growing focus on mitochondrial impairment and cardiovascular diseases (CVD) in type 2 diabetes (T2D), and the development of novel therapeutic strategies in this context. It is unknown whether mitochondrial-targeting antioxidants such as SS-31 protect sufficiently against oxidative damage in diabetes. We aimed to evaluate if SS-31 modulates SIRT1 levels and ameliorates leukocyte-endothelium interactions, oxidative stress and inflammation in T2D patients. Anthropometric and metabolic parameters were studied in 51 T2D patients and 57 controls. Production of mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, glutathione content, leukocyte-endothelium interactions, NFκB-p65, TNFα and SIRT1 levels was measured in leukocytes treated or not with SS-31. We observed increased mitochondrial ROS production that was restored by SS-31 treatment. SS-31 also increased mitochondrial membrane potential, glutathione content, SIRT1 levels and leukocyte rolling velocity and reduced rolling flux and adhesion in T2D patients. NFκB-p65 and TNFα, which were enhanced in diabetic patients, were also reduced by SS-31 treatment. Our results reveal that SS-31 exerts beneficial effects on the leukocytes of T2D patients by reducing oxidative stress, leukocyte-endothelium interactions, NFκB and TNFα and by increasing SIRT1 levels. These actions support its use as a potential agent against CVD risk.

Effects of Quercetin on Lipid and Protein Damage in the Liver of Streptozotocin-Induced Experimental Diabetic Rats.

Quercetin (QR) is part of a subclass of flavonoids called flavonols. We aimed to investigate the effect of QR on malondialdehyde (MDA), advanced oxidation protein products (AOPPs), and glutathione peroxidase (GSH-Px) activity in the liver of diabetic rats. We compared four groups of male adult Wistar albino rats: a control group, an untreated diabetic group, diabetic groups treated with QR, and QR group. Diabetes was induced by a single injection of streptozotocin (STZ) (50 mg/kg). Animals were kept in standard condition. On the 31st day of the study, the liver tissue was removed for biochemical parameters and histopathological evaluations. In an untreated diabetic group, liver MDA and AOPP levels were significantly higher than all groups. QR treatment significantly decreased the increased MDA, AOPP levels, and increased the decreased GSH-Px enzyme activity in liver tissues. The QR-treated rats in the diabetic group showed an improved histological appearance. Lesser vesicular vacuolization and fibrotic areas were observed in the QR-treated diabetic group than in the diabetic group. The STZ-induced liver injury is associated with oxidative stress, and coadministration of QR may reduce this damage effectively in a rat model. Our results are also supported by morphological improvement in liver tissue. Therefore, we think QR may be effective in treating hyperglycemia and oxidative damage in diabetes.

Mitigating effects of antioxidant properties of Artemisia herba alba aqueous extract on hyperlipidemia and oxidative damage in alloxan-induced diabetic rats

Chronic hyperglycemia and excess reactive oxygen species overproduced in diabetes were associated with oxidative stress, led to continuous injury and functions damage to different organs: eyes, kidneys, neural and cardiovascular system. The present study was undertaken to evaluate the protective effect of Artemisia herba alba (AHA) leaf powder against alloxane-induced oxidative damage in diabetic rats. Rats were randomly divided into four groups: Group I controls received saline solution 9%; Group II was treated with 150 mg alloxane/(kg body weight) administered by intraperitoneal. Rats of Group III have received saline solution and treated with 400 mg AHA/(kg body weight). Animals of Group IV were treated with alloxane and AHA. Alloxane exposure led to increased blood glucose, total cholesterol, triglycerides, malondialdehyde, and a decrease in the antioxidants enzymes activities (catalase, glutathione peroxidase and glutathione-S-transferase). Administration of AHA aqueous extract ameliorated these parameters. These results demonstrate that AHA ameliorates hyperglycemia, hyperlipidemia and oxidative damage in alloxan-induced diabetes in rats.

Label-free optical detection of age-related and diabetic oxidative damage in human aqueous humors.

In this study, we investigate the biochemical characteristics of oxidative stress in age-related macular degeneration (AMD) and diabetic retinopathy (DR) by analyzing aqueous humors. Nondiabetic cataract aqueous humor was used as the control. The level of oxidative damage was evaluated based on changes in Raman spectral intensity. Seven prominent peaks were detected at 1002, 1043, 1062, 1352, 1419, 1454, and 1656 cm-1 . We proposed four multimodal biomarkers to distinguish these peaks based on the ratios of Raman intensities in two wavelengths, including CHO (C-O stretching or C-O-H bending modes), AG (adenine and guanine), PRO-AG (protein and AG), and PHEα (phenylalanine symmetric ring breath and amide I α-helix) markers. The presence of oxidative damage was detected by CHO and AG markers associated with C-O stretching, C-O-H bending modes in carbohydrates (1043 cm-1 ), and the nucleic acids adenine and guanine (1352 cm-1 ), respectively. DR-related oxidative damage was identified by PRO-AG and PHEα markers associated with adenine, guanine, and protein components (1419 and 1454 cm-1 ) and amide I α-helix protein structure (1656 cm-1 ), respectively. AMD-related oxidative damage was identified by four biomarkers. Four multimodal biomarkers with simple linear threshold values achieved high sensitivity of 100% and high specificity of 100% for classifying oxidative stress-induced AMD and DR diseases. Therefore, Raman-based label-free optical detection is effective for detecting the presence of age-related or diabetic oxidative damage in aqueous humor.

Ischemia modified albumin (IMA) and albumin adjusted-IMA (AAIMA) as biomarkers for diabetic retinopathy.

Oxidative stress has important role in the pathophysiology of diabetic retinopathy (DR). Ischemia modified albumin (IMA) has been recently considered as a marker of oxidative damage in diabetes. However, there is scarcity of published information about both IMA and albumin adjusted-IMA (AAIMA) in DR patients. To evaluate the serum levels of IMA and AAIMA in patients with DR and in healthy controls. This was a cross sectional study. Serum was obtained to measure lipids, albumin and IMA from the the patients with DR and non-diabetic subjects. The IMA level was measured by a colorimetric albumin cobalt binding (ACB) assay and the values were presented as absorbance units (ABSU). The IMA levels were adjusted for albumin interference and the AAIMA by using a formula [Individual serum albumin/median albumin concentration of the population X IMA]. This study was done on 18 DR and 20 non- diabetic patients. The mean Serum IMA values in DR group and controls were 0.50±0.17 and 0.32±0.17, respectively (P=0.002). The mean serum AAIMA values in DR group and controls were 0.48±0.20 and 0.32±0.17, respectively (P=0.01). The albumin and HDL- Cholesterol levels were significantly lower in DR patients compared to controls (p=0.004 and p=0.01, respectively). The level of IMA and AAIMA were higher in cases of DR compared to that of non-diabetic subjects. The levels of albumin and HDL-Cholesterol were lower in DR patients compared to controls.

Macrophages in diabetic gastroparesis--the missing link?

Diabetic gastroparesis results in significant morbidity for patients and major economic burden for society. Treatment options for diabetic gastroparesis are currently directed at symptom control rather than the underlying disease and are limited. The pathophysiology of diabetic gastroparesis includes damage to intrinsic and extrinsic neurons, smooth muscle, and interstitial cells of Cajal (ICC). Oxidative damage in diabetes appears to be one of the primary insults involved in the pathogenesis of several complications of diabetes, including gastroparesis. Recent studies have highlighted the potential role of macrophages as key cellular elements in the pathogenesis of diabetic gastroparesis. Macrophages are important for both homeostasis and defense against a variety of pathogens. Heme oxygenase 1 (HO1), an enzyme expressed in a subset of macrophages has emerged as a major protective mechanism against oxidative stress. Activation of macrophages with high levels of HO1 expression protects against development of delayed gastric emptying in animal models of diabetes, while activation of macrophages that do not express HO1 are linked to neuromuscular cell injury. Targeting macrophages and HO1 may therefore be a therapeutic option in diabetic gastroparesis. This report briefly reviews the pathophysiology of diabetic gastroparesis with a focus on oxidative damage and how activation and polarization of different subtypes of macrophages in the muscularis propria determines development of delay in gastric emptying or protects against its development.

Therapeutic potential of pterostilbene against pancreatic beta‐cell apoptosis mediated through Nrf2

Nuclear factor erythroid 2-related factor 2 (Nrf2) is considered to be a 'master regulator' of the antioxidant response as it regulates the expression of several genes including phase II metabolic and antioxidant enzymes and thus plays an important role in preventing oxidative stress-mediated disorders, including diabetes. In this study, for the first time, we investigated the protective properties of a naturally available antioxidant, pterostilbene (PTS), against pancreatic beta-cell apoptosis and the involvement of Nrf2 in its mechanism of action. Immunoblotting and quantitative reverse transcriptase (qRT)-PCR analysis were performed to identify PTS-mediated nuclear translocation of Nrf2 protein and the following activation of target gene expression, respectively, in INS-1E cells. In addition, an annexin-V binding assay was carried out to identify the apoptotic status of PTS-treated INS-1E cells, while confirming the anti-apoptotic potential of Nrf2 by qRT-PCR analysis of the expressions of both pro- and anti-apoptotic genes. PTS induced significant activation of Nrf2, in dose- and time-dependent manner, in streptozotocin-treated INS-1E rat pancreatic beta-cells. Furthermore, PTS increased the expression of target genes downstream of Nrf2, such as heme oxygenase 1 (HO1), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), that confer cellular protection. PTS also up-regulated the expression of anti-apoptotic gene, Bcl-2, with a concomitant reduction in pro-apoptotic Bax and caspase-3 expression. Collectively, our findings indicate the therapeutic potential of Nrf2 activation by PTS as a promising approach to safeguard pancreatic beta-cells against oxidative damage in diabetes.

Neuromodulatory effects of hesperidin in mitigating oxidative stress in streptozotocin induced diabetes.

Oxidative stress has been implicated in pathogenesis of streptozotocin- (STZ-) induced diabetes mellitus and its complication in central nervous system (CNS). Recent studies have provided insights on antioxidants and their emergence as potential therapeutic and nutraceutical. The present study examined the hypothesis that hesperidin (HP) ameliorates oxidative stress and may be a limiting factor in the extent of CNS complication following diabetes. To test this hypothesis rats were divided into four groups: control, diabetic, diabetic-HP treated, and vehicle for HP treatment group. Diabetes mellitus was induced by a single injection of STZ (65 mg/kg body weight). Three days after STZ injection, HP was given (50 mg/kg b.wt. orally) once daily for four weeks. The results of the present investigation suggest that the significant elevated levels of oxidative stress markers were observed in STZ-treated animals, whereas significant depletion in the activity of nonenzymatic antioxidants and enzymatic antioxidants was witnessed in diabetic rat brain. Neurotoxicity biomarker activity was also altered significantly. HP treatment significantly attenuated the altered levels of oxidative stress and neurotoxicity biomarkers. Our results demonstrate that HP exhibits potent antioxidant and neuroprotective effects on the brain tissue against the diabetic oxidative damage in STZ-induced rodent model.

In vitro effects of resveratrol on oxidative stress in diabetic platelets

To evaluate the in vitro effects of resveratrol (RSV) incubation on platelets from compensated and decompensated diabetic patients in order to use it as an adjuvant therapy. The study was performed on 77 diabetic patients and divided into two phases: 29 compensated and 48 decompensated diabetic platelets were analyzed at recruitment (T₀) and after in vitro RSV incubation (20 μg/ml) for 3 h at 37 °C (T₁). Lipoperoxide and nitric oxide (NO) levels, superoxide dismutase (SOD) and Na(+)/K(+) ATPase activities, total antioxidant capacity (TAC), and membrane fluidity tested by anisotropy of fluorescent probes TMA-DPH and DPH were determined. In vitro RSV incubation counteracts oxidative damage associated with diabetes and its complications; it is able to improve platelet function through augmented membrane fluidity and Na(+)/K(+) ATPase activity; it enhances antioxidant systems' functionality by increasing NO levels, SOD activity, and TAC and by decreasing lipoperoxide levels in both compensated and decompensated patients. Such platelet functionality enhancement suggests a new method of secondary prevention of complications associated with platelet dysfunction. Being free from one of the major risks associated with many antidiabetic agents, it can be assumed that RSV utilization in the diabetic diet may have a preventive and protective role in the progression of diabetic oxidative damage.

Effects of glutamine supplementation on oxidative stress-related gene expression and antioxidant properties in rats with streptozotocin-induced type 2 diabetes

There are close links among hyperglycaemia, oxidative stress and diabetic complications. Glutamine (GLN) is an amino acid with immunomodulatory properties. The present study investigated the effect of dietary GLN on oxidative stress-relative gene expressions and tissue oxidative damage in diabetes. There were one normal control (NC) and two diabetic groups in the present study. Diabetes was induced by an intraperitoneal injection of nicotinamide followed by streptozotocin (STZ). Rats in the NC group were fed a regular chow diet. In the two diabetic groups, one group (diabetes mellitus, DM) was fed a common semi-purified diet while the other group received a diet in which part of the casein was replaced by GLN (DM-GLN). GLN provided 25% of total amino acid N. The experimental groups were fed the respective diets for 8 weeks, and then the rats were killed for further analysis. The results showed that blood thioredoxin-interacting protein (Txnip) mRNA expression in the diabetic groups was higher than that in the NC group. Compared with the DM group, the DM-GLN group had lower glutamine fructose-6-phosphate transaminase 1, a receptor of advanced glycation end products, and Txnip gene expressions in blood mononuclear cells. The total antioxidant capacity was lower and antioxidant enzyme activities were altered by the diabetic condition. GLN supplementation increased antioxidant capacity and normalised antioxidant enzyme activities. Also, the renal nitrotyrosine level and Txnip mRNA expression were lower when GLN was administered. These results suggest that dietary GLN supplementation decreases oxidative stress-related gene expression, increases the antioxidant potential and may consequently attenuate renal oxidative damage in rats with STZ-induced diabetes.

Oxidative stress and diabetes mellitus

Increasing evidences have suggested that oxidative stress plays a major role in the pathogenesis of diabetes mellitus (DM). Oxidative stress also appears to be the pathogenic factor in underlying diabetic complications. Reactive oxygen species (ROS) are generated by environmental factors, such as ionizing radiation and chemical carcinogens, and also by endogenous processes, including energy metabolism in mitochondria. ROS produced either endogenously or exogenously can attack lipids, proteins and nucleic acids simultaneously in living cells. There are many potential mechanisms whereby excess glucose metabolites traveling along these pathways might promote the development of DM complication and cause pancreatic β cell damage. However, all these pathways have in common the formation of ROS, that, in excess and over time, causes chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. Various methods for determining biomarkers of cellular oxidative stress have been developed, and some have been proposed for sensitive assessment of antioxidant defense and oxidative damage in diabetes and its complications. However, their clinical utility is limited by less than optimal standardization techniques and the lack of sufficient large-sized, multi-marker prospective trials.

Metabolomic approach to the nutraceutical effect of rosemary extract plus ω-3 PUFAs in diabetic children with capillary electrophoresis

Type 1 diabetes mellitus is a major endocrine disorder, affecting approximately 5% of the world's population. It not only leads to hyperglycaemia but also causes many complications, and numerous studies have demonstrated that oxidative stress contributes to these complications. As a new strategy to improve the oxidative damage in diabetes, interest has grown in the usage of natural antioxidants, even more in the long term. Among them, Rosmarinus officinalis (rosemary) has been widely accepted as one of the species with the highest antioxidant activity. In addition, ω-3 polyunsaturated fatty acids were efficient in delaying and decreasing cardiovascular risk factors associated with diabetes. Type 1 diabetic children and the corresponding controls were enrolled in the assay. The aim was evaluating the effect of a special additive containing rosemary extract, vitamin E and PUFAs added to their standard diet through the meat. In the analytical point of view, a metabolomic approach with CE-UV was used to detect possible differences in urine of diabetic children as compared to controls. After the application of the appropriate multivariate statistical tools, clear differences could be observed between treated and non-treated diabetic children and some of the metabolites associated could be identified. This was specially challenging as most of the clinical biochemical parameters measured by target analysis showed no differences between the groups.

Ethanolic extracts of seeds of Parinari curatellifolia exhibit potent antioxidant properties: A possible mechanism of its antidiabetic action

The present study sought to evaluate the antioxidative property of seed of Parinari curatellifolia (P. curatellifolia) that has been previously reported to attenuate high glucose level in type 2 diabetes. The amount of antioxidant agents such as phenols, flavonoids, vitamin C and glutathione were determined in the ethanolic extracts of the seed. In addition, the possible antioxidant mechanisms of the extracts were assessed by measuring their reducing property, iron (II) chelating ability and their ability to scavenge 2, 2-diphenyl-2-picrylhydrazyl hydrate (DPPH) radicals. In addition, the ability of the extracts to prevent deoxyribose degradation and inhibits lipid peroxidation in the brain, liver, heart and pancrease were also determined. The results show that the seed contains phenols (9.4 ± 0.89 mg gallic acid equivalent), flavonoids (1.57 ± 0.17 mg quercetin equivalent), vitamin C (46.82 mg/g of seed) and glutathione (24.22 µg/g of seed). Furthermore, P. curatellifoliasignificantly scavenged DPPH radicals, reduced Fe3+ and chelated Fe2+ in a dose dependent manner. Likewise, P. curatellifolia caused a marked reduction in the degradation of deoxyribose induced by Fe2+, H2O2 or both. However, the seed inhibited peroxidation of cerebral, hepatic and cardiac but not pancreatic lipids subjected to either iron or sodium nitroprusside oxidative assaults. Taken together, we conclude that since type-2 diabetes is intrinsically linked with oxidative stress,P. curatellifolia possibly exerts its antidiabetic action using a combination of mechanisms and its antioxidant potency possibly play a major role in ameliorating secondary complications resulting from oxidative damage in diabetes. Key words: Parinari curatellifolia, diabetes, antioxidant, oxidative stress, lipid peroxidation.

The Histologic Evaluation of Atorvastatin and Melatonin Treatment on Oxidative Stress and Apoptosis of Diabetic Rat Pancreas

Summary In the diabetic state, there is an enhanced oxidative stress due to excessive production of reactive oxygen compounds and decreased bioavailability of nitric oxide. Antioxidant treatment has been used to prevent oxidative damage in diabetes. The objective of the present study was to explore the effects of atorvastatin (AT) and melatonin (MLT) on oxidative stress in diabetic rat pancreas. We also assessed nitric oxide synthase (NOS) activity and apoptosis. Diabetes was induced by an alkylating agent steptozotocin (STZ, 55 mg/kg, IP). Six weeks later rats were divided into five groups: STZ-induced diabetic group received atorvastatin (STZ+AT), STZ-induced diabetic group received melatonin (STZ+MLT) and STZ-induced diabetic group received atorvastatin and melatonin (STZ+AT+MLT). The vehicle-treated non-diabetic (CT) and diabetic group (STZ-CT) served as normoglycemic and diabetic controls. AT was given 8 mg/kg orally and MLT was given 10 mg/kg/IP once a day for 2 weeks beginning from the sixth week. Pancreatic tissue was examined by immunohistochemical methods. Although no significant difference was observed with respect to antioxidant status, NOS activity was tended to be higher in the untreated diabetic rats than in the treated rats. We observed that AT and MLT treatment improved the histopathological changes including apoptosis and oxidative stress in diabetic pancreas.

Oxidative damage indices for the assessment of subclinical diabetic macrovascular complications

Subclinical cardiovascular disease (SCVD), including complications in diabetes, is associated with oxidative damage and precedes future cardiovascular disease (CVD). Hence, assessment and management of oxidative damage is imperative. This study investigates biomarkers associated with CVD, diabetes and oxidative stress in order to determine a set of indices that could be useful to assess oxidative damage in diabetic macrovascular pathogenesis. A total of 266 participants were selected and divided into seven groups (control, family history of diabetes, prediabetes, prediabetes with CVD, diabetes mellitus [DM], DM+CVD and CVD) based on clinical history/status. Blood glucose (BG) level, erythrocyte glutathione (GSH), malondialdehyde, methaemoglobin, D-dimer, homocysteine, blood viscosity and cholesterol profile were determined. Factorial MANOVA and independent univariate analyses were performed. Prevalence of significant biomarkers was assessed following a 3.5-year retrospective study. Multivariate analysis showed statistically significant differences between groups (P<0.0001) with post hoc tests identifying a statistically significant association for BG level (P<0.0001), GSH (P<0.0001), D-dimer (P<0.02) and total cholesterol (P<0.0001). Of the subjects who showed hyperglycaemia-associated progression in clinical and biochemistry status, 89% had low-level GSH and 44% had high-level D-dimer. Four individuals exhibited prediabetic status at some stage and would qualify for macrovascular disease intervention. The results of this study suggest that BG level, D-dimer, GSH and total cholesterol contribute significantly to a diabetic oxidative damage panel of markers that could assist in evidence-based pharmacological intervention with anti-aggregation and/or antioxidant agents against future CVD in diabetes.

Effect of vitamin C and lipoic acid on streptozotocin-induced diabetes gene expression: mRNA and protein expressions of Cu–Zn SOD and catalase

The involvement of oxidative stress in the pathogenesis of diabetes mellitus has been confirmed by numerous studies. In this study, the expression of two antioxidant enzymes, superoxide dismutase (SOD), and catalase which are involved in the detoxification of reactive oxygen species was studied in the streptozotocin-induced diabetic rat liver tissues. The enzyme assays showed a significant decrease in both enzymes activities compared to control animals. The RT-PCR and Western-blot analysis results demonstrated that this decrease in activity is regulated at the level of gene expression, as both catalase and Cu-Zn SOD mRNA and protein expressions were also suppressed. Supplementing the animals with vitamin C, a powerful antioxidant increased both SOD and catalase activities with no change in both mRNA and protein expressions suggesting a role of post-translational modification. However, even though mRNA expressions of both catalase and Cu-Zn SOD were not changed, the protein levels increased in parallel to activities in the case of another antioxidant, alpha-lipoic acid. An increase in the rate of translation, without changing the rate of transcription indicates a translational effect of lipoic acid in changing the activities of antioxidant enzymes to prevent the oxidative damage in diabetes.

Oxidative Damage in the Retinal Mitochondria of Diabetic Mice: Possible Protection by Superoxide Dismutase

Superoxide levels are elevated in the retina in patients with diabetes, and cytochrome c is released from the mitochondria. The purpose of this study was to elucidate the mechanism involved in the oxidative damage of retinal mitochondria in diabetes and to determine whether mitochondrial superoxide dismutase (MnSOD) provides protection. Effects of diabetes were investigated on superoxide and GSH levels, electron transport complexes I and III, and membrane permeability in the isolated mitochondria prepared from the retinas of streptozotocin diabetic mice. To investigate the effect of MnSOD, retinal mitochondrial oxidative stress and electron transport complexes were determined in mice overexpressing MnSOD (MnSOD-Tg). Histopathology was evaluated in trypsin-digested retina. Retinal mitochondria had twofold increase in superoxide levels in nontransgenic (wild-type [WT]) diabetic mice compared with WT nondiabetic mice. In the same retina, diabetes decreased mitochondrial GSH levels by 40% and complex III activity by approximately 20%, and it increased mitochondrial membrane permeability (swelling) by more than twofold; however, complex I activity was not affected. Overexpression of MnSOD inhibited diabetes-induced increases in mitochondrial superoxide levels and membrane permeability and the decrease in complex III activity. GSH values, however, were not statistically different in WT and MnSOD-Tg diabetic mice. In contrast to the diabetes-induced increase in the number of degenerate (acellular) capillaries in WT diabetic mice, the numbers of acellular capillaries in MnSOD-Tg nondiabetic and diabetic mice were similar to those in WT nondiabetic mice. Retinal mitochondria experience increased oxidative damage in diabetes, and complex III is one of the sources of increased superoxide. MnSOD protects the retina from diabetes-induced abnormalities in the mitochondria and prevents vascular histopathology, strongly implicating the role for MnSOD in the pathogenesis of retinopathy in diabetes.