Oxidative Stress In Type 2 Diabetes Mellitus Research Articles

Oxidative Stress, Endothelial Dysfunction, and N-Acetylcysteine in Type 2 Diabetes Mellitus.

Significance: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Endothelial dysfunction is closely associated with the development and progression of CVDs. Patients with diabetes mellitus (DM) especially type 2 DM (T2DM) exhibit a significant endothelial cell (EC) dysfunction with substantially increased risk for CVDs. Recent Advances: Excessive reactive oxygen species (ROS) and oxidative stress are important contributing factors to EC dysfunction and subsequent CVDs. ROS production is significantly increased in DM and is critically involved in the development of endothelial dysfunction in diabetic patients. In this review, efforts are made to discuss the role of excessive ROS and oxidative stress in the pathogenesis of endothelial dysfunction and the mechanisms for excessive ROS production and oxidative stress in T2DM. Critical Issues: Although studies with diabetic animal models have shown that targeting ROS with traditional antioxidant vitamins C and E or other antioxidant supplements provides promising beneficial effects on endothelial function, the cardiovascular outcomes of clinical studies with these antioxidant supplements have been inconsistent in diabetic patients. Future Directions: Preclinical and limited clinical data suggest that N-acetylcysteine (NAC) treatment may improve endothelial function in diabetic patients. However, well-designed clinical studies are needed to determine if NAC supplementation would effectively preserve endothelial function and improve the clinical outcomes of diabetic patients with reduced cardiovascular morbidity and mortality. With better understanding on the mechanisms of ROS generation and ROS-mediated endothelial damages/dysfunction, it is anticipated that new selective ROS-modulating agents and effective personalized strategies will be developed for the management of endothelial dysfunction in DM.

Dapagliflozin restores diabetes-associated decline in vasculogenic capacity of endothelial progenitor cells via activating AMPK-mediated inhibition of inflammation and oxidative stress

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) provide added vascular protection beyond glucose lowering to patients with type 2 diabetes mellitus (T2DM). Endothelial progenitor cells (EPCs) are an important endogenous repair mechanism for diabetic vascular complications. Yet, whether SGLT2i protect vessels in diabetic patients by improving the function of EPCs remains to be elucidated. Here we enrolled Sixty-three T2DM patients and 60 healthy participants and 15 of T2DM group took dapagliflozin for 3 months. Retinal capillary density (RCD) was examined before and after meditation. Moreover, vasculogenic capacity of EPCs cocultured with or without dapagliflozin in vitro and in vivo (hind limb ischemia model) were assessed. Mechanically, genes related to inflammation/oxidative stress, and the AMPK signaling of EPCs were determined. Our results found T2DM demonstrated a declined RCD and a decreased number of circulating EPCs compared with healthy controls. Compared with the EPCs from healthy individuals, vasculogenic capacity of T2DM EPCs was significantly impaired, which could be restored by dapagliflozin meditation or dapagliflozin coculture. Increased expression of inflammation correlative genes and decreased anti-oxidative stress related genes expression were found in EPCs form T2DM, which were accompanied with reduced phosphorylation level of AMPK. Dapagliflozin treatment activated AMPK signaling, decreased the level of inflammation and oxidative stress, and rescued vasculogenic capacity of EPCs from T2DM. Furthermore, AMPK inhibitor pretreatment diminished the enhancement vasculogenic capacity of diabetic EPCs from dapagliflozin treatment. This study demonstrates for the first time that dapagliflozin restores vasculogenic capacity of EPCs via activating AMPK-mediated inhibition of inflammation and oxidative stress in T2DM.

Evaluation of Serum Selenium and Copper Levels with Inflammatory Cytokines and Indices of Oxidative Stress in Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is a metabolic and multifactorial disease in which inflammatory markers, oxidative stress, and certain trace elements seem to have an essential role. This study investigated the relationship between serum selenium and copper level with inflammatory cytokines and oxidative stress in T2DM.In this case-control study, 30 patients with T2DM and 30 healthy individuals were selected. Serum levels of copper and selenium were measured by atomic absorption spectrometry, and TNF-α and IL-6 and oxidative stress markers were measured by ELISA. The SPSS v.22 was used for data analysis and the significance level is less than 5%.The mean age of patients was 52.9 ± 10.4years, and the control group was 48.5 ± 10.4years. In this study, 53.3% were female, and 46.7% were male. The levels of BMI (p = 0.002), systolic pressure (p = 0.034), insulin, selenium, malondialdehyde, and glutathione peroxidase (p = 0.0001; each), insulin resistance, copper, and superoxide dismutase, IL6, and TNF-α (p = 0.001; each) in T2DM were significantly higher than the control group. While levels of lipid profile, uric acid, creatinine, and diastolic pressure were not significantly different between the two groups. Selenium and copper are related to insulin resistance, and their increasing levels are associated with increased levels of markers of oxidative stress and inflammatory cytokines (p < 0.05).Increased levels of copper and selenium are associated with T2DM and this increase is also associated with increased levels of TNF-α, IL-6, and oxidative stress in T2DM. Therefore, controlling these markers can lead us to control this disease better.

Diabetes and Alzheimer's Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?

A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer’s disease (AD). Indeed, the proposed definition of Alzheimer’s disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated.

Vitamin C supplementation reduces expression of circulating miR-451a in subjects with poorly controlled type 2 diabetes mellitus and high oxidative stress.

BackgroundVitamin C is an essential element required for normal metabolic function. We investigated the effect of vitamin C supplementation on circulating miRNA (miR) expression in subjects with poorly controlled type 2 diabetes mellitus (T2DM). Changes in miR expression were also correlated with clinical measures of disease.MethodsPre- and post-vitamin C supplementation samples from five participants who had increased vitamin C levels, improved oxidative status and polymorphonuclear (PMN) function after receiving 1,000 mg of vitamin C daily for six weeks were screened for miRNA expression using the NanoString miRNA assay. Differences in miRNA expression identified from the miRNA screen were validated by qRT-PCR.ResultsFour miRNAs showed significantly different expression post-vitamin C supplementation relative to baseline, including the down-regulation of miR-451a (−1.72 fold change (FC), p = 0.036) and up-regulation of miR-1253 (0.62 FC, p = 0.027), miR-1290 (0.53 FC, p = 0.036) and miR-644a (0.5 FC, p = 0.042). The validation study showed only miR-451a expression was significantly different from baseline with vitamin C supplementation. MiR-451a expression was negatively correlated with vitamin C levels (r = − 0.497, p = 0.049) but positively correlated with levels of malondialdehyde (MDA) (r = 0.584, p = 0.017), cholesterol (r = 0.564, p = 0.022) and low-density lipoproteins (LDL) (r = 0.522, p = 0.037). Bioinformatics analysis of the putative target genes of miR-451a indicated gene functions related to signaling pathways involved in cellular processes, such as the mammalian target of rapamycin (mTOR) signaling pathway.ConclusionsVitamin C supplementation altered circulating miR-451a expression. The results from this pilot study suggest that miRNAs could be used as biomarkers to indicate oxidative status in subjects with T2DM and with poor glycemic control and could lead to a novel molecular strategy to reduce oxidative stress in T2DM.

Effect of probiotics supplementation on glucose and oxidative stress in type 2 diabetes mellitus: a meta-analysis of randomized trials.

The role of oxidative stress in pathogenesis of diabetes is well established. In addition, an association between gut microbiota and type 2 diabetes mellitus (T2DM) is widely observed in previously published reports. This meta-analysis critically examines the association between gut microbiota, and oxidative stress in T2DM. A systematic search for clinical trials was performed in PubMed, Web of Science and Scopus web databases up to 1 Jan 2019. Primary search terms include "microbiota", "diabetes", and "oxidative stress". Study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline. All clinical trials that compared the effects of probiotic supplementations with a control group using end points serum levels of fasting blood sugar (FBS), hemoglobin A1C (HbA1C) and oxidative stress biomarkers were included. Two independent researchers screened the data extracted from the relevant studies. The pooled standardized mean difference (SMD) was estimated using the random or fixed effects model. Heterogeneity among the studies was assessed using Q-test. Overall, 13 randomized clinical trials (RCTs) involving 840 subjects with T2DM were included in the meta-analysis. The analysis showed that probiotics intake resulted in significant improvement in serum levels of FBS [SMD: -0.35, 95% CI: (-0.59, -0.12)], total antioxidant status (TAS) [SMD: 0.33, 95% CI: (0.11, 0.55)], total glutathione (GSH) [SMD: 0.41, 95% CI: (0.26, 0.56)] and malondialdehyde (MDA) [SMD: -0.54, 95% CI: (-0.83, -0.26)]. No significant improvement was found in HbA1C [SMD: -0.06, 95% CI:(-0.82, 0.69)], and nitric oxide (NO) [SMD:-0.24, 95% CI:(-1.10, 0.62)] levels. It seems that gut microbiota can exert beneficial effects in diabetic patients via altering oxidative stress' biomarkers. The beneficial effect of gut microbiota however was modest on FBS and non-significant on HbA1C. These results need to be confirmed by conducting more reliable RCTs. CRD42019134905. Graphical abstract Flow diagram of the study selection process.

The Effects of Combined High-Intensity Interval and Resistance Training on Glycemic Control and Oxidative Stress in T2DM

Background: As part of type 2 diabetes mellitus (T2DM) lifestyle management, exercise programs must be demonstrably effective and safe. Objectives: A randomized controlled trial (RCT) was used to evaluate the results of glycemic control and oxidative stress of a new T2DM management exercise program in a training facility setting. Methods: The study participants were randomly allocated into either an experimental (EXP) group who participated in the new training program or a control (CTR) group who participated in continuous cardiorespiratory exercise. Each participant’s glycemic control (glycated hemoglobin A, HbA1c), fitness level (maximum oxygen uptake, VO2max), and oxidative stress (malondialdehyde, MDA and superoxide dismutase, SOD) were measured before and after the training program. The 12-week training program combined high-intensity interval training (HIIT) three times a week with resistance training (RT) twice a week while gradually increasing the intensity. The HIIT element was comprised of one minute of high-intensity exercise and four minutes of low-intensity exercise. The RT element was comprised of nine exercises for the core, upper extremities, and lower extremities. Results: The 42 T2DM patients who participated in this RCT were 35 - 64 years old. The HbA1c level of the EXP group decreased (Δ = -0.43 ± 1.01%), although not significantly. The VO2max was higher in the EXP group (38.13 ± 5.93 mL/kg/min) than in the CTR group (32.09 ± 5.24 mL/kg/min, P = 0.004). The overall oxidative stress decreased in the EXP group (MDA level Δ = -0.14 ± 0.39 nm/mL) when compared to the CTR group (MDA level Δ = 0.18 ± 0.26 nm/mL, P = 0.011), and the SOD level significantly increased more in the EXP group [median Δ = 0.47 U/mL (interquartile range = 0.08 - 0.74 U/mL)] when compared to the CTR group (Δ = 0.14 ± 0.35 U/mL, P = 0.036). The EXP group’s composite effects score was significantly higher (8.72 ± 1.27) than the CTR group’s score (7.20 ± 1.08, P = 0.001). Conclusions: The combined HIIT and RT exercise program was not significantly improving glycemic control, however it lowered oxidative stress.

Markers of Oxidative Stress and Antioxidant Defense in Romanian Patients with Type 2 Diabetes Mellitus and Obesity

Type 2 diabetes mellitus (T2DM) is strongly associated with obesity. The adipose tissue secretes bioactive adipokines leading to low grade inflammation, amplified by oxidative stress, which promotes the formation of advanced glycation end products and eventually leads to dyslipidemia and vascular complications. The aim of this study was to correlate anthropometric, biochemical and oxidative stress parameters in newly diagnosed (ND) T2DM patients and to investigate the role of oxidative stress in T2DM associated with obesity. A group of 115 ND- T2DM patients was compared to a group of 32 healthy subjects in terms of clinical, anthropometric, biochemical and oxidative stress parameters. ND-T2DM patients had significantly lower adiponectin, glutathione (GSH) and gluthatione peroxidase (GPx) and elevated insulin, proinsulin, HOMA-IR index, proinsulin/insulin (P/I) and proinsulin/adiponectin (P/A) ratio, fructosamine, and total oxidant status (TOS). The total body fat mass was positively correlated with total oxidant status (TOS). Positive correlations were found between TOS and glycated hemoglobin (HbA1c), and between TOS and glycaemia. Negative correlations were identified between: GPx and glycaemia, GPx and HbA1c, and also between GSH and fructosamine. The total antioxidant status was negatively correlated with the respiratory burst. The identified correlations suggest the existence of a complex interplay between diabetes, obesity and oxidative stress.

Levels of heavy metals and their binding protein metallothionein in type 2 diabetics with kidney disease.

Hyperglycemia, a major metabolic disturbance present in diabetes, promotes oxidative stress. Activation of antioxidant defense is an important mechanism to prevent cell damage. Levels of heavy metals and their binding proteins can contribute to oxidative stress. Antiradical capacity and levels of metallothionein (MT), metals (zinc and copper), and selected antioxidants (bilirubin, cysteine, and glutathione) were determined in 70 type 2 diabetes mellitus (T2DM) subjects and 80 healthy subjects of Caucasian origin. Single nucleotide polymorphism (rs28366003) in MT gene was detected. Antiradical capacity, conjugated bilirubin, and copper were significantly increased in diabetics, whereas MT and glutathione were decreased. Genotype AA of rs28366003 was associated with higher zinc levels in the diabetic group. The studied parameters were not influenced by renal function. This is the first study comprehensively investigating differences in MT and metals relevant to oxidative stress in T2DM. Ascertained differences indicate increased oxidative stress in T2DM accompanied by abnormalities in non-enzymatic antioxidant defense systems.

Role of Vitamin D on glycemic control and oxidative stress in type 2 diabetes mellitus.

Background:Vitamin D deficiency may play a key role in the development of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), and metabolic syndrome. Several studies have shown that Vitamin D has an antioxidant property. We aimed to investigate 25-hydroxy Vitamin D (25[OH]D) levels in patients with T2DM and in nondiabetic healthy controls and to ascertain the impact of 25(OH)D levels on glycemic control and oxidative stress in T2DM patients.Materials and Methods:Thirty male patients with T2DM and twenty age- and socioeconomic status-matched male healthy controls were included in the study. Fasting and postprandial blood sugar and glycated hemoglobin (HbA1c) were measured. Enzyme activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) was determined by spectrophotometric assay, and serum levels of 25(OH)D were measured using radioimmunoassay.Results:Serum Vitamin D levels were significantly lower in patients with T2DM than healthy controls (P = 0.015). There was a significantly lower GPx activity in patients with T2DM than controls (P = 0.048), but the difference in SOD activity did not reach statistical significance. There was a significant negative correlation between serum Vitamin D levels and HbA1c (P = 0.016), but no statistical correlation was shown between serum Vitamin D levels and GPx and SOD.Conclusion:We conclude that low level of Vitamin D might play a significant role in T2DM pathogenesis. Hence, Vitamin D supplementation may improve glycemic control and oxidative stress in T2DM.

Targeting mitochondrial alterations to prevent type 2 diabetes—Evidence from studies of dietary redox‐active compounds

As a growing epidemic, type 2 diabetes mellitus (T2DM) has significantly affected the individual's quality of life and economy of the society. Understanding the mechanisms of the disease and discovery of new therapeutic options has become more urgent than ever before. Mitochondrial alterations (e.g. functional alterations, and impaired biogenesis and dynamics) are strongly associated with the development of T2DM. Accumulation of reactive oxygen species or intermediates of incomplete fatty acid oxidation due to mitochondrial deficiency activates stress kinases and dampens insulin signaling. Redox-active compounds such as resveratrol, pyrroloquinoline quinone, and hydroxytyrosol can potently counteract reactive oxygen species, and improve mitochondrial function and biogenesis. Therefore, targeting the mitochondrial alterations with these redox-active compounds may lead to new therapeutic or preventive options for T2DM. In this article, we review the molecular mechanisms of mitochondrial alterations in T2DM, and the action of redox-active compounds to reverse mitochondrial changes and oxidative stress in T2DM. In addition, the current challenges and future directions are discussed and prospected.

Levo-carnitine supplementation normalizes skeletal muscle functions in type 2 diabetic rats

Levo-carnitine is known to improve skeletal muscle contractile functions in healthy humans and rats. It has also been claimed to correct metabolic derangements in type 2 diabetes mellitus (T2DM). This randomized control trial was designed to determine the effect of levo-carnitine on isometric contraction, force frequency relationship and fatigue of skeletal muscles along with oxidative stress in T2DM. Sprague-dawley rats (n=90) were randomly divided in three equal groups. Control group remained healthy while T2DM was induced in the diabetic and carnitine groups. Then, carnitine group was administered levo-carnitine 200mg/kg/day intraperitonealy for 6 days. At 28th day, extensor digitorum longus (EDL) muscles were removed and their functions were assessed using iWorx data acquisition unit (AHK/214). Blood obtained by intra-cardiac sampling at 28th day was used for estimation of serum malondialdehyde (MDA) levels. Regarding muscle parameters, no significant difference was found in maximum isometric twitch tension, time-to-peak twitch tension and time-to-relax to 50% of the peak twitch tension amongst the three groups. However, carnitine group showed significant improvement in maximum fused tetanic tension, maximum fused tetanic tension after fatigue protocol and recovery from fatigue after 5 minutes of rest period when compared with diabetic group. Serum MDA levels were reduced in carnitine group as compared to the diabetic group. These findings suggest that levo-carnitine supplementation reduces oxidative stress, improves work capacity and delays fatigue in T2DM.

Plasma Heme Oxygenase-1 Concentration Is Elevated in Individuals with Type 2 Diabetes Mellitus

BackgroundCirculating concentrations of heme oxygenase-1 (HO-1) have been recently reported to be elevated in several chronic disorders. However, no study has ever examined the association between circulating HO-1 concentrations and type 2 diabetes mellitus (T2DM).Methods and Findings581 cases with newly-diagnosed T2DM (New-T2DM) and 611 comparison controls were recruited in this two-phase case-control study, comprising 420 cases and 429 controls collected in the first phase study and 161 cases and 182 controls in the second phase replication study. Analyses, using both separated data and combined data from the two-phase studies, show that plasma HO-1 concentrations were significantly increased in New-T2DM cases compared to controls (P<0.001). Plasma HO-1 concentrations were significantly correlated with plasma glucose concentrations, HOMA-beta and HOMA-IR (P<0.001). After adjustment for age, sex, BMI and family history of diabetes, the ORs for New-T2DM in the highest quartile of plasma HO-1 concentrations, compared with the lowest, was 8.23 (95% CI 5.55–12.21; P for trend <0.001). The trend remained significant after additional adjustment for fasting plasma glucose/insulin, HOMA-beta/HOMA-IR, TC/TG, smoking, drinking and history of hypertension, and even in further stratification analysis by age, sex, BMI, smoking, drinking and history of hypertension.ConclusionsElevated plasma HO-1 concentrations are associated with higher ORs for New-T2DM, which add more knowledge regarding the important role of oxidative stress in T2DM. More consequent studies were warranted to confirm the clinical utility of plasma HO-1, especially in diagnosis and prognosis of T2DM and its complications.