8-hydroxy-2--deoxyguanosine and Diabetes-Mellitus--Type-2

The growing clinical and epidemiological significance of gestational diabetes mellitus results from its constantly increasing worldwide prevalence, obesity, and overall unhealthy lifestyle among women of childbearing age. Oxidative stress seems to be the most important predictor of gestational diabetes mellitus development. Disturbances in the cell caused by oxidative stress lead to different changes in biomolecules, including DNA. The nucleobase which is most susceptible to oxidative stress is guanine. Its damage results in two main modifications: 8-hydroxy-2'-deoxyguanosineor 8-oxo-7,8-dihydro-2'-deoxyguanosine. Their significant level can indicate pathological processes during pregnancy, like gestational diabetes mellitus and probably, type 2 diabetes mellitus after pregnancy. This review provides an overview of current knowledge on the use of 8-hydroxy-2'-deoxyguanosineand/or 8-oxo-7,8-dihydro-2'-deoxyguanosine as a biomarker in gestational diabetes mellitus and allows us to understand the mechanism of 8-hydroxy-2'-deoxyguanosineand/or 8-oxo-7,8-dihydro-2'-deoxyguanosine generation during this disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Humans; Pregnancy; Pregnancy in Diabetics

Type 2 diabetes (T2DM) and its complications constitute a major worldwide public health problem, with high rates of morbidity and mortality. Biomarkers for predicting the occurrence and development of the disease may therefore offer benefits in terms of early diagnosis and intervention. This review provides an overview of human studies on circulating biomarkers of oxidative stress and antioxidant defence systems and discusses their usefulness from a clinical perspective. Most case-control studies documented an increase in biomarkers of oxidative lipid, protein, and nucleic acid damage in patients with prediabetes and in those with a diagnosis of T2DM compared to controls, and similar findings were reported in T2DM with micro- and macrovascular complications compared to those without. The inconsistence of the results regarding antioxidant defence systems renders difficulty to draw a general conclusion. The clinical relevance of biomarkers of oxidative lipid and protein damage for T2DM progression is uncertain, but prospective studies suggest that markers of oxidative nucleic acid damage such as 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine are promising for predicting macrovascular complications of T2DM. Emerging evidence also points out the relationship between serum PON1 and serum HO1 in T2DM and its complications. Overall, enhanced oxidative damage represents an underlying mechanism of glucose toxicity in T2DM and its related micro- and macrovascular complications suggesting that it may be considered as a potential additional target for pharmacotherapy. Therefore, further studies are needed to understand whether targeting oxidative stress may yield clinical benefits. In this view, the measurement of oxidative stress biomarkers in clinical trials deserves to be considered as an additional tool to currently used parameters to facilitate a more individualized treatment of T2DM in terms of drug choice and patient selection.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aryldialkylphosphatase; Biomarkers; Blood Vessels; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus, Type 2; DNA Damage; Heme Oxygenase-1; Humans; Lipid Metabolism; Oxidative Stress

Exercise is recommended for the management of type 2 diabetes, but its effects on diabetic nephropathy (DN) are still unknown. We hypothesized that appropriate exercise improves early DN via attenuation of inflammation and oxidative damage. Type 2 diabetic KK-A(y) mice, a spontaneous DN model, underwent two different kinds of exercise (i.e., moderate and low intensity). Sedentary mice or those undergoing an exercise regimen causing no significant body weight loss were used. We examined the urinary excretion of albumin, number of podocytes and macrophages, renal expressions of HIF-1α and MCP-1, and biomarkers of oxidative stress such as urinary 8-OHdG and serum SOD. Exercise reduced urinary levels of albumin and also maintained the number of podocytes in the exercised KK-A(y) mice independently of improvements of overweight and hyperglycemia, although moderate-intensity exercise increased expression of HIF-1α. Sedentary KK-A(y) mice showed increased expression of MCP-1 and infiltration of macrophage, increased urinary 8-OhdG, and decreased serum SOD levels compared with exercised KK-A(y) mice. On the whole, low-intensity exercise attenuates progression of early DN without affecting marked renal ischemia. Reduction rates of urinary albumin and maintained podocyte numbers, with parallel improvements in oxidative damage and inflammation, are related to beneficial effects of exercise in diabetic kidney disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albumins; Animals; Biomarkers; Cell Proliferation; Chemokine CCL2; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Ischemia; Macrophages; Male; Mice; Oxidative Stress; Podocytes; Rats; Superoxide Dismutase

The increasing prevalence of diabetes together with the associated morbidity and mortality calls for additional preventive and therapeutic strategies. New biomarkers that can be used in therapy control and risk stratification as alternatives to current methods are needed and can facilitate a more individualized and sufficient treatment of diabetes. Evidence derived from both epidemiological and mechanistic studies suggests that oxidative stress has an important role in mediating the pathologies of diabetic complications. A marker of intracellular oxidative stress that potentially could be used as a valuable biomarker in diabetes is the DNA oxidation marker 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which can be assessed noninvasively in the urine, with minimal discomfort for the patient. In this review the analytical validity of 8-oxodG is addressed by highlighting important methodological issues. The available epidemiological evidence regarding urinary 8-oxodG and type 2 diabetes is presented. A possible role for DNA oxidation in cancer development in type 2 diabetes patients is discussed, followed by an evaluation of the potential of urinary 8-oxodG as a clinical biomarker in type 2 diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Humans; Oxidative Stress; Risk

Because of Westernized life style, diabetes and its complications become one of the most popular diseases in Asian countries as well as Westernized countries. Compared with diabetic microvascular complications, several risk factors such as postprandial hyperglycemia, increased coagulability, chronic inflammation, and genetic risk factors may lead to augment atherosclerosis, are shown to result in diabetic macroangiopathies (acute coronary syndrome, brain infarction, and ASO). Addition to candidate gene approach, genome wide association study (GWAS) successfully elucidated several novel single nuclear polymorphisms (SNP), contributing atherosclerosis. However, these genetic risk factors are still shown to contribute a relatively small part of atherosclerosis. Recently we have determined more than 100 atherosclerosis-related SNPs of around 2,000 subjects with type 2 diabetes. We have shown the combination of two atherosclerosis-prone SNPs highly significantly contribute to carotid atherosclerosis and coronary artery disease in subjects with type 2 diabetes. Also, accumulation of oxygen stress-prone alleles of some SNPs are proven to relate with serum level of 8-OHdG, as oxidative stress marker, carotid IMT, and prevalence of old myocardial infarction. These data clearly indicate that several genetic risk factors as well as conventional risk factors additively or synergistically contribute to diabetic macroangiopathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Oxidative Stress; Polymorphism, Single Nucleotide

This study aimed to evaluate the impacts of dapagliflozin on 24-hour glucose variability and diabetes-related biochemical variables in Japanese patients with type 2 diabetes who had received basal insulin supported oral therapy (BOT).. Changes in mean daily blood glucose level before and after 48-72 hours of add-on or no add-on of dapagliflozin (primary end point) and diabetes-related biochemical variables and major safety variables during the 12 weeks (secondary end point) were evaluated in the multicenter, randomized, two-arm, open-label, parallel-group comparison study.. Among 36 participants, 18 were included in the no add-on group and 18 were included in the dapagliflozin add-on group. Age, gender, and body mass index were comparable between the groups. There were no changes in continuous glucose monitoring metrics in the no add-on group. In the dapagliflozin add-on group, mean glucose (183-156 mg/dL, p=0.001), maximum glucose (300-253, p<0.01), and SD glucose (57-45, p<0.05) decreased. Time in range increased (p<0.05), while time above the range decreased in the dapagliflozin add-on group but not in the no add-on group. After 12-week treatment with dapagliflozin add-on, 8-hydroxy-2'-deoxyguanosine (8OHdG), as well as hemoglobin A1c (HbA1c), decreased.. This study showed that the mean daily blood glucose and other daily glucose profiles were amended after 48-72 hours of dapagliflozin add-on in Japanese patients with type 2 diabetes who received BOT. The diabetes-related biochemical variables such as HbA1c and urinary 8OHdG were also obtained during the 12 weeks of dapagliflozin add-on without major adverse events. A preferable 24-hour glucose profile in 'time in ranges' and an improvement in reactive oxygen species by dapagliflozin warrant us to evaluate these benefits in larger clinical studies.. UMIN000019457.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; East Asian People; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulins; Treatment Outcome

This secondary analysis aimed to investigate the effects of a 12 months intensive exercise-based lifestyle intervention on systemic markers of oxidative stress in persons with type 2 diabetes. We hypothesized lifestyle intervention to be superior to standard care in decreasing levels of oxidative stress.. A total of 77 participants, 21 participants receiving standard care and 56 participants receiving the lifestyle intervention, were included in the analysis. Mean age at baseline was 54.1 years (SD 9.1), 41% were women and mean duration of type 2 diabetes was 5.0 years (SD 2.8). From baseline to follow-up the lifestyle group experienced a 7% decrease in 8-oxoGuo (-0.15 nmol/mmol creatinine [95% CI -0.27, -0.03]), whereas standard care conversely was associated with a 8.5% increase in 8-oxoGuo (0.19 nmol/mmol creatinine [95% CI 0.00, 0.40]). The between group difference in 8-oxoGuo was -0.35 nmol/mmol creatinine [95% CI -0.58, -0.12,], p = 0.003. No between group difference was observed in 8-oxodG.. A 12 months intensive exercise-based lifestyle intervention was associated with a decrease in RNA, but not DNA, oxidation in persons with type 2 diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Female; Glycation End Products, Advanced; Humans; Life Style; Male; Oxidative Stress; RNA

Glucagon-like peptide 1 receptor agonists have shown cardioprotective effects which have been suggested to be mediated through inhibition of oxidative stress. We investigated the effect of treatment with a glucagon-like peptide 1 receptor agonist (liraglutide) on oxidative stress measured as urinary nucleic acid oxidation in persons with type 2 diabetes. Post-hoc analysis of two independent, randomised, placebo-controlled and double-blinded clinical trials. In a cross-over study where persons with type 2 diabetes and microalbuminuria (LIRALBU, n = 32) received liraglutide (1.8 mg/day) or placebo for 12 weeks in random order, separated by 4 weeks of wash-out. In a parallel-grouped study where obese persons with type 2 diabetes (SAFEGUARD, n = 56) received liraglutide (1.8 mg/day), sitagliptin (100 mg/day) or placebo for 12 weeks. Endpoints were changes in the urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG)) and RNA oxidation [8-oxo-7,8-dihydroguanosine (8-oxoGuo)]. In LIRALBU, we observed no significant differences between treatment periods in urinary excretion of 8-oxodG [0.028 (standard error (SE): 0.17] nmol/mmol creatinine, p = 0.87) or of 8-oxoGuo [0.12 (0.12) nmol/mmol creatinine, p = 0.31]. In SAFEGUARD, excretion of 8-oxodG was not changed in the liraglutide group [2.8 (- 8.51; 15.49) %, p = 0.62] but a significant decline was demonstrated in the placebo group [12.6 (- 21.3; 3.1) %, p = 0.02], resulting in a relative increase in the liraglutide group compared to placebo (0.16 nmol/mmol creatinine, SE 0.07, p = 0.02). Treatment with sitagliptin compared to placebo demonstrated no significant difference (0.07 (0.07) nmol/mmol creatinine, p = 0.34). Nor were any significant differences for urinary excretion of 8-oxoGuo liraglutide vs placebo [0.09 (SE: 0.07) nmol/mmol creatinine, p = 0.19] or sitagliptin vs placebo [0.07 (SE: 0.07) nmol/mmol creatinine, p = 0.35] observed. This post-hoc analysis could not demonstrate a beneficial effect of 12 weeks of treatment with liraglutide or sitagliptin on oxidatively generated modifications of nucleic acid in persons with type 2 diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Diabetes Mellitus, Type 2; Female; Guanosine; Humans; Liraglutide; Male; Middle Aged; Outcome Assessment, Health Care; Oxidative Stress; Sitagliptin Phosphate

To study oxidative stress status of early type 2 diabetic nephropathy (DN) patients with subclinical hypothyroidism (SCH) and to assess effect of L-thyroxine therapy on the oxidative stress in these patients.. It is a randomized double-blind and placebo-controlled trial. A total of 48 patients with early type 2 DN were included as Euthyroid group, and 92 early type 2 DN with SCH were selected and randomly assigned to L-thyroxine treatment group (LT4 group) and placebo group (SCH group). Changes in urinary albumin excretion rate (UAER), serum malondialdehyde (MDA), superoxide dismutase (SOD) activity, urine 8-hydroxyl deoxyguanosine (8-OHdG), serum creatinine, estimated glomerular filtration rate, and lipid profile before and after 24 weeks of follow-up were examined and compared.. The levels of UAER, MDA, 8-OHdG were higher, while the SOD activity was lower in DN patients with SCH than in DN patients (p < 0.05 for all). In the LT4 group, the levels of UAER, MDA, 8-OHdG decreased significantly (p < 0.05) to levels no longer different from the Euthyroid group. The SOD activity increased significantly. But in SCH group, the levels of mAlb, MDA, 8-OHdG were greater after 24 weeks of follow-up and greater than patients in the Euthyroid group. SOD activity decreased significantly after 24 weeks in the SCH group (p < 0.05).. Oxidative stress is greater in the DN patients with SCH, and SCH may exacerbate kidney injury in early DN patients. The LT4 treatment may decrease the oxidative stress and attenuate renal injury in DN patient with SCH.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Albuminuria; Creatinine; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypothyroidism; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Superoxide Dismutase; Thyroxine

Cardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). Although glycaemic control reduces microvascular complications, the effect of intensive treatment strategies or individual drugs on macrovascular diseases is still debated. RNA oxidation is associated with increased mortality in patients with T2D. Inspired by animal studies showing effect of a sodium-glucose cotransporter-2 (SGLT-2) inhibitor (empagliflozin) on oxidative stress and a recent trial evaluating empagliflozin that demonstrated improved cardiovascular outcomes in patients with T2D at high risk of cardiovascular events, we hypothesise that empagliflozin lowers oxidative stress.. In this randomised, double-blinded and placebo-controlled study, 34 adult males with T2D will be randomised (1:1) to empagliflozin or placebo once daily for 14 days as add-on to ongoing therapy. The primary endpoints will be changes in 24-hour urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) determined before and after intervention (by ultra-performance liquid chromatography tandem mass-spectrometry). Additionally, fasting levels of malondialdehyde (MDA) will be determined in plasma before and after intervention (by high-performance liquid chromatography). Further, the plasma levels of iron, transferrin, transferrin-saturation, and ferritin are determined to correlate the iron metabolism to the markers of oxidative modifications.. The study protocol has been approved by the Regional Committee on Biomedical Research Ethics (approval number H-16017433), the Danish Medicines Agency, and the Danish Data Protection Agency, and will be carried out under the surveillance and guidance of the GCP unit at Bispebjerg Frederiksberg Hospital, University of Copenhagen in compliance with the ICH-GCP guidelines and in accordance with the Declaration of Helsinki. The results of this study will be presented at national and international conferences, and submitted to a peer-reviewed international journal with authorship in accordance with Internation Committee of Medical Journal Editors (ICMJE) Recommendations state.. Study name: EMPOX; Pre-results: clinicaltrials.gov (NCT02890745). Protocol version 5.1 - August, 2016.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Aged; Benzhydryl Compounds; Biomarkers; Denmark; Deoxyguanosine; Diabetes Mellitus, Type 2; Double-Blind Method; Glucosides; Guanosine; Humans; Hypoglycemic Agents; Logistic Models; Male; Middle Aged; Nucleic Acids; Oxidative Stress; Research Design; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Young Adult

This study aimed to examine the effects of hesperidin supplement on the glycemic parameters, oxidative DNA damage, and lipid peroxidation in patients with type 2 diabetes. Sixty-four patients were randomly allocated to receive 500 mg/day hesperidin or placebo capsules for 6 weeks. Data on glycemic parameters, total antioxidant capacity (TAC), 8-hydroxydeoxyguanosine (8-OHDG), and malondialdehyde (MDA) were collected at the baseline and at the end of the study. In hesperidin group, TAC increased (0.74 ± 0.16 vs. 0.82 ± 0.18), while serum froctoseamin (5.79 ± 5.86 vs. 5.01 ± 4.95; p = 0.001), 8-OHDG (14.32 ± 6.4 vs. 11.00 ± 7.0; p = 0.000), and MDA (5.78 ± 1.76 vs. 4.60 ± 0.75; p = 0.000) decreased in comparison with the baseline values. There was a significant difference in percent change of TAC (13.35 ± 19.21 vs. 3.13 ± 10.02; p = 0.043), froctoseamin (-10.10 ± 16.84 vs. 4.27 ± 34.646), 8-OHDG (-25.11 ± 28.23 vs. 8.69 ± 35.41; p = 0.000), and MDA (-16.46 ± 18.04 vs. -1.82 ± 22.63; p = 0.007) between hesperidin and control groups following intervention in adjusted models. These results suggest that hesperidin may improve TAC and alleviate serum froctoseamin, 8-OHDG, and MDA levels in type 2 diabetes. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Blood Glucose; Deoxyguanosine; Diabetes Mellitus, Type 2; Diet; Dietary Supplements; DNA Damage; Double-Blind Method; Female; Hesperidin; Humans; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Oxidative Stress

Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects, we performed a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1α (SDF-1α) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Chemokine CXCL12; Cross-Over Studies; Cyclic AMP; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Male; Middle Aged; Piperidines; Pyrazines; Receptor, Angiotensin, Type 1; Sitagliptin Phosphate; Triazoles; Up-Regulation; Uracil

We have previously demonstrated the increased salt sensitivity of blood pressure (BP) in diabetic patients with early nephropathy. Here, we examined the effects of an angiotensin II receptor blocker (ARB) on salt sensitivity and renal oxidative stress or nitric oxide (NO) in those patients.. Type 2 diabetic patients with (n = 6) and without (n = 6) microalbuminuria were studied on a high-salt diet for one week and on a salt-restricted diet for one week. The study was repeated in the patients with microalbuminuria during treatment with an ARB, valsartan (80 mg/day). Salt sensitivity was assessed from the BP/sodium excretion curve. Urinary excretion rates of NOx, 8-hydroxy-2-deoxyguanosine as a marker of oxidative stress, and plasma tetrahydrobiopterin as a cofactor for NO synthase were measured.. Compared with diabetic patients without microalbuminuria, patients with microalbuminuria showed greater salt sensitivity and lower urinary excretion of NOx. In the patients with microalbuminuria, treatment with valsartan reduced salt sensitivity in association with increased NOx excretion, reduced 8-hydroxy-2,-deoxyguanosine excretion, and increased plasma tetrahydrobiopterin levels.. These data support the hypothesis that ARBs reduce the salt sensitivity of BP by decreasing renal oxidative stress and restoring NO activity in diabetic patients with microalbuminuria.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Angiotensin Receptor Antagonists; Biopterins; Blood Pressure; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Hemodynamics; Humans; Kidney; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Receptors, Angiotensin; Sodium Chloride, Dietary; Tetrazoles; Valine; Valsartan

Type 2 diabetes is a multifactorial disease associated with increased oxidative stress, which may lead to increased DNA damage. The aim of this study was to investigate the effect of a healthy diet on DNA oxidation in diabetics and nondiabetics.. Seventy-six diabetic and 21 nondiabetic individuals participated in this study. All subjects received information about the benefits of a healthy diet, while subjects randomly assigned to the intervention group received additionally 300 g of vegetables and 25 mL PUFA-rich plant oil per day. DNA damage in mononuclear cells (Comet Assay), urinary excretion of 8-oxo-7-hydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and glycated hemoglobin (HbA1c) were measured at baseline, after 4, 8 (end of intervention), and 16 weeks. The intervention with vegetables and PUFA-rich oil led to a significant increase in plasma antioxidant concentrations. Diabetic individuals of the intervention group showed a significant reduction in HbA1c and DNA strand breaks. Levels of HbA1c were also improved in diabetics of the information group, but oxidative damage to DNA was not altered. Urinary 8-oxodG and 8-oxoGuo excretion remained unchanged in both groups.. This study provides evidence that a healthy diet rich in antioxidants reduces levels of DNA strand breaks in diabetic individuals.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Antioxidants; Comet Assay; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Fatty Acids, Unsaturated; Female; Glycated Hemoglobin; Glycemic Index; Guanosine; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Oxidative Stress; Patient Compliance; Plant Oils; Vegetables

Despite well-controlled blood glucose levels, diabetic complications still inevitably take place via several mechanisms including excessive generation of free radicals in patients who suffer from diabetes mellitus (DM). A randomized double-blind placebo-controlled clinical trial to investigate the effectiveness of oral supplementation of DL-alpha-lipoic acid (ALA) on glycemic and oxidative status in DM patients was conducted. Thirty eight outpatients with type 2 DM were recruited and randomly assigned to either placebo or treatment in various doses of ALA (300, 600, 900, and 1200 mg/day) for 6 months. Following the treatment, all subjects were evaluated for glucose status and oxidative biomarkers. Results showed that fasting blood glucose, HbA1c trended to decrease in a dose-dependent manner. Increase of urinary PGF2α-Isoprostanes (F2α-IsoP) was noted in placebo but not ALA-treated groups, indicating possible suppressing action of ALA on lipid peroxidation in DM subjects. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) levels, however, were similar in both placebo and ALA groups as well as urinary microalbumin and serum creatinine. Safety evaluation was monitored and treatment was found to be well tolerated despite some minor side effects. Results from this study reflected the benefits of ALA in glucose status with slight efficiency on oxidative stress-related deterioration in DM patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Adult; Antioxidants; Biomarkers; Blood Glucose; Creatinine; Deoxyguanosine; Diabetes Mellitus, Type 2; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; F2-Isoprostanes; Female; Follow-Up Studies; Glycated Hemoglobin; Glycemic Index; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Thioctic Acid; Treatment Outcome

This open-label, randomized, parallel-controlled study investigated the effects of the direct renin inhibitor aliskiren on 64 hypertensive type 2 diabetic patients with chronic kidney disease (CKD) and stable glycemic control who were already being treated with fixed doses of antihypertensive agents over a 24-week period. These agents were 80 mg of the angiotensin II receptor blocker (ARB) telmisartan and 5 mg of the calcium channel blocker (CCB) amlodipine. Patients were randomly assigned to two groups: the aliskiren group, receiving 150 mg per day aliskiren, which was increased to 300 mg per day (n=32), and the CCB group, which received an increased dose (7.5 mg per day) of amlodipine that was increased to 10 mg per day (n=32). Urinary albumin excretion and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) were investigated in each group. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, but percent changes of urinary albumin/creatinine ratios, 8-OHdG and L-FABP levels decreased significantly in the aliskiren group compared with the CCB group. Plasma aldosterone levels were significantly decreased in the aliskiren group, which correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of aliskiren to the maximal recommended dose of ARB and usual dose of amlodipine is more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than increasing the dose of amlodipine.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Albuminuria; Aldosterone; Amides; Amlodipine; Angiotensin II Type 2 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Calcium Channel Blockers; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Fatty Acid-Binding Proteins; Female; Fumarates; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Male; Middle Aged; Renin; Telmisartan; Young Adult

Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress in patients without arteriosclerosis. This study aimed to evaluate (1) whether an ARB (candesartan) decreases values for inflammatory parameters in hypertensive patients with type 2 diabetes mellitus of long duration accompanied by arteriosclerosis and (2) whether there any predictors of which patients would receive the benefits of organ protection by candesartan.. We administered candesartan therapy (12 mg daily) for 6 months and evaluated whether there was improvement in serum inflammatory parameters high molecular weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1) in serum and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of lowering of blood pressure and inflammatory factors and the relationship between pulse pressure and inflammatory factors. Finally, we analyzed predictive factors in patients who received the protective benefit of candesartan.. After 6 months of treatment, significant improvements from baseline values were observed in all patients in HMW-ADN and PAI-1 but not in Hs-CRP, VCAM-1 and U-8-OHdG. Multilinear regression analysis was performed to determine which factors could best predict changes in HMW-ADN and PAI-1. Changes in blood pressure were not significant predictors of changes in metabolic factors in all patients. We found that the group with baseline pulse pressure <60 mmHg had improved HMW-ADN and PAI-1 values compared with the group with baseline pulse pressure ≥ 60 mmHg. These results suggest that pulse pressure at baseline could be predictive of changes in HMW-ADN and PAI-1.. Candesartan improved inflammatory parameters (HMW-ADN and PAI-1) in hypertensive patients with type 2 diabetes mellitus of long duration independent of blood pressure changes. Patients with pulse pressure <60 mmHg might receive protective benefits by candesartan.. UMIN000007921.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adiponectin; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Pressure; C-Reactive Protein; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Inflammation; Inflammation Mediators; Japan; Linear Models; Male; Middle Aged; Multivariate Analysis; Plasminogen Activator Inhibitor 1; Prospective Studies; Tetrazoles; Time Factors; Treatment Outcome; Vascular Cell Adhesion Molecule-1

Bezafibrate and fenofibrate show different binding properties against peroxisome proliferator-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers.. An open, randomized, four-phased crossover study using 400 mg of bezafibrate or 200mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61 ± 16 years, body mass index (BMI) 26 ± 3 kg/m², total cholesterol (TC) 219 ± 53 mg/dL, triglyceride (TG) 183 ± 83 mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46 ± 8 mg/dL, fasting plasma glucose 133 ± 31 mg/dL and HbA1c 6.2 ± 0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks.. Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p<0.001) in all patients except for one subject when treated with bezafibrate. Both bezafibrate and fenofibrate caused reductions in TG (-38.3%, p<0.001 vs. -32.9%, p<0.01) and increases in HDL-C (+18.0%, p<0.001 vs. +11.7%, p<0.001). Fenofibrate significantly reduced serum cholesterol levels (TC, -11.2%, p<0.01; non-HDL-C, -17.3%, p<0.01; apolipoprotein B, -15.1%, p<0.01), whereas bezafibrate significantly improved glucose tolerance (insulin, -17.0%, p<0.05) and metabolic markers (γ-GTP, -38.9%, p<0.01; adiponectin, +15.4%, p<0.05; urine 8-OHdG/Cre, -9.5%, p<0.05).. Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adipokines; Adiponectin; Adult; Aged; Bezafibrate; Body Mass Index; Cholesterol; Cholesterol, HDL; Cross-Over Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Fenofibrate; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Peroxisome Proliferator-Activated Receptors; Proprotein Convertase 9; Proprotein Convertases; Serine Endopeptidases; Time Factors; Triglycerides

Growing evidence indicates that oxidative stress induced by excessive superoxide has a central role in the pathogenesis of diabetic nephropathy (DN). Telmisartan, one of the currently available angiotensin II type 1 receptor blockers (ARBs), has been shown to exert a more powerful proteinuria (albuminuria) reduction in patients with DN, but whether the prominent renoprotective effect of telmisartan is mediated through enhancing antioxidant defense capacity and reducing oxidative stress has not been fully elucidated. The present study first revealed that the serum activity of superoxide dismutase (SOD) responsible for superoxide removal is reduced in the DN stage of microalbuminuria, but not in normoalbuminuria in type 2 diabetic patients. We next examined the alteration of SOD and oxidative stress following an 8-week treatment with telmisartan (40 mg per day) in 12 type 2 diabetic patients with microalbuminuria. Interestingly, the telmisartan treatment not only reduced the circulating levels of two oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine (NT), but also enhanced serum SOD activity. Notably, a significant correlation was observed between the increase in serum SOD activity and the reduction in albuminuria. We further compared the anti-oxidative effect of telmisartan with that of losartan, another member of the ARB class, by implementing an 8-week interval crossover treatment with these ARBs in another 12 microalbuminuric type 2 diabetic patients. The patients showed higher serum SOD activity, and lower circulating levels of 8-OHdG and NT, during treatment with telmisartan than with losartan. These results suggest that telmisartan has a more potent antioxidative effect through its ability to enhance SOD activity in type 2 diabetic patients with microalbuminuria.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Antioxidants; Benzimidazoles; Benzoates; Cross-Over Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Japan; Losartan; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Superoxide Dismutase; Telmisartan; Tyrosine

Glimepiride, a third generation sulfonylurea (SU), is known to have extrapancreatic effects, but its vascular effect is unclear. We investigated the efficacy of glimepiride in improving arterial stiffness assessed by cardio-ankle vascular index (CAVI) in type 2 diabetic patients, compared with glibenclamide, a conventional SU.. Forty type 2 diabetic patients were randomly assigned to two groups. One group was administered glimepiride 1.5 mg/day, and the other group was administered glibenclamide 1.25 mg/day for 6 months.. No significant difference in hypoglycaemic effect was observed between two groups. CAVI significantly decreased only in glimepiride group (9.4 ± 1.4→8.9 ± 0.8, p < 0.05). Decrease in CAVI was greater in glimepiride group than in glibenclamide group (-0.50 ± 0.98 vs. -0.04 ± 0.57, p = 0.048). Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) decreased in glimepiride group and increased in glibenclamide group, and the changes were significantly different between groups (-1.5 ± 3.5 vs. + 1.8 ± 3.6, p = 0.009); whereas serum lipoprotein lipase mass increased in glibenclamide group and decreased in glibenclamide group, and the changes tended to be different between groups (+ 2.1 ± 19.1 vs. -7.4 ± 19.2, p = 0.096). Change in urinary 8-OHdG was a significant independent predictor for change in CAVI in all subjects.. These results suggest that glimepiride improves CAVI compared with glibenclamide. Reduced oxidative stress and improved insulin resistance may contribute to the improvement of CAVI by glimerpiride.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Ankle; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Sulfonylurea Compounds; Vascular Resistance; Vascular Stiffness

The aim of the present study was to determine whether red or white wine affects urinary protein, 8-hydroxydeoxyguanosine (8-OHdG), and liver-type fatty acid-binding protein (L-FABP) excretion in type 2 diabetic nephropathy patients. Twenty-four type 2 diabetes mellitus patients with nephropathy were randomly allocated to drink a 118-mL (4-oz) glass of red wine (n = 12, group A) or white wine (n = 12, group B) daily for 6 months. Twelve type 2 diabetes mellitus patients with nephropathy who did not drink any wines served as control subjects (group C). Serum creatinine, 24-hour creatinine clearance, hemoglobin A(1c), urinary protein, urinary 8-OHdG, and urinary L-FABP were measured before and 3 and 6 months after the start of the study. In groups A, B, and C, serum creatinine, 24-hour creatinine clearance, and hemoglobin A(1c) changed little during the experimental period. However, urinary protein, 8-OHdG, and L-FABP excretions were significantly decreased at 3 (P < .05) and 6 months (P < .01) compared with the baseline values in group A. In contrast, these markers changed little during the experimental period in groups B and C. Thus, these urinary markers were significantly lower in group A than in groups B and C at 3 and 6 months. These results suggest that red wine is renoprotective whereas white wine has no such effect in type 2 diabetes mellitus patients with nephropathy. The renoprotective effect of red wine may be due in part to its ability to reduce oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Antihypertensive Agents; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fatty Acid-Binding Proteins; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Oxidative Stress; Proteinuria; Time Factors; Wine

The three types of calcium channel blocker (CCB), L-, T- and N-type, possess heterogeneous actions on endothelial function and renal microvascular function. In the present study, we evaluated the effects of two CCBs, efonidipine and amlodipine, on renal function and arterial stiffness.. Forty type 2 diabetic patients with hypertension and nephropathy receiving angiotensin receptor II blockers were enrolled and randomly divided into two groups: the efonidipine group was administered efonidipine hydrochloride ethanolate 40 mg/day and the amlodipine group was admin-istered amlodipine besilate 5 mg/day for 12 months. Arterial stiffness was evaluated by the cardio-ankle vascular index (CAVI).. Changes in blood pressure during the study were almost the same in the two groups. Sig-nificant increases in serum creatinine and urinary albumin and a significant decrease in the esti-mated glomerular filtration rate were observed in the amlodipine group, but not in the efonidipine group. On the other hand, significant decreases in plasma aldosterone, urinary 8-hydroxy-2'-deoxy-guanosine and CAVI were observed after 12 months in the efonidipine group, but not in the amlo-dipine group.. These results suggest that efonidipine, which is both a T-type and L-type calcium chan-nel blocker, has more favorable effects on renal function, oxidative stress and arterial stiffness than amlodipine, an L-type calcium channel blocker.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aldosterone; Amlodipine; Arteries; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Glycated Hemoglobin; Humans; Hypertension; Kidney; Lipids; Male; Middle Aged; Nitrophenols; Organophosphorus Compounds

A novel device has been developed for measuring the cardio-ankle vascular index (CAVI) as an indicator of arterial stiffness. In this study, we evaluated the effect of pitavastatin on CAVI in type 2 diabetic patients.. Forty-five type 2 diabetes mellitus patients with low-density lipoprotein cholesterolemia were enrolled and treated with pitavastatin 2 mg/day for 12 months. Before and after pitavastatin administration, HbA1c, serum lipids, serum malondialdehyde-LDL (MDA-LDL), urinary 8-hydroxy- 2'-deoxyguanosine (8-OHdG) and CAVI were measured.. After pitavastatin treatment for 12 months, significant decreases in 8-OHdG, MDA-LDL and CAVI were observed. DeltaCAVI significantly correlated with DeltaMDA-LDL.. In type 2 diabetic patients, pitavastatin may have an oxidative stress-reducing effect, especially in a state of enhanced oxidative stress, and CAVI may be useful as a routine test for the diagnosis and therapeutic monitoring of atherosclerosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Ankle; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Malondialdehyde; Middle Aged; Pulsatile Flow; Quinolines

Recently, a novel device for measuring the cardio-ankle vascular index (CAVI) as an arterial stiffness parameter has been developed. In this study, we evaluated the effect of angiotensin II receptor blocker (ARB) and calcium channel (Ca) blocker on CAVI in type 2 diabetic patients with hypertension.. Seventy type 2 diabetes mellitus patients with hypertension were enrolled and randomly divided into two groups. One group was administered olmesartan medoxomil 20 mg/day [DOSAGE ERROR CORRECTED] for 12 months (ARB group), and the other group was administered amlodipine besilate 5 mg/day for 12 months (Ca blocker group).. In the ARB group, a significant decrease in CAVI was observed after 12 months; however, no significant change in CAVI was observed in the Ca blocker group although changes in blood pressure were almost the same. By simple regression analyses, CAVI changes correlated positively with 8-OHdG changes.. Olmesartan, an ARB, improved arterial stiffness more than amlodipine, and this effect might be due to not only the blood pressure-lowering effect but also to reducing the potential of oxidative stress recognized in olmesartan.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Ankle; Antihypertensive Agents; Body Weight; Calcium Channel Blockers; Deoxyguanosine; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypertension; Imidazoles; Lipids; Male; Middle Aged; Tetrazoles

To clarify whether probucol and statins suppress oxidative stress in diabetic patients, we studied the effects of probucol and the statin atorvastatin on urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) levels in diabetics with hypercholesterolemia. A randomized, open study was performed on a total of 36 patients with type 2 diabetes and hypercholesterolemia. The patients were randomly assigned to a probucol group (500 mg/day, n = 18) or an atorvastatin group (10 mg/day, n = 18). During three months, total- and LDL-cholesterol decreased significantly in both groups. LDL-cholesterol was significantly lower in the atorvastatin group than probucol group. HDL-C decreased significantly in the probucol group and did not change in the atorvastatin group. 8-OHdG decreased significantly in both groups after 3 months; 12.4 +/- 7.5 to 8.1 +/- 4.2 ng/mg/Cr in the atorvastatin group (p < 0.05) and 12.3 +/- 8.8 to 6.8 +/- 2.6 ng/mg/Cr in the probucol group (p < 0.05), and these changes did not differ significantly between the two groups. But, in patients with high 8-OHdG levels (more than 10 ng/mg/Cr) before administration, urinary 8-OHdG decreased significantly from 19.5 +/- 4.9 to 9.2 +/- 3.4 ng/mg Cr (p < 0.01) in the atorvastatin group, and from 19.7 +/- 8.2 to 6.67 +/- 2.2 ng/mg Cr (p < 0.01) in the probucol group. Urinary 8-OHdG was significantly lower in the probucol group than in the atorvastatin group after the second and third months of administration (p < 0.05). These results suggest that while probucol and atorvastatin both reduce systemic oxidative stress, probucol might be the more useful in patients with strong oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Anticholesteremic Agents; Antioxidants; Atorvastatin; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Heptanoic Acids; Humans; Hypercholesterolemia; Male; Middle Aged; Oxidative Stress; Probucol; Pyrroles; Treatment Outcome

The factors determining the course of glomerular filtration rate (GFR) and albumin excretion rate (AER) and the expression of mRNA of slit diaphragm (SD) and podocyte proteins in microalbuminuric, hypertensive type II diabetic patients are not fully understood. GFR, AER, and SD protein mRNA were studied in 86 microalbuminuric, hypertensive, type II diabetics at baseline and after 4-year random double-blind treatment either with 40 mg simvastatin (Group 1) or with 30 g cholestyramine (Group 2) per day. Both groups had at baseline a GFR decay per year in the previous 2-4 years of 3 ml/min/1.73 m(2). Both Groups 1 and 2 showed a significant decrease of low-density lipoprotein cholesterol levels after simvastatin and cholestyramine treatment (P<0.01). No change from base line values was observed as for hs-C-reactive protein and interleukin-6. A significant decrease of 8-hydroxydeoxyguanosine urinary excretion was observed after simvastatin treatment. GFR did not change from baseline with simvstatin, whereas a decrease was observed with cholestyramine treatment (simvastatin vs cholestyramine: -0.21 vs -2.75 ml/min/1.73 m(2), P<0.01). AER decreased in Group 1 (P<0.01), but not in Group 2 patients. Real-time polymerase chain reaction measurement of mRNA SD proteins (CD2AP, FAT, Actn 4, NPHS1, and NPHS2) significantly increased in kidney biopsy specimens after simvastatin, but not cholestyramine treatment. Simvastatin, but not cholestyramine, 4-year treatment maintains steady patterns of GFR, and improves AER and expression of SD proteins in type II diabetes, despite similar hypocholesterolemic effects in circulation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albumins; Albuminuria; Anticholesteremic Agents; Cholestyramine Resin; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Kidney Glomerulus; Lipids; Male; Middle Aged; Podocytes; Proteins; RNA, Messenger; Simvastatin

Previous researches have assessed the relationships of urinary arsenic metabolism with type 2 diabetes (T2D) and glucose-insulin homeostasis, but the results were controversial, and potential mechanisms remain largely unclear.. This study aimed to investigate the cross-sectional and longitudinal associations of urinary arsenic metabolism with T2D prevalence and glucose changes in relatively higher arsenic exposure, and further to evaluate the underlying roles of oxidative damage in these relationships.. We included 796 participants at baseline, among them 509 participants were followed up after 2 years. Logistic regression model and leave-one-out approach were applied to evaluate the associations of arsenic metabolism with T2D prevalence. Linear mixed model was conducted to estimate the relationship of arsenic metabolism with glycemic changes over two years. The associations between arsenic metabolism and indicators of oxidative stress were assessed with a linear regression model. We further performed mediation analysis to investigate the role of oxidative stress in the associations of arsenic metabolism with 2-year change of glucose levels.. Higher urinary MMA% increased T2D prevalence and baseline glucose levels. MMA% was positively associated with 2-year change of glucose levels. Moreover, we observed significant dose-response relationship between MMA% and 8-hydroxy-2-deoxyguanosine (8-OHdG). However, the mediating role of 8-OHdG in the association of MMA% and 2-year change of glucose levels was not observed in this population.. In this population exposure to relatively higher arsenic levels, higher MMA% contributed to increased T2D prevalence and glucose homeostasis disorder. Arsenic metabolism also affected oxidative stress levels, especially 8-OHdG. Further studies are required to investigate the potential mechanisms.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Arsenic; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Environmental Exposure; Glucose; Homeostasis; Humans

To explore the protective effect and molecular mechanism of electroacupuncture (EA) preconditioning on renal injury in type 2 diabetic rats.. Fifty male Wistar rats were randomly divided into control, model, EA, EA+inhibitor, and inhibitor groups, with 10 rats in each group. Diabetes model was established by high fat and high glucose diet and intraperitoneal injection of streptozotocin (40 mg/kg). EA (2 Hz, 1 mA) preconditioning was applied to "Guanyuan" (CV4), "Zhongwan" (CV12), bilateral "Zusanli" (ST36) and "Fenglong" (ST40) for 15 min, once every other day for 8 weeks. Rats of the inhibitor and EA+inhibitor groups were given intraperitoneal injection of 3-TYP (50 mg/kg) once every other day for a total of 3 times. The body weight, kidney mass, and renal index were recorded. The contents of urine microalbumin (ALB), 24 h urine 8-hydroxydeoxyguanosine (8-OHdG) and activities of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), glutathione glycine peroxidase (GSH-Px) in kidney were detected by ELISA. The activities of mitochondrial respiratory chain enzyme complex (RCCⅠ-RCCⅣ) in kidney were detected using spectrophotometric method. HE staining, Masson staining and transmission electron microscopy were used to observe the changes of renal structure. The protein and mRNA expressions of silent information regulator 3 (Sirt3), manganese superoxide dismutase (MnSOD) in kidney were detected by Western blot and quantitative real-time PCR, respectively.. After modeling and compared with the control group, the contents of ALB, the renal index, activity of ROS and content of 8-OHdG, and the renal collagen volume fraction (CVF) were increased (. EA preconditioning can increase the expressions of renal Sirt3 and MnSOD in type 2 diabetic rats, thereby reducing the oxidative stress response and protecting the kidneys.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acupuncture Points; Animals; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Electroacupuncture; Glucose; Glutathione; Glutathione Peroxidase; Glycine; Kidney; Male; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; RNA, Messenger; Sirtuin 3; Streptozocin; Superoxide Dismutase

The link between zinc exposure and glucose metabolism or the development of type 2 diabetes (T2D) is controversial, and underlying mechanisms are unclear. This study aimed to explore the associations of zinc exposure with glucose-insulin homeostasis traits and the long-term effects of zinc on the development of T2D, and further to estimate the potential roles of inflammation and oxidative damage in such relationships. We investigated 3890 urban adults from the Wuhan-Zhuhai cohort, and followed up every three years. Mixed linear model was applied to estimate dose-response associations between urinary zinc and glycemia traits [fasting plasma insulin (FPI), fasting plasma glucose (FPG), insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR), and β-cell dysfunction (homeostasis model assessment of β-cell function, HOMA-B)], as well as zinc and biomarkers for systemic inflammation (C-reactive protein) and oxidative damage (8-isoprostane and 8-hydroxy-2'-deoxyguanosine). Logistic regression model and Cox regression model were conducted to evaluate the relationships between urinary zinc and prevalence and incidence of T2D, respectively. We further performed mediation analysis to assess the roles of inflammation and oxidative damage biomarkers in above associations. At baseline, we observed significant dose-response relationships of elevated urinary zinc with increased FPI, FPG, HOMA-IR, and T2D prevalence and decreased HOMA-B, and such associations could be strengthened by increased C-reactive protein, 8-isoprostane, and 8-hydroxy-2'-deoxyguanosine. Elevated C-reactive protein significantly mediated 9.09% and 17.67% of the zinc-related FPG and HOMA-IR increments, respectively. In longitudinal analysis, a significantly positive association between urinary zinc and T2D incidence was observed among subjects with persistent high urinary zinc levels when compared with those with persistent low zinc levels. Our results suggested that high levels of zinc exposure adversely affected on glucose-insulin homeostasis and further contributed to increased risk of T2D cross-sectionally and longitudinally. Moreover, inflammatory response might play an important role in zinc-related glucose metabolic disorder.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Blood Glucose; C-Reactive Protein; China; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Homeostasis; Humans; Inflammation; Insulin; Insulin Resistance; Oxidative Stress; Zinc

Sericin could be degraded well into low-molecular-weight sericin (SS) through a novel and environmentally friendly recycling process using an ultrasonically degumming method in Ca(OH)

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animal Feed; Animals; Blood Glucose; Body Weight; Bombyx; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Homeostasis; Insulin; Insulin Resistance; Lipids; Liver; Male; Organ Size; Oxidative Stress; Pancreas; Peptides; Rats; Rats, Sprague-Dawley; Sericins

Little is known about whether mitochondria 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of mitochondrial DNA (mtDNA) oxidative damage, contributes to the development of coronary artery disease (CAD) in diabetic patients. Here, we explored the associations of mtDNA 8-OHdG in leukocytes with obstructive CAD, coronary stenosis severity, cardiovascular biomarkers, and 1-year adverse outcomes after coronary revascularization in patients with type 2 diabetes mellitus (T2DM).. In a total of 1920 consecutive patients with T2DM who underwent coronary angiography due to symptoms of angina or angina equivalents, the presence of obstructive CAD, the number of diseased vessels with ≥ 50% stenosis, and modified Gensini score were cross-sectionally evaluated; the level of mtDNA 8-OHdG was quantified by quantitative PCR. Then, 701 of 1920 diabetic patients who further received coronary revascularization completed 1-year prospective follow-up to document major adverse cardiovascular and cerebral events (MACCEs). In vitro experiments were also performed to observe the effects of mtDNA oxidative damage in high glucose-cultured human umbilical vein endothelial cells (HUVECs).. Cross-sectionally, greater mtDNA 8-OHdG was associated with increased odds of obstructive CAD (odds ratio [OR] 1.38, 95% CI confidence interval 1.24-1.52), higher degree of coronary stenosis (number of diseased vessels: OR 1.29, 95% CI 1.19-1.41; modified Gensini scores: OR 1.28, 95% CI 1.18-1.39), and higher levels of C-reactive protein (β 0.18, 95% CI 0.06-0.31) after adjusting for confounders. Sensitivity analyses using propensity score matching yielded similar results. Stratification by smoking status showed that the association between mtDNA 8-OHdG and obstructive CAD was most evident in current smokers (P. Greater mtDNA 8-OHdG in leukocytes may serve as an independent risk factor for CAD in patients with T2DM.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Cells, Cultured; China; Coronary Artery Disease; Coronary Stenosis; Cross-Sectional Studies; Diabetes Mellitus, Type 2; DNA Damage; DNA, Mitochondrial; Female; Human Umbilical Vein Endothelial Cells; Humans; Leukocytes; Male; Middle Aged; Myocardial Revascularization; Oxidative Stress; Prospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome

The role of exendin-4 in brown adipose tissue (BAT) activation was not very clear. This study is to verify the role of BAT involved in renal benefits of exendin-4 in diabetes mellitus (DM).. In vivo, C57BL/6 mice were randomly divided into nondiabetic (control) and diabetic groups (DM). The diabetic mice were randomized into a control group (DM-Con), BAT-excision group (DM+Exc), exendin-4-treated group (DM+E4), and BAT-excision plus exendin-4-treated group (DM+Exc+E4). The weight, blood glucose and lipids, 24 h urine albumin and 8-OH-dG, and renal fibrosis were analyzed. In vitro, we investigated the role of exendin-4 in the differentiation process of 3T3-L1 and brown preadipocytes and its effect on the rat mesangial cells induced by oleate.. The expressions of UCP-1, PGC-1. Exendin-4 could decrease the renal lipid deposit and improve diabetic nephropathy via activating the renal AMPK pathway independent of BAT activation.

Topics: 3T3-L1 Cells; 8-Hydroxy-2'-Deoxyguanosine; Adenylate Kinase; Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Albuminuria; Animals; Blood Glucose; Blotting, Western; Body Weight; CD36 Antigens; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Exenatide; Fibrosis; Gene Expression; Incretins; Kidney; Lipase; Mesangial Cells; Mice; Mice, Inbred C57BL; Myofibroblasts; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Random Allocation; Rats; Real-Time Polymerase Chain Reaction; Triglycerides; Uncoupling Protein 1

Diabetic retinopathy (DRP) is the formation of edema and small vessels in the retina due to high blood glucose levels. Asprosin is a hormone that stimulates the release of glucose from the liver into the circulation. Considering the relationship between oxidative stress and DRP, our study aimed to determine the levels of the oxidative stress markers 4-hydroxynonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), as well as asprosin, in the blood and aqueous humor (Aq) of patients with and without DRP.. Thirty patients with single-eye DRP and cataract (DRP + C), 30 patients with diabetes mellitus and cataract without DRP (DM + C), and 30 healthy control (CON) participants were enrolled into this retrospective study. Except for healthy controls, Aq and blood samples were taken from these patients during their cataract operation. Asprosin, 4-HNE, and 8-OHdG concentrations were analyzed using enzyme-linked immunosorbent assays.. In patients with DRP, the levels of asprosin, 4-HNE, and 8-OHdG were significantly higher in both Aq and blood samples compared with the group of patients without DRP.. These findings suggest that the measurement of asprosin, 4-HNE, and 8-OHdG levels may support clinicians in determining the risk of DRP development.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aldehydes; Aqueous Humor; Biomarkers; Cataract; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Female; Fibrillin-1; Humans; Male; Middle Aged; Oxidative Stress; Retrospective Studies

Polycyclic aromatic hydrocarbons (PAHs) are key air pollutants that may contribute to the risk of numerous diseases by inducing inflammation and oxidative stress. Individuals with metabolic disorders may be more susceptible to PAH-induced inflammation and oxidative stress. To test this hypothesis, we designed a panel study involving 60 patients with pre-type 2 diabetes (pre-T2D) and 60 reference participants, and conducted up to seven repeated clinical examinations. Urinary metabolites of PAHs (i.e., OH-PAHs), measured as indicators of total PAH exposure, showed significant associations with markers of respiratory and systemic inflammation, including exhaled nitric oxide, interleukin (IL)-6 in exhaled breath condensate, and blood IL-2 and IL-8 levels and leucocyte count. The most significant effect was on urinary malondiadehyde (MDA), a marker of lipid peroxidation; a onefold increase of OH-PAHs was associated with 9.2-46.0% elevation in MDA in pre-T2D participants and 9.8-31.2% increase in healthy references. Pre-T2D participants showed greater increase in MDA, suggesting that metabolic disorder enhanced the oxidative damage induced by PAH exposure. This study revealed the association between PAH exposure and markers of inflammation and oxidative stress, and the enhanced responses of pre-T2D patients suggested that individuals with metabolic disorders were more susceptible to the adverse health effects of PAH exposure.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 2; Environmental Exposure; Environmental Pollutants; Female; Humans; Inflammation; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Polycyclic Aromatic Hydrocarbons; Prediabetic State

Homalium zeylanicum (Gardner) Benth. is a medicinal plant traditionally used in controlling diabetes which thus far has been assessed by the authors only to a very limited extent.. To fill the research gap in the literature review, we investigated the antihyperglycemic effects of hydro alcohol fraction of bark of H. zeylanicum (HAHZB) by modulating oxidative stress and inflammation in high-fat diet fed-streptozotocin (HFD/STZ)-induced type-2 diabetic rats.. To understand the antioxidant capacity of HAHZB, oxygen radical absorbance capacity (ORAC) and cell-based antioxidant protection in erythrocytes (CAP-e) were performed. GC-MS/MS analysis was performed to assess the bioactive components in HAHZB. HFD/STZ-induced diabetic rats were treated orally with HAHZB (300 and 400 mg/kg) for 28 days. After the end of the experiment, marker profiling and histopathological observation of blood and pancreas were examined. The study also highlights interaction between diabetes, oxidative stress and inflammation by examining the increased pro-inflammatory cytokines e.g. TNF-α and C-reactive protein (CRP) promotes DNA damage e.g. oxidation of 8-hydroxy-2-deoxyguanosine (8-OHdG) in chronic hyperglycaemia.. In ex vivo cellular antioxidant capacity of -CAP-e and ORAC assays, HAHZB showed remarkable free radical scavenging ability in a dose dependent manner. GC-MS/MS analysis identified 28 no. of compounds and out of which, oleic acid (1.03%), ethyl tridecanoate (11.77%), phytol (1.29), 9,12-octadecadienoic acid, methyl ester, (E,E)-(5.97%), stigmasterol (1.30%) and β-sitosterol (2.86%) have antioxidant, anti-inflammatory and anti-diabetic activities. HAHZB 400 mg/kg significantly (p < 0.001) improved the lipid profile (TC: 74.66 ± 0.59, HDL-C: 22.08 ± 0.46, LDL-C: 38.06 ± 0.69, and TG: 171.92 ± 1.01 mg/dL) as well as restoring antidiabetic markers (SG: 209.62 ± 1.05 mg/dL, SI: 15.07 ± 0.11 μIU/mL, HOMA-IR: 7.79 ± 0.04 %, and HbA1C: 8.93 ± 0.03 %) and renal functional markers (Tg: 291.26 ± 0.57 pg/mL, BUN: 23.79 ± 0.14 mg/dL, and Cr: 1.34 ± 0.04 mg/dL) in diabetic rats. Oxidative stress markers of pancreas (MDA: 3.65 ± 0.17 nM TBARS /mg protein, SOD: 3.14 ± 0.28 U/mg protein, CAT: 7.88 ± 0.23 U/mg protein, GSH: 12.63 ± 0.28 µM/g of tissue) were restored to normal as evidenced by histological architecture of pancreatic islet cells. The increased level of pro-inflammatory cytokines and oxidative DNA damage were significantly restored (TNF-α: 54.48 ± 3.19 pg/mL, CRP: 440.22 ± 7.86 ng/mL, and 8-OHdG: 63.65 ± 1.84 ng/mL) by HAHZB in diabetic rats.. The present findings confirm that the presence of bioactive compounds in HAHZB exert therapeutic protective effect by decreasing oxidative, inflammation and pancreatic β-cell damage in oxidative stress induced diabetic rats.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Blood Glucose; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; DNA Damage; Female; Hypoglycemic Agents; Inflammation Mediators; Insulin-Secreting Cells; Male; Oxidative Stress; Plant Bark; Plant Extracts; Rats, Wistar; Salicaceae; Streptozocin

Patients with type 2 diabetes (T2DM) are prone to cardiovascular disease, and both conditions are linked to oxidative DNA damage, which produces 8-hydroxy-2'-deoxyguanosine (8-OHdG). We investigated the impact of 8-OHdG on coronary heart disease (CHD) in elderly patients with T2DM.. We assessed the demographic, clinical, and biochemical characteristics of 147 patients with T2DM (mean age 73.29 ± 8.19 years) with or without CHD. Serum 8-OHdG was detected by enzyme-linked immunosorbent assay. CHD was diagnosed as ≥50% stenosis in at least one main branch of the coronary arteries determined by coronarography, evaluated by Gensini score.. Serum 8-OHdG, number of stenotic branches, and Gensini score were all significantly increased in the CHD group. After adjustment for various factors, the number of stenotic branches and Gensini score remained positively correlated with 8-OHdG levels in the CHD group. Coronary artery lesions were significantly more severe in the CHD compared with the non-CHD group when 8-OHdG levels were >0.523 ng/mL. The number of stenotic branches and Gensini score were significantly independently associated with 8-OHdG levels in patients with T2DM.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Biomarkers; Coronary Disease; Coronary Vessels; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Humans; Oxidative Stress

Studies have shown that liraglutide, or human umbilical cord mesenchymal stem cell (hUC-MSCs) can improve non-alcoholic fatty liver disease (NAFLD). However there have been no studies on the combination of the two used to treat NAFLD. This study aimed to explore the therapeutic effects of combination of liraglutide and hUC-MSCs on liver injury in rats with type 2 diabetes mellitus (T2DM) and NAFLD, and further investigate their mechanisms. Sprague Dawley rats fed by a high fat and high sucrose diet were randomly divided into 5 groups, including NC group, T2DM/NAFLD group, liraglutide group (treated with liraglutide, 200 μg/kg, twice daily for 8 weeks), hUC-MSCs group (treated with hUC-MSCs at the first and fifth weeks), liraglutid＋hUC-MSCs group (treated with liraglutide and hUC-MSCs). Liver tissue was procured for histological examination, real-time qRT-PCR and Western blot analysis. After treatment, liraglutide and hUC-MSCs reduced serum ALT and AST levels, alleviate liver inflammation and improved liver histopathology. The expressions of inflammatory cytokines, TLR4 and NF-κB in serum and liver were significantly inhibited, particularly in the combination treatment group. Eight weeks after liraglutide or hUC-MSCs administration, FBG, HbA1c, HOMA-IR, ALT, AST, Liver wet eight and hepatic TLR4, NF-κB, IL-6, TNF-α, 8-OHdG mRNA and proteins were significantly decreased, and the levels of SOD expression were significantly increased in three treatment groups compared with T2DM/NAFLD group. This study suggests that liraglutide in combination with hUC-MSCs could significantly improve glycolipid metabolism, insulin resistance and liver injury in T2DM/NAFLD rats. Its mechanism may be related to the down-regulation of the TLR4/NF-κB inflammatory pathway and improvement in oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Combined Modality Therapy; Cytokines; Diabetes Mellitus, Type 2; Humans; Inflammation; Liraglutide; Liver; Liver Neoplasms; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; NF-kappa B; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats, Sprague-Dawley; Superoxide Dismutase; Toll-Like Receptor 4; Umbilical Cord

The accelerate loss of skeletal muscle mass, strength, and function, named sarcopenia, is a progressive and generalised skeletal muscle disorder, and it is always associated with increased outcomes including falls, frailty, and disability. Diabetes mellitus is associated with significant muscle and physical complications. We aimed at clarifying the changes and risk factors of skeletal muscle mass and strength in elderly with type 2 diabetes.. The study consisted of patients with type 2 diabetes (. T2DM patients exhibited lower muscle strength compared with the non-T2DM subjects (. These findings suggest that diabetic patients may be more susceptible to sarcopenia at an older age. And it also provides evidences that among elderly with diabetes mellitus, oxidative damage and HCY as well as IGF-1 are important predictors of age-dependent sarcopenia.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Age Factors; Aged; Biomarkers; Body Composition; Case-Control Studies; China; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Hand Strength; Homocysteine; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Muscle, Skeletal; Oxidative Stress; Risk Assessment; Risk Factors; Sarcopenia

Adiponectin and 8-Hydroxy-2'-deoxyguanosine (8-OHdG) are identified as important biomarkers in the pathogenesis process of type 2 diabetes mellitus (T2DM). Whether adiponectin and 8-OHdG have a relation to cognitive decline in the elderly T2DM patients has been poorly understood. The aim of this study was to evaluate the effects of adiponectin and 8-OHdG in the elderly patients with T2DM and to determine the role of adiponectin and 8-OHdG in the cognitive impairment of the elderly patients with T2DM.. 57 individuals were recruited and analyzed , with 26 cases of T2DM without cognitive impairment and 31 cases of T2DM with cognitive impairment. All of them underwent an examination of diabetes scales and blood glucose at different times. A primary diagnosis of diabetes was in line with the diagnosis criteria set by the American Diabetes Association (ADA). Statistical significance was defined as a P-value of less than 0.05.. The variables of sex, age, body mass index (BMI), hypertension, diabetes, metabolic syndrome, lacunar cerebral infarction, smoking and drinking in T2DM patients without cognitive impairment and with cognitive impairment showed no difference according to the univariate analysis exploring each variable separately (p>0.05). A significant difference was observed in the serum levels of adiponectin and 8-OHdG and the scales of MMSE and MoCA (p<0.05). Therefore, it was inferred that there is no correlation between glucose metabolic value and cognitive outcome of T2DM patients. Serum levels of adiponectin and 8-OHdG could act as biomarkers of cognitive impairment degree in the elderly T2DM patients.. Serum levels of adiponectin and 8-OHdG could act as specific and sensitive biomarkers for the early diagnosis and treatment of cognitive impairment in elderly T2DM patients. Serum levels of adiponectin and 8-OHdG have a close relation to the neurological cognitive outcome of the elderly T2DM patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adiponectin; Aged; Biomarkers; Blood Glucose; Body Mass Index; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Male; Middle Aged; Risk Factors

Oxidative stress is a potential biological mediator of the higher rates of psychiatric illness (PI) observed after the onset of type 2 diabetes (T2DM). We investigated validated urinary markers of systemic DNA/RNA damage from oxidation (8-oxodG/8-oxoGuo respectively) as predictors of incident PI in a cohort of 1381 newly diagnosed T2DM patients, who were followed prospectively for a total of 19 years after diagnosis. Psychiatric diagnoses were from Danish national registries. Patients were examined at the time of diagnosis and at a 6-year follow-up. At baseline, 8-oxodG was slightly lower in PI vs. non-PI patients, while at 6-year follow-up, 8-oxoGuo was significantly higher in PI patients. Using Cox proportional hazard models, we found that higher levels of 8-oxodG at 6-year follow-up significantly predicted lower incidence of PI after the adjustment for confounders. In a subgroup analysis, this association was most predominant in minor PIs (unipolar depression and anxiety) compared to major PIs such as schizophrenia and bipolar disorder. These observations indicate that higher levels of systemic oxidative stress are not associated with a higher risk of PI after T2DM onset. Only PI patients treated in hospital care were included in the registries, and the conclusion thus only applies to these individuals.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Denmark; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA; DNA Damage; Female; Follow-Up Studies; Guanosine; Humans; Incidence; Male; Mental Disorders; Middle Aged; Oxidation-Reduction; Oxidative Stress; Proportional Hazards Models; Prospective Studies; Registries; RNA

Sirtuins (SIRTs) is a family of NAD

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Down-Regulation; Female; Humans; Male; Middle Aged; Oxidative Stress; Prediabetic State; Sirtuins

Haptoglobin (Hp) functions as an antioxidant by binding with haemoglobin. We investigated whether serum Hp has a causal effect on macroangiopathy via Mendelian randomization (MR) analysis with common variants of the Hp gene in Chinese patients with type 2 diabetes.. A total of 5687 type 2 diabetes patients were recruited and genotyped for the Hp gene. Clinical features and vascular imaging tests were applied to diagnose macroangiopathy. The association between common Hp genotypes and macroangiopathy was analyzed in the whole population. Serum Hp levels were measured by enzyme-linked immunosorbent assay in a subset of 935 patients. We individually analyzed the correlations among Hp levels, Hp genotypes and macroangiopathy. Further, 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative marker of DNA damage, was examined to evaluate the levels of oxidative stress.. Common Hp genotypes were correlated with macroangiopathy (OR = 1.140 [95% CI 1.005-1.293], P = 0.0410 for the Hp 1 allele). Serum Hp levels were associated with both common Hp genotypes (P = 3.55 × 10. Our study provides evidence for a causal relationship between serum Hp levels and macroangiopathy in Chinese type 2 diabetes patients by MR analysis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Asian People; China; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; DNA Damage; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Haptoglobins; Humans; Male; Mendelian Randomization Analysis; Middle Aged; Oxidative Stress; Phenotype; Risk Factors

8-Oxo-2'-deoxyguanosine (8-oxo-2'-dG) is a biomarker of oxidative DNA damage that is associated with cardiovascular disease and premature mortality in the general population. Although oxidative stress has a proven role in cardiovascular complications in diabetes mellitus, evidence for a relationship between plasma 8-oxo-2'-dG and major cardiovascular outcomes in diabetes mellitus is weak.. A case-cohort study was performed in 3766 participants with prevalent diabetes mellitus in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (ClinicalTrials.gov number NCT00145925). The hazard ratios for mortality and major acute cardiovascular events were derived using Cox regression models. During a median of 5 years of follow-up, 695 (18.4%) participants in this enriched cohort died (including 354 deaths from cardiovascular disease). Individuals with higher levels of 8-oxo-2'-dG were more likely to die. After adjusting for cardiovascular disease risk factors, the hazard ratio for a 1-SD increase in plasma 8-oxo-2'-dG was 1.10 (95% confidence interval, 1.01-1.20;. In adults with type 2 diabetes mellitus, increased levels of 8-oxo-2'-dG are independently associated with all-cause mortality and cardiovascular mortality in adults with longstanding type 2 diabetes mellitus who participated in the ADVANCE trial, consistent with the role of oxidative damage in the development and progression of cardiovascular decompensation in diabetes mellitus.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00145925.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Cardiovascular Diseases; Cause of Death; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Female; Humans; Male; Middle Aged; Oxidative Stress; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Up-Regulation

Uric acid presents different roles in an organism, since it can act as an antioxidant or a pro-oxidant molecule. High serum uric acid levels may cause damage to several structures, including nucleic acids and its components. Therefore, in this study the association between increased serum uric acid concentrations and oxidation of nucleosides was investigated by assessment of urinary 8-hydroxydeoxyguanosine (8-OHdG) in patients with type 2 diabetes (T2D) and in healthy individuals. Urinary 8-OHdG and biochemical parameters were assessed in 61 patients who were initially grouped into 2 groups based on the median serum uric acid levels (<5.3 mg/dL and ≥5.3 mg/dL). Urinary 8-OHdG was higher in patients with T2D and serum uric acid levels ≥5.3 mg/dL, when compared with the patients with serum uric acid levels <5.3 mg/dL; however, co-occurrence of high serum uric acid with high urinary 8-OHdG was not observed in healthy individuals. A significant positive correlation between 8-OHdG and uric acid (r = 0.40, P < 0.01) was observed in patients with T2D. High serum uric acid levels were associated with high urinary 8-OHdG levels in patients with T2D, and this association was independent of gender, hypertension, body mass index, and serum creatinine.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Creatinine; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Nucleosides; Oxidation-Reduction; Uric Acid

Epidemiological studies show that 5-40 % of type 2 diabetes (T2DM) patients have diabetic nephropathy, and oxidative stress is one of several underlying mechanisms. We investigated associations between oxidative stress markers and severity of diabetic nephropathy.. Fifty-nine T2DM patients from the endocrinology outpatient department were included, and their levels of oxidative stress markers were measured. Three groups were determined by their urine albumin-to-creatinine ratio (UACR): group A (UACR < 30 mg/g, n = 22); group B (30 ≤ UACR < 300 mg/g, n = 22); and group C (UACR ≥ 300 mg/g, n = 15).. Vitamin C levels correlated negatively and moderately with serum creatinine (γ = -0.459, p < 0.001), urine albumin (γ. Our results identified several oxidative stress markers that may be clinically important in diabetic nephropathy. Studies with larger sample sizes should be undertaken to confirm these findings.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albuminuria; Antioxidants; Ascorbic Acid; Biomarkers; Creatinine; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Oxidative Stress; Predictive Value of Tests; Prognosis; Prospective Studies; Severity of Illness Index

Over the past decades, attention has been paid to understanding the impact of oxidative stress and related modifications of DNA and RNA on various human health risks. A recent meta-analysis comprising 1915 smokers and 3462 non-smokers found a significantly higher level of DNA oxidation measured as urinary 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) excretion in smokers compared with non-smokers in a healthy population. We aimed to investigate if an increased urinary excretion of 8-oxodG in smokers versus never smokers and former smokers could be verified in a population with type 2 diabetes. Additionally, we measured RNA oxidation levels through urinary excretion of 8-oxo-7, 8-dihydroguanosine (8-oxoGuo). Our study included urinary samples from 2721 type 2 diabetic patients, analyzed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Logistic regression was used to examine the relationship between daily smokers (n = 462) versus former (n = 1341) and never smokers (n = 918) regarding the RNA and DNA oxidation, respectively. We did not find any significant effect of smoking on urinary excretion of 8-oxodG or 8-oxoGuo in our study. Due to a sparse study area, it is still too early to draw any conclusions on smoking and RNA-oxidation. Regarding DNA oxidation, our study suggests that the effect of smoking seen in healthy populations might be attenuated in patients with type 2 diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Chromatography, Liquid; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Guanosine; Humans; Male; Middle Aged; Smoking; Tandem Mass Spectrometry

The mechanisms underlying progression of type 2 diabetes are complex and varied. Recent studies indicated that oxidative stress provided a new sight. To further assess the relationship between nucleic acid oxidation and complications in patients with type 2 diabetes and explore its possible molecular mechanisms, we studied 1316 subjects, including 633 type 2 diabetes patients and 683 age- and sex-matched healthy controls. Urinary levels of DNA oxidation marker 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and RNA oxidation marker 8-oxo-7,8-dihydroguanosine (8-oxoGuo) were measured by ultraperformance liquid chromatography and mass spectrometry (UPLC-MS/MS). Serum glucose, HbA1c, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides (TG) were also determined. The results showed significantly elevated levels of both the urinary 8-oxodGuo and 8-oxoGuo in diabetes patients with/without complications compared with age-matched healthy control subjects (p = 0.02 and p < 0.001, resp.). Patients with complications, especially macrovascular complications, exhibited higher levels of 8-oxoGuo than those without complications, while there was no difference in the concentrations of serum glucose and lipids. The finding indicates the role for oxidative damage to DNA and RNA, as a molecular mechanism contributing to the progression of type 2 diabetes. Elevated levels of 8-oxoGuo may be a risk factor for type 2 diabetes complications, especially in diabetic macrovascular complications.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Demography; Deoxyguanosine; Diabetes Complications; Diabetes Mellitus, Type 2; DNA; DNA Damage; Female; Guanosine; Humans; Male; Middle Aged; Oxidation-Reduction; RNA

Urinary excretion of the RNA and DNA oxidation markers, 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in newly diagnosed adult type 2 diabetics are reported to be long-term predictors of mortality independent of conventional risk factors. In the current study, we investigated the relationships between urinary markers of nucleic acid oxidation concentrations and the degree of obesity and glucose metabolism in overweight compared to lean children. Forty-two (24 girls) overweight and 35 lean (19 girls) children and adolescents were recruited from the Registry of the Danish Childhood Obesity Biobank. Anthropometric measurements were collected at baseline and glucose metabolism was assessed by an oral glucose tolerance test. A urine sample was obtained during the test. Linear regression did not demonstrate any associations between the urinary markers and the degree of obesity or glucose metabolism in lean and obese children. However, sub-analyses adjusted for age, sex, and the degree of obesity showed positive associations between the 2 h glucose and the urinary markers, 8-oxoGuo (p = 0.02, r(2)= 0.63) and 8-oxodG (p = 0.046, r(2)= 0.48), and between the insulinogenic index and 8-oxoGuo (p = 0.03, r(2 )=( )0.60) in the 12 obese children exhibiting impaired glucose tolerance. Excretion of the urinary markers of nucleic acid oxidation and the degree of obesity or the glucose metabolism were not associated in this study. Nevertheless, obese children with impaired glucose tolerance seem to exhibiting an increased oxidative stress level, but due to the small sample size in this study, further investigations are required to elucidate this correlation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Biomarkers; Child; Cross-Sectional Studies; Denmark; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Guanosine; Humans; Male; Obesity; Oxidative Stress; Pilot Projects

To evaluate oxidative damage in leukocytes from patients with type 2 diabetes by examining 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels.. Patients with type 2 diabetes and healthy controls were assessed for demographic, clinical and biochemical characteristics. Levels of 8-OHdG in extracted leukocyte DNA were determined by enzyme linked immunosorbent assay.. Of 108 patients with type 2 diabetes (56 with microangiopathy, 52 without) and 65 healthy controls, leukocyte 8-OHdG levels were higher in patients with type 2 diabetes versus controls (median ± interquartile range [IQR], 3.19 ± 2.17 versus 0.38 ± 1.00 ng/ml), and higher in patients with type 2 diabetes and microangiopathy versus those without microangiopathy (median ± IQR, 3.34 ± 1.87 versus 2.71 ± 2.26 ng/ml). Patients with type 2 diabetes and microangiopathy had higher serum creatinine and urinary albumin levels versus those without microangiopathy. Leukocyte 8-OHdG levels, duration of type 2 diabetes, albuminuria, use of insulin and use of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) were independently associated with microangiopathy in patients with type 2 diabetes after adjustment for smoking.. Leukocyte oxidative DNA damage was high in patients with type 2 diabetes and microangiopathy. Presence of microangiopathy was associated with leukocyte 8-OHdG levels, duration of type 2 diabetes, albuminuria and use of ACE inhibitors/ARBs or insulin.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Asian People; Case-Control Studies; Demography; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; DNA; DNA Damage; Female; Humans; Leukocytes; Logistic Models; Male; Middle Aged; Multivariate Analysis

Blood levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured by enzyme immunoassay after overnight fasting in untreated breast cancer and endometrial cancer patients (N=170) of mainly postmenopausal age with and without type 2 diabetes mellitus. The concentrations of 8-OHdG in patients with breast cancer were higher than in patients with endometrial cancer and in patients with breast cancer and diabetes in comparison with patients with breast cancer without diabetes. No correlations of blood 8-OHdG levels with glycemia, age, and clinical stage of disease were detected. In cancer patients with diabetes, the concentration of 8-OHdG increases proportionally to the increase in body mass index, though this does not lead to disappearance of the above differences between patients with breast cancer and endometrial cancer by the level of 8-OHdG. The causes of the trend to a less favorable course of tumor process in patients with breast cancer and diabetes in comparison with endometrial cancer and diabetes deserve further studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Body Mass Index; Breast Neoplasms; Deoxyguanosine; Diabetes Mellitus, Type 2; Endometrial Neoplasms; Female; Humans; Middle Aged

Prediabetes is the preclinical stage of type 2 diabetes mellitus (T2DM) with intermediate state of hyperglycemia. Hyperglycemia results in a state of oxidative stress, which may contribute to the production of insulin resistance, β-cell dysfunction and long-term complications of diabetes. Novel approaches are required for prevention and treatment of diabetes. New biomarkers that can be used in risk stratification and therapy control as supplementary to current parameters are needed. These biomarkers may facilitate a more individualized and sufficient treatment of diabetes. Therefore, the aim of this study was to investigate the levels of oxidatively induced DNA damage products, 8-oxo-2'-deoxyguanosine (8-oxo-dG) (also known as 8-OH-dG), (5'R)- and (5'S)-8,5'-cyclo-2'-deoxyadenosines (R-cdA and S-cdA), and the lipid peroxidation product 8-iso-prostaglandin F

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; C-Reactive Protein; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Chromatography, Liquid; Deoxyadenosines; Deoxyguanosine; Diabetes Mellitus, Type 2; Dinoprost; DNA Damage; Female; Glycated Hemoglobin; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Prediabetic State; Tandem Mass Spectrometry; Triglycerides

Our previous clinical indicated that urinary cyclophilin A was a good marker for diabetic nephropathy.. We used animal and cell models of diabetic nephropathy to examine the role of cyclophilin A in disease progression.. Significantly increased urinary cyclophilin A could be detected in db/db at the 8th week. Linagliptin (3mg/kg/day and 15mg/kg/day) could suppress urinary 8-hydroxy-2'-deoxyguanosine at the 8th and 16th week but only the high dose Linagliption could suppress cyclophilin A at the 8th week. Compared to 8-hydroxy-2'-deoxyguanosine, cyclophilin A was a stronger, earlier, and more sensitive marker. Immunohistochemical staining for cyclophilin A was also positive for db/db. In cell studies, oxidative stress and hyperglycemia could stimulate MES-13 and HK-2 cells to secrete cyclophilin A. Hyperglycemia stimulated HK-2 cells to secrete TGFβ1, which caused secretion of cyclophilin A. The secreted cyclophilin A further stimulated CD 147 to move outward from cytosol onto cell membrane in confocal microscopy, which was associated with the p38 MAPK pathway in the downstream.. Secreted cyclophilin A may play an important role in diabetic nephropathy in the mouse model and is associated with TGFβ1, CD 147, and the p38 MAPK pathway.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cells, Cultured; Cyclophilin A; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Kidney Diseases; Linagliptin; Mice; Mice, Transgenic

We investigated whether urinary markers of nucleic acid oxidation are associated with an increased risk of cancer in type 2 diabetes patients.. Urine samples from 1381 newly diagnosed diabetes patients were assayed for the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo). Cox proportional hazards regression was used to examine the relationship between the urinary markers and cancer incidence.. The crude analyses showed an association between overall cancer and urinary excretion of the RNA oxidation marker 8-oxoGuo (unadjusted hazard ratio for cancer per natural log increase in 8-oxoGuo 1.35 [95% CI, 1.01-1.81]), however, in the adjusted analyses, no significant associations between 8-oxodG or 8-oxoGuo and overall cancer were found. For site-specific cancers 8-oxodG was associated with breast cancer in the crude analyses (unadjusted hazard ratio for breast cancer per natural log increase in 8-oxodG was 2.37 [95% CI, 1.07-5.26]), although the association was attenuated in the adjusted analyses (sex- and age-adjusted hazard ratio 2.15 [95% CI, 0.92-5.02] and multivariate adjusted hazard ratio1.98 [95% CI, 0.95-4.10]).. Urinary excretion of the nucleic acid oxidation markers 8-oxodG and 8-oxoGuo at the time of diagnosis was not associated with cancer overall in type 2 diabetes patients. For site-specific cancers, risk elevations were seen for breast cancer (8-oxodG). These findings should be examined in future and larger studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers, Tumor; Breast Neoplasms; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA; DNA Damage; Female; Guanosine; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; RNA

Oxidative stress (OS) contributes to cardiovascular damage in type 2 diabetes mellitus (T2DM). The peptide glucagon-like peptide-1 (GLP-1) inhibits OS and exerts cardiovascular protective actions. Our aim was to investigate whether cardiac remodeling (CR) and cardiovascular events (CVE) are associated with circulating GLP-1 and biomarkers of OS in T2DM patients. We also studied GLP-1 antioxidant effects in a model of cardiomyocyte lipotoxicity. We examined 72 T2DM patients with no coronary or valve heart disease and 14 nondiabetic subjects. A median of 6 years follow-up information was obtained in 60 patients. Circulating GLP-1, dipeptidyl peptidase-4 activity, and biomarkers of OS were quantified. In T2DM patients, circulating GLP-1 decreased and OS biomarkers increased, compared with nondiabetics. Plasma GLP-1 was inversely correlated with serum 3-nitrotyrosine in T2DM patients. Patients showing high circulating 3-nitrotyrosine and low GLP-1 levels exhibited CR and higher risk for CVE, compared to the remaining patients. In palmitate-stimulated HL-1 cardiomyocytes, GLP-1 reduced cytosolic and mitochondrial oxidative stress, increased mitochondrial ATP synthase expression, partially restored mitochondrial membrane permeability and cytochrome c oxidase activity, blunted leakage of creatine to the extracellular medium, and inhibited oxidative damage in total and mitochondrial DNA. These results suggest that T2DM patients with reduced circulating GLP-1 and exacerbated OS may exhibit CR and be at higher risk for CVE. In addition, GLP-1 exerts antioxidant effects in HL-1 palmitate-overloaded cardiomyocytes. It is proposed that therapies aimed to increase GLP-1 may counteract OS, protect from CR, and prevent CVE in patients with T2DM.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Animals; Antioxidants; Atrial Remodeling; Cardiomegaly; Cardiovascular System; Case-Control Studies; Cell Line; Deoxyguanosine; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Glucagon-Like Peptide 1; Humans; Male; Mice; Middle Aged; Mitochondria; Myocytes, Cardiac; Oxidative Stress; Palmitic Acid; Pilot Projects; Retrospective Studies; Tyrosine; Ventricular Remodeling

The aim of this study was to assess the changes of markers of DNA damage by glycation and oxidation in patients with type 2 diabetes and the association with diabetic nephropathy.. DNA oxidation and glycation adducts were analysed in plasma and urine by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. DNA markers analysed were as follows: the oxidation adduct 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-OxodG) and glycation adducts of glyoxal and methylglyoxal--imidazopurinones GdG, MGdG, and N2-(1,R/S-carboxyethyl)deoxyguanosine (CEdG).. Plasma 8-OxodG and GdG were increased 2-fold and 6-fold, respectively, in patients with type 2 diabetes, with respect to healthy volunteers. Median urinary excretion rates of 8-OxodG, GdG, MGdG, and CEdG were increased 28-fold, 10-fold, 2-fold, and 2-fold, respectively, in patients with type 2 diabetes with respect to healthy controls. In patients with type 2 diabetes, nephropathy was associated with increased plasma 8-OxodG and increased urinary GdG and CEdG. In a multiple logistic regression model for diabetic nephropathy, diabetic nephropathy was linked to systolic blood pressure and urinary CEdG.. DNA oxidative and glycation damage-derived nucleoside adducts are increased in plasma and urine of patients with type 2 diabetes and further increased in patients with diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA Damage; Female; Glycation End Products, Advanced; Humans; Male; Middle Aged; Oxidation-Reduction

Podocytes participate in the formation and regulation of the glomerular filtration barrier. Loss of podocytes occurs during the early stages of diabetic nephropathy and impairs glomerular filtration. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as anti-diabetic agents in clinical practice. In this study, we showed that gemigliptin, a novel DPP-4 inhibitor, reduced podocyte apoptosis in type 2 diabetic db/db mice without reducing hyperglycemia. Gemigliptin (100mg/kg/day) was administered orally for 12 weeks in db/db mice. Blood glucose levels and albuminuria were measured. The renal cortex was collected for histological examination, and molecular assays were used to detect 8-hydroxydeoxyguanosine, advanced oxidation protein products (AOPP), the receptor for advanced glycation end products (RAGE), and integrin-linked kinase (ILK). Type 2 diabetic db/db mice exhibited albuminuria, renal histopathological changes, and podocyte loss. Administration of gemigliptin to db/db mice suppressed albuminuria, enzyme activity and expression of DPP-4, and podocyte apoptosis. The effect of gemigliptin on diabetes-induced podocyte loss was associated with the suppression of oxidative damage, AOPP accumulation, RAGE expression, and ILK expression. These results indicate the possible benefits of using gemigliptin in diabetes patients to treat renal impairment without affecting glycemic control.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Advanced Oxidation Protein Products; Albuminuria; Animals; Apoptosis; Blood Glucose; Cytoprotection; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glomerular Filtration Rate; Guanine; Male; Mice, Inbred C57BL; Piperidones; Podocytes; Protein Serine-Threonine Kinases; Pyrimidines; Receptor for Advanced Glycation End Products

We previously showed that urine and serum Angiopoietin-2 (Ang-2) levels increased significantly with the degree of albuminuria in diabetes patients, but the reasons remain unclear. Consequently we aimed to determine whether there was an association between Ang-2, inflammatory cytokines (TNF-α and IL-18) and reactive oxygen species (8-OHdG and SOD) in type 2 diabetes patients with albuminuria.. This retrospective study evaluated 113 patients with type 2 diabetes and normoalbuminuria, microalbuminuria, or macroalbuminuria and 30 healthy controls. Serum and urine TNF-α, IL-18 and 8-OHdG levels were measured by ELISA. Superoxide dismutase (SOD) activity was determined by spectrophotometry.. Serum and urine TNF-α, IL-18 and 8-OHdG levels increased significantly with the degree of albuminuria, and were positively correlated with increased Ang-2. In contrast, SOD activity decreased with the degree of albuminuria and was negatively correlated with Ang-2. Multivariable linear regression analysis revealed that serum Ang-2 level was independently associated with serum levels of TNF-α (P<0.001), 8-OHdG (P=0.001), and IL-18 (P=0.003). Urinary Ang-2 level was independently associated with urinary TNF-α (P<0.001) and 8-OHdG (P=0.004) levels.. TNF-α and 8-OHdG are associated with elevated urinary Angiopoietin-2 levels in type 2 diabetic patients with albuminuria.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Albuminuria; Angiopoietin-2; Cross-Sectional Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-18; Kidney Glomerulus; Male; Middle Aged; NADPH Oxidase 4; NADPH Oxidases; Reactive Oxygen Species; Retrospective Studies; Superoxide Dismutase; Superoxide Dismutase-1; Tumor Necrosis Factor-alpha

Urinary markers of nucleic acid oxidation may be useful biomarkers in diabetes. It has been demonstrated that T2DM patients have an increased level of oxidative DNA damage; however, it is unclear whether increased DNA damage may be related to a greater degree of inflammation and insulin resistance. Thus, the aim of this present study was to investigate the relation of the impact of oxidative DNA damage, assessed by urinary 8-OHdG, on the levels of inflammatory cytokines, as well as insulin resistance. In addition, we also investigated the diagnostic ability of urinary 8-OHdG in the identification of microvascular complications in T2DM.A case-control study, enrolling 22 healthy controls and 54 subjects with T2DM, was performed to evaluate the relation between oxidative DNA damage and interleukin-6 (IL-6), IL-1,tumor necrosis factor-alpha (TNF-α), IL-10, and Homeostasis Model Assessment (HOMA-IR) index. T2DM patients presented higher urinary 8-OHdG, IL-6, IL-1, TNF-α levels and HOMA-IR, and lower IL-10 levels than control subjects. Moreover, urinary 8-OHdG levels were significantly higher in the group T2DM with microvascular complications when compared to the without complications. The areas under the curve for urinary 8-OHdG and urinary albumin were, respectively, 0.836 (P<0.001) and 0.786 (P=0.002). Thus, urinary 8-OHdG has a slightly higher ability to discriminate microvascular complications in T2DM compared with urinary albumin. It was also demonstrated that T2DM patients with higher median of urinary 8-OHdG had significantly elevated levels of IL-6, TNF-α and HOMA-IR, and decreased IL-10 levels. Our findings showed that T2DM patients with higher urinary 8-OHdG levels showed a greater inflammatory degree and higher insulin resistance. It is possible to speculate that T2DM patients present a cascade of events as increasing metabolic abnormalities such as insulin resistance and inflammatory activation, as well as increased ROS generation factors that may contribute directly to greater oxidative DNA damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Case-Control Studies; Cytokines; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; DNA Damage; Female; Humans; Insulin Resistance; Linear Models; Male; Microvessels; Middle Aged; Oxidative Stress; ROC Curve

Oxidative stress, assessed using 8-hydroxy-2'-deoxyguanosine (8-OHdG), can be associated with arterial stiffness in patients with type 2 diabetes mellitus (T2DM) and/or hypertension (HT). We investigated the correlation between urinary 8-OHdG and pulse wave velocity (PWV) in hypertensive and non-hypertensive T2DM patients with fair glycaemic control to determine the clinical significance of HT as a comorbidity in the diabetic state.. Clinical data, including traditional cardiovascular risk factors, diabetic complications, prescribed agents, urinary 8-OHdG level and brachial-ankle PWV, was collected from T2DM patients with and without HT.. There were 76 patients (45 men, 31 women; mean age 61 years; mean haemoglobin A1c level 6.5%) in the study cohort. T2DM patients with HT had significantly higher mean PWV than patients without HT (1,597 cm/s vs 1,442 cm/s; p < 0.05). Patients with HT showed no significant difference in 8-OHdG levels relative to those without HT (median 7.9 ng/mg creatinine vs 8.8 ng/mg creatinine; p > 0.05). Simple linear correlation and stepwise multiple linear regression analyses revealed that 8-OHdG levels correlated independently, significantly and positively with PWV among T2DM patients with HT (r = 0.33, p < 0.05; β= 0.23, p < 0.05). No significant correlation was observed between 8-OHdG levels and PWV among T2DM patients without HT.. In the hypertensive state, oxidative stress can be responsible for the development of arterial stiffness, even in patients with fairly well controlled T2DM. Oxidative stress management may be necessary for the prevention of cardiovascular disease in this population.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Ankle Brachial Index; Cohort Studies; Deoxyguanosine; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Pulse Wave Analysis; Vascular Stiffness

The goal of this study is to investigate the association between oxidative stress and telomere length shortening in the comorbid depression and diabetes. Therefore, 71 patients with newly diagnosed type 2 diabetes (T2D) and 52 subjects with normal glycemic level (control, Ctrl) were enrolled. Depressive status was identified with the Depression Subscale of Hospital Anxiety and Depression Scale (HADS-D). Leukocyte telomere length ratio (T/S ratio) was determined with quantitative PCR. Oxidative stress status was evaluated with 8-hydroxy-desoxyguanosine (8-OHdG) assay kit. Some other biochemical blood testing was also performed. The data showed that T2D patients had higher proportion of depression evaluated by the HADS-D (x(2) = 4.196, P = 0.041). T/S ratio was significantly negatively correlated with 8-OHdG, HADS-D, age, HbA1c, FPG, and HOMA-IR. In addition, HADS-D was significantly positively correlated with HbA1c, FPG, HOMA-IR, and 8-OHdG. Both HADS-D and 8-OHdG were the major independent predictors for T/S ratio. This study indicates that oxidative stress contributes to both telomere length shortening and depression development in newly diagnosed type 2 diabetic patients, while in depression status, some other mechanisms besides oxidative stress may also affect the telomere length.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Age Factors; Aged; Blood Glucose; Deoxyguanosine; Depression; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leukocytes; Male; Middle Aged; Oxidative Stress; Telomere; Telomere Shortening

Bariatric surgery is an effective treatment option for both obesity and obesity-related type 2 diabetes mellitus (T2DM). However, little is known regarding the effects of bariatric surgery on erectile dysfunction among patients with T2DM. Therefore, we investigated whether bariatric surgery would lead to structural and biochemical changes in the corpus cavernosum.. Twenty-five male Otsuka Long-Evans Tokushima Fatty rats were assigned to either a control group (sham operation, n = 10) or a bariatric surgery group (gastric bypass surgery, n = 15). Four weeks after the operation, each group of rats was evaluated with an oral glucose tolerance test (OGTT). The penile intracavernous pressure was measured for erectile functional analysis. Histologic evaluation of the tissue was performed with Masson's trichrome staining. Endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), Rho kinase, and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels in the corpus cavernosum were assayed by using western blot and ELISA.. The mean body weight of the bariatric surgery group was lower than the control group (p = 0.002). The postoperative OGTT result was lower in the bariatric surgery group than in the control group (p = 0.014), and this was lower than the preoperative value (p = 0.037). The intracavernous pressure/mean arterial pressure ratio was higher in the bariatric surgery group compared to the control group (p = 0.021), and a higher cavernosum smooth muscle/collagen ratio was observed in the bariatric surgery group compared to the control group (p = 0.025). Likewise, the expression of eNOS and nNOS was higher in bariatric surgery group than in the control group (p = 0.027 and p = 0.008, respectively). Decreased expression of Rho kinase and levels of 8-OHdG were observed in the bariatric surgery group (p = 0.032).. In this animal model, bariatric surgery appears to ameliorate T2DM-related metabolic dysfunction leading to structural and biochemical changes in the corpus cavernosum, and thus, results in improvement of erectile dysfunction associated with T2DM.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Body Weight; Collagen; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Erectile Dysfunction; Gastric Bypass; Gene Expression; Glucose; Glucose Tolerance Test; Homeostasis; Humans; Male; Muscle Contraction; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Penile Erection; Penis; Rats; Rats, Inbred OLETF; rho-Associated Kinases; Vasodilation

Vascular disease is one of the critical complications of diabetes. A growing body of evidence suggests that oxidative stress plays a key role for vascular disease progression. Recent studies have demonstrated a strong link between vitamin D and cardiovascular disease.. We investigated the anti-oxidative effects of a vitamin D analog, 22-oxacalcitriol (maxacalcitol), on vascular lesions in type 2 diabetic rats. We used Spontaneously Diabetic Torii (SDT) rats, a model of non-obese type 2 diabetes. At 20 weeks of age, SDT rats were randomly divided into three groups: diabetes mellitus (DM, n = 10), DM + maxacalcitol (DM + D, n = 10), and DM + insulin (DM + I, n = 10). The rats were sacrificed at 30 weeks for the evaluation of blood and urine samples as well as histopathology and mRNA expression in the aorta.. Urinary 8-hydroxydeoxyguanosine (8-OHdG) excretion and the number of 8-OHdG-positive cells were significantly lower in the DM + I and DM + D groups than in the DM group. Real-time polymerase chain reaction analysis demonstrated that NADPH p22 phox and NADPH p47 phox mRNA levels were markedly decreased in the DM + I and DM + D groups compared with the DM group. Furthermore, the mRNA expression of MCP-1, ICAM-1 and VCAM-1 was significantly reduced in the DM + I and DM + D groups compared with the DM group.. Our results suggest that the vasoprotective effects of vitamin D are mediated by reducing oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Aorta; C-Reactive Protein; Calcitriol; Chemokine CCL2; Deoxyguanosine; Diabetes Mellitus, Type 2; Insulin; Intercellular Adhesion Molecule-1; Interleukin-1; NADPH Oxidases; Oxidative Stress; Rats; RNA, Messenger; Vascular Cell Adhesion Molecule-1; Vascular Diseases

Increasing evidence showed that telomere length was shorter in age-related diseases, but the mechanism of this phenomenon is still unclear.. To determine whether telomere shortening occurs in Type 1 diabetes (T1D) and Type 2 diabetes (T2D), and explore the effect of antioxidant status on the telomere length.. T2D patients (no.=62), T1D patients (no.=34), and non-diabetic subjects used as control (CTL) (no.=40) were included in this study. Leukocyte telomere length ratio (T/S ratio) was measured using a quantitative PCR and analyzed. Antioxidant status was estimated by human 8-hydroxy-desoxyguanosine quantization. Other biomarkers, such as fasting plasma glucose, fasting insulin, glycated hemoglobin (HbA1c) and lipid profile were also measured.. Compared with CTL group [T/S ratio (mean ± SD), 2.39 ± 0.55], leukocyte telomere length was significantly shorter in T2D group (1.67 ± 0.50) and T1D group (1.77 ± 0.50). 8-OHdG that indicated oxidative stress was significantly higher in T2D (2.99 ± 0.85 ng/ml) and T1D (2.03 ± 0.92 ng/ml) group than in CTL group (0.90 ± 0.46 ng/ml). T/S ratio was significantly negatively correlated with age, waist circumference, waist-to-hip ratio, diastolic blood pressure, fasting plasma glucose, HbA1c, homeostasis model assessment of insulin resistance and 8- OHdG in the whole population. 8-OHdG was independent risk factor for telomere shortening in both T1D (p=0.018) and T2D group (p=0.022).. In our study, shorter telomere length and increased oxidative stress were observed in both T1D and T2D. Older people with central obesity, hyperglycemia, insulin resistance and severe antioxidant status tended to have shorter telomere length. In addition, 8- OHdG was an independent predictor for telomere length for both T1D and T2D patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Deoxyguanosine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Leukocytes; Male; Middle Aged; Oxidative Stress; Telomere

Preliminary data are confirmed on the more rare prevalence of family history of diabetes mellitus (DM) in cancer patients, mainly females, with diabetes in comparison with diabetics without cancer pathology. Familial diabetes does not worsen additionally tumor characteristics against the same in patients with non-familial diabetes. More than that, familial diabetes in diabetics with breast cancer goes together with lesser size of tumor and demonstrates an inclination to the rarer distant metastases in breast and endometrial cancer patients. The signs of systemic DNA damage (evaluated, in particular, on the basis of 8-OH-dG serum levels) are pronounced in postmenopausal diabetic cancer patients with familial diabetes in lesser degree than in non-familial variant of DM. In toto, this allows to consider family history of DM in patients with type-2 diabetes as a particular factor of tumor growth containment, which mechanisms and causes, warrant further studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers, Tumor; Breast Neoplasms; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Endometrial Neoplasms; Female; Humans; Incidence; Male; Middle Aged; Postmenopause

(-)-Epigallocatechin-3-gallate (EGCG), which is largely found in green tea, is known to eliminate reactive oxygen species and associated inflammatory responses in vitro and in cells. However, the in vivo mechanisms underlying the effects of EGCG on the amelioration of metabolic disorders are not fully understood. In this study, we examined whether dietary supplementation with EGCG reduces inflammatory responses in peripheral leukocytes of a non-obese type 2 diabetes animal model, Goto-Kakizaki (GK) rats. GK rats at 9 wk of age were fed a control high-fat diet (46 energy % from lard and corn oil) or a high-fat diet containing 0.1%, 0.2%, or 0.5% EGCG (w/w) for 25 wk. The oxidative stress markers 8-hydroxydeoxyguanosine (OHdG) and total malondialdehyde (MDA) were reduced by supplementation with EGCG at 0.1%, but not at 0.2% or more. Significant reductions in the mRNA levels of genes related to inflammatory responses (TNF-α, IFN-γ, IL-1β, IL-6, IL-18, MCP-1, CD11b, and S100a6), 8-OHdG, and total MDA were induced in peripheral leukocytes of GK rats by EGCG supplementation at 0.1%, but not at 0.2% or more, compared with rats fed the control diet. The present results suggest that supplementation with a low dose of EGCG reduces oxidative stress and the expressions of genes involved in inflammation in peripheral leukocytes of GK rats.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Analysis of Variance; Animals; Catechin; Chemokines; Corn Oil; Cytokines; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; Dietary Fats; Dietary Supplements; Disease Models, Animal; Inflammation; Leukocytes; Male; Malondialdehyde; Oxidative Stress; Polymerase Chain Reaction; Rats; Rats, Wistar

This study investigated whether the angiotensin II type-1 receptor blocker (ARB) candesartan affects markers of oxidative stress in type 2 diabetes mellitus (DM) patients with essential hypertension (EH).. Urinary excretion of pyrraline (PR), pentosidine (PT), acrolein (AC), and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and microalbuminuria were assessed in patients with DM complicated by EH who were treated with candesartan 4 mg/day for 3 months.. In a total of 25 patients urinary excretion of PR (nmol/g · cr), PT (pmol/g · cr), and 8-OH-dG (ng/mg · cr) was significantly (all P < 0.05) decreased from (mean ± SEM) 11.9 ± 1.9, 30.6 ± 2.4, and 7.9 ± 0.6, respectively, at baseline to 8.4 ± 1.4, 27.1 ± 2.0, and 6.9 ± 0.6, respectively, at 3 months. Meanwhile, excretion of AC was unaltered from 209.6 ± 40.0 to 189 ± 24.8 nmol/mgcr (P = NS). Urinary albumin excretion was significantly (P < 0.05) reduced from 27.7 ± 4.6 to 14.1 ± 1.1 mg/g · cr. There were weak but statistically significant positive correlations between the change of urinary 8-OH-dG excretion and that of albumin (r = 0.414; P < 0.05) and change of hemoglobin (Hb) A1c (r = 0.45; P < 0.05).. Candesartan exerts protective effect(s) on the cardiovascular system by suppression of oxidative stress--mainly through inhibiting production of advanced glycation end products (AGEs) rather than of advanced lipoxidation end products (ALEs)--in type 2 DM patients with EH.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Deoxyguanosine; Diabetes Mellitus, Type 2; Essential Hypertension; Female; Glycation End Products, Advanced; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Tetrazoles

We recently showed that RNA oxidation, estimated by urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo), independently predicted mortality in a cohort of 1,381 treatment-naive patients with newly diagnosed type 2 diabetes. In the present investigation, we analyzed urine collected 6 years after the diagnosis to assess the association between urinary markers of nucleic acid oxidation and mortality in patients with established and treated diabetes.. We used data from the 970 patients who attended the screening for diabetes complications 6 years after the diagnosis. Cox proportional hazards regression was used to examine the relationship between urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG] [n = 938]) and RNA oxidation (8-oxoGuo [n = 936]) and mortality.. During a median of 9.8 years of follow-up, 654 patients died. Urinary 8-oxoGuo assessed 6 years after the diagnosis was significantly associated with mortality. The multivariate-adjusted hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.86 (95% CI 1.34-2.58) and 1.72 (1.11-2.66), respectively. Conversely, 8-oxodG was not associated with mortality. In addition, we found an association between changes in 8-oxoGuo from diagnosis to 6-year follow-up and mortality, with increased risk in patients with an increase and decreased risk in patients with a decrease in 8-oxoGuo.. The RNA oxidation marker 8-oxoGuo is an independent predictor of mortality in patients with established and treated type 2 diabetes, and changes in 8-oxoGuo during the first 6 years after diagnosis are associated with mortality.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Nucleic Acids; Oxidation-Reduction

Oxidative stress has been implicated in the pathogenesis of diabetes mellitus (DM). Levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-epi-prostaglandin-F(2α) (8-epi-PGF2α), and total protein carbonyls were measured to assess whether DM is associated with altered salivary redox homeostasis.. A total of 215 patients with diabetes and 481 healthy controls were recruited from the Department of Endocrinology at the Jewish General Hospital in Montreal. Levels of oxidative biomarkers were assayed using enzyme-linked immunosorbent assay (ELISA) in whole unstimulated saliva. Associations of the redox data with exposure to insulin, metformin and dietary control were assessed by logistic regression analyses.. We observed (i) significantly higher mean levels of 8-OHdG and protein carbonyls in whole unstimulated saliva of patients with diabetes compared to controls, (ii) higher mean levels of protein carbonyls in type 1 diabetes as well as higher mean levels of 8-OHdG and protein carbonyls in type 2 diabetes compared to controls, (iii) elevated levels of protein carbonyls in diet-controlled patients and in patients with diabetes on insulin and metformin, (iv) elevated levels of 8-OHdG in patients on metformin, and (v) significant associations between subjects with DM and salivary 8-OHdG and protein carbonyls.. DM is associated with increased oxidative modification of salivary DNA and proteins. Salivary redox homeostasis is perturbed in DM and may inform on the presence of the disease and efficacy of therapeutic interventions.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Age Factors; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diet, Diabetic; Dinoprost; DNA Damage; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Lipid Peroxidation; Metformin; Oxidation-Reduction; Oxidative Stress; Protein Carbonylation; Saliva; Salivary Proteins and Peptides; Sex Factors

Many models of diabetic nephropathy have been reported. However, it is rare that the characteristic findings of severe human diabetic nephropathy, such as diffuse, nodular, and exudative lesions, are all detected in one model mouse. Previously, we reported that MAFA-deficient and beta cell-specific MAFK-overexpressing hybrid transgenic (Mafa(-/-)Mafk (+)) mice develop diabetes mellitus and, after uninephrectomy, demonstrate these characteristic lesions. In this study, we administered TCV-116 (candesartan cilexetil) to Mafa(-/-)Mafk (+) mice after uninephrectomy and examined whether TCV-116 ameliorated the diabetic nephropathy. We also evaluated the utility of these mice as a model for developing treatments for diabetic nephropathy. We performed uninephrectomy of the Mafa(-/-)Mafk (+) mice at 8 weeks old. We then divided these mice into two groups as follows: 1) an untreated group and 2) a group treated with TCV-116 at 5 µg/g/day from 10 to 20 weeks. TCV-116 treatment did not affect serum glucose levels. However, in the treated group, urinary protein excretion, mesangial matrix expansion, enlargement of the kidney, and glomerular surface area were all improved relative to untreated mice. Oxidative stress is known to be increased in diabetic nephropathy and to be suppressed by TCV-116. The urinary level of 8-OHdG, an oxidative stress marker, at 20 weeks was lower in the TCV-116-treated group than in the untreated group. From these results, we concluded that the Mafa(-/-)Mafk (+) mouse is a useful model to analyze diabetic nephropathy and a useful tool for the development of new drugs to treat diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Kidney; Maf Transcription Factors, Large; MafK Transcription Factor; Male; Mice; Mice, Transgenic; Nephrectomy; Tetrazoles

Because of the demographic transition, lifestyle changes, urbanization, and nutrition transition, Central Africans are at higher risk of ocular diseases associated with oxidative stress and visual disability. This study aimed to estimate the normal values of oxidant status defined by oxidized low-density lipoprotein (Ox-LDL), 8-Isoprostane and 8-hydroxy-deoxyguanosine (8-OHdG) and to determine their pathogenic role in the prevalence and the severity of visual disability among these black Africans.. This was a cross-sectional study, run in a case-control study randomly selected from Kinshasa province, DR Congo. The study included 150 type 2 diabetes mellitus (T2DM) patients (cases) matched for sex and age to 50 healthy non diabetic controls. Logistic regression models were used to identify independent determinants of visual disability.. The presence rates were 8.5% for blindness, 20.5% for visual impairment and 29% for visual disability including blindness and visual impairment. After adjusted for taro leaves intake, red beans intake, T2DM, aging, waist circumference, and systolic blood pressure, we identified low education level (OR=3.3 95%CI 1.5-7.2; p=0.003), rural-urban migration (OR=2.6 95% CI 1.2-5.6; p=0.017), and high Ox-LDL (OR=2.3 95% CI 1.1-4.7; p=0.029) as the important independent determinants of visual disability. After adjusted for education, intake of red beans, intake of taro leaves, triglycerides, and T2DM, we identified no intake of safou fruit (OR=50.7 95% CI 15.2-168.5; p<0.0001), rural-urban migration (OR=3.9 95%CI 1.213; p=0.012), and high 8-OHdG (OR=14.7 95% CI 3.9-54.5; p<0.0001) as the significant independent determinants of visual disability. After adjusted for education level, no intake of red beans, no intake of Taro leaves, triglycerides, and T2DM, we identified no intake of Safou fruit (OR=43.1 95% CI 13.7-135.4; p<0.0001), age ≥ 60 years (OR=3.4 95% CI 1.3-9; p=0.024), and high 8-Isoprostane (OR=11 95% CI 3.4-36.1; p<0.0001) as the significant independent determinants of visual disability.. Visual disability remains a public health problem in Central Africa. Antioxidant supplement, fruit intake, nutrition education, control of migration, and blocking of oxidative stress are crucial steps for delayed development of vision loss.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Black People; Blindness; Case-Control Studies; Cross-Sectional Studies; Democratic Republic of the Congo; Deoxyguanosine; Diabetes Mellitus, Type 2; Dinoprost; Educational Status; Female; Humans; Lipoproteins, LDL; Male; Middle Aged; Oxidative Stress; Population Dynamics; Prevalence; Severity of Illness Index; Triglycerides; Visually Impaired Persons; Waist Circumference

Measurement of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has recently become more popular as a means of assessing oxidative stress in the human body. The aim of this study is to compare the levels of urine 8-OHdG in patients with type 2 diabetes with and without nephropathy and to evaluate its role as a biochemical marker for distinguishing these patients from healthy and patients without complications.. For this purpose, 52 patients with type 2 diabetes mellitus (32 with nephropathy (DMN), 20 without nephropathy (DM)) and 20 healthy control subjects (C) were included in this study. The urine concentrations of 8-OHdG were measured by modified LC-MS/MS method and compared with the first morning voiding urine albumin/creatinine ratio (UACR) and HbA1c values of the same patients.. The concentrations of urine 8-OHdG in DMN and DM patients were higher than those of the control subjects (3.47 ± 0.94, 2.92 ± 1.73, 2.1 ± 0.93 nmol/mol creatinine, respectively). But there was no statistical difference between DMN and DM (p = 0.115). There is significant correlation between urinary 8-OHdG and UACR (r = 0.501, p < 0.001). According to ROC analysis, the AUC value of HbA1c was higher than the value of the AUC of 8-OHdG (0.882 and 0.771, respectively).. This study shows that the urine 8-OHdG levels increase in diabetic patients. However, urinary 8-OHdG is not a useful clinical marker, compared with UACR, to predict the development of diabetic nephropathy in diabetic patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Biomarkers; Case-Control Studies; Creatinine; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Male; Mass Spectrometry; Middle Aged; Reactive Oxygen Species; Tandem Mass Spectrometry

Reduced β cell mass is a characteristic feature of type 2 diabetes and incretin therapy is expected to prevent this condition. However, it is unknown whether dipeptidyl peptidase-4 inhibitors influence β and α cell mass in animal models of diabetes that can be translated to humans. Therefore, we examined the long-term effects of treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet morphology in Goto-Kakizaki (GK) rats, a spontaneous, non-obese model of type 2 diabetes, and explored the underlying mechanisms. Four-week-old GK rats were orally administered with vildagliptin (15 mg/kg) twice daily for 18 weeks. Glucose tolerance was monitored during the study. After 18 weeks, β and α cell morphology and the expression of molecules involved in cell proliferation and cell death were examined by immunohistochemistry and morphometric analysis. We found that vildagliptin improved glucose tolerance and insulin secretion, and suppressed hyperglucagonemia by increasing plasma active glucagon-like peptide-1 concentrations. β cell mass was reduced in GK rats to 40% of that in Wistar rats, but was restored to 80% by vildagliptin. Vildagliptin enhanced β and α cell proliferation, and increased the number of small neogenetic islets. Vildagliptin also reduced the number of 8-hydroxy-2'-deoxyguanosine-positive cells and forkhead box protein O1 expression, inhibited macrophage infiltration, and enhanced S6 ribosomal protein, molecule of target of rapamycin, and pancreatic duodenal homeobox 1 expression. These results indicate that starting vildagliptin treatment from an early age improved glucose tolerance and preserved islet β cell mass in GK rats by facilitating the proliferation of islet endocrine cells.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adamantane; Animals; Apoptosis; Cell Proliferation; Deoxyguanosine; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Eating; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Nitriles; Pyrrolidines; Rats; Time Factors; Vildagliptin

Oxidative stress plays an important role in the pathogenesis of diabetes and its complications. Genetic variations of enzymes producing reactive oxygen species could change their activity, thus contributing to the susceptibility to oxidative stress. The aim of this study was to examine the role of the NADPH oxidase C242T polymorphism in the development of carotid atherosclerosis in patients with type 2 diabetes. 286 diabetic patients and 150 healthy controls were enrolled in the study. Carotid atherosclerosis was quantified ultrasonographically as carotid intima-media thickness, plaque score (0-6) and plaque type (1-5). Diabetic patients were divided into low and high risk groups based on ultrasound phenotypes of carotid atherosclerosis. Genotypes were determined by real-time PCR. Levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) were measured by enzyme-linked immunosorbent assay (ELISA). Diabetic patients demonstrated a statistically significant difference compared to healthy controls in the following parameters: age, BMI, waist circumference, smoking prevalence, glucose, triglyceride and 8-OHdG serum levels. Control subjects had significantly higher levels of HDL, LDL and total cholesterol than diabetics (p < 0.001). The NADPH C242T polymorphism was not related with clinical characteristics, lipid parameters and 8-OHdG serum levels. We found no significant difference in the NADPH genotype distribution between diabetics and controls (p = 0.19) nor between low and high risk subgroups of diabetics (mean CIMT: p = 0.67; plaque score: p = 0.49, plaque type: p = 0.56). In the present study the NADPH C242T polymorphism was not associated with the degree of oxidative stress and carotid atherosclerosis. Further studies will show if it can be used as a genetic marker for carotid atherosclerosis in diabetic patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Carotid Arteries; Carotid Artery Diseases; Case-Control Studies; Cross-Sectional Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Association Studies; Humans; Male; Middle Aged; Multivariate Analysis; NADPH Oxidases; Oxidative Stress; Plaque, Atherosclerotic; Polymorphism, Single Nucleotide; Risk Factors; Sequence Analysis, DNA; Slovenia; Statistics, Nonparametric; Ultrasonography

Type 2 diabetes mellitus (T2DM) is a chronic degenerative disease that promotes autoxidation of sugars, leading to the production of reactive oxygen species. This damage occurs especially at the level of cellular proteins, carbohydrates, lipids and DNA, thus playing an important role in the pathogenesis of late complications of T2DM. We investigated the effect of folic acid on DNA and oxidative damage in patients with T2DM.. We studied 30 individuals diagnosed with T2DM and 30 control individuals without disease. Individuals with T2DM were prescribed 5 mg of folic acid, taken orally three times daily for 1 month. Samples were taken 15 and 30 days after treatment. DNA damage was determined using the micronucleus test in oral mucosa and oxidative stress by quantifying 8-hydroxy-2'-deoxyguanosine (8-OHdG) as well as by quantifying total lipid peroxides.. Individuals with T2DM had a higher number of micronuclei as well as higher levels of 8-OHdG and lipid peroxides than the control group (p = 0.001). Individuals with T2DM showed a significant reduction in the number of micronuclei and the concentration of 8-OHdG and lipid peroxides over time with folic acid intake.. A positive correlation exists between oxidative stress produced by T2DM and DNA damage, so the use of an antioxidant such as folic acid in DM2 therapy is advisable for delaying complications due to T2DM-induced oxidative stress and DNA damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Case-Control Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Female; Folic Acid; Humans; Male; Micronucleus Tests; Middle Aged; Oxidative Stress

Hyperglycemia promotes oxidative stress and hence generation of reactive oxygen species (ROS), which is known to play a crucial role in the pathogenesis of diabetic nephropathy. Metformin, an oral hypoglycemic drug, possesses antioxidant effects. The aim of this paper is to investigate the protective effects of metformin on the injury of renal podocytes in spontaneously diabetic Torii (SDT) rats, a new model for nonobese type 2 diabetes. Metformin (350 mg/kg/day) was given to SDT rats for 17 weeks. Blood glucose, glycated haemoglobin (HbA1c), and albuminuria were examined. Kidney histopathology, renal 8-hydroxydeoxyguanosine (8-OHdG) levels and apoptosis were examined. In 43-week-old SDT rats, severe hyperglycemia was developed, and albuminuria was markedly increased. Diabetes induced significant alterations in renal glomerular structure. In addition, urinary and renal 8-OHdG levels were highly increased, and podocyte loss was shown through application of the TUNEL and synaptopodin staining. However, treatment of SDT rats with metformin restored all these renal changes. Our data suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxidative injury.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Animals; Antioxidants; Apoptosis; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; DNA Fragmentation; Hypoglycemic Agents; Kidney; Male; Metformin; Microfilament Proteins; Oxidative Stress; Podocytes; Random Allocation; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley

Resveratrol (RSV) has anti-inflammatory and anti-oxidant actions which may contribute to its cardiovascular protective effects. We examined whether RSV has any beneficial effects on pancreatic islets in db/db mice, an animal model of type 2 diabetes. The db/db and db/dm mice (non-diabetic control) were treated with (db-RSV) or without RSV (db-control) (20 mg/kg daily) for 12 weeks. After performing an intraperitoneal glucose tolerance test and insulin tolerance test, mice were sacrificed, the pancreas was weighed, pancreatic β-cell mass was quantified by point count method, and the amount of islet fibrosis was determined. 8-Hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, was determined in 24 h urine and pancreatic islets. RSV treatment significantly improved glucose tolerance at 2 hrs in db/db mice (P = 0.036), but not in db/dm mice (P = 0.623). This was associated with a significant increase in both pancreas weight (P = 0.011) and β-cell mass (P = 0.016). Islet fibrosis was much less in RSV-treated mice (P = 0.048). RSV treatment also decreased urinary 8-OHdG levels (P = 0.03) and the percentage of islet nuclei that were positive for 8-OHdG immunostaining (P = 0.019). We conclude that RSV treatment improves glucose tolerance, attenuates β-cell loss, and reduces oxidative stress in type 2 diabetes. These findings suggest that RSV may have a therapeutic implication in the prevention and management of diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Blood Glucose; Deoxyguanosine; Diabetes Mellitus, Type 2; Disease Models, Animal; Fibrosis; Glucose Tolerance Test; Immunohistochemistry; Insulin; Insulin Resistance; Islets of Langerhans; Male; Mice; Organ Size; Oxidative Stress; Resveratrol; Stilbenes

The aim was to investigate indicators related to DNA damage and cancer pathogenesis in Type II diabetes cases with breast cancer. It was planned to evaluate the relationship between these markers with oral antidiabetic drugs.. Fourty patients and 10 healthy individuals were included in the study. HIF-1α and 8-OHdG are examined in blood samples taken from these individuals with an ELISA Kit. Statistical analysis of data was performed with 95% confidence using Windows package program SPSS 15.0.. HIF-1α parameters were found to be meaningfully higher in the patient group than the controls in both pretreatment and posttreatment periods (p<0.05). No significant differences in terms of 8-OHdG between patients and controls. However, posttreatment serum HIF-1α ve 8-OHdG levels was found lower than pretreatment levels in patients receiving metformin, but not with pioglitazone. Conversely, serum 8-OHdG levels decreased significantly in these patients. When patients were evaluated according to the treatment groups (pioglitazone vs. metformin) no significant differences in terms of serum HIF-1? and 8-OHdG levels between treatment groups.. HIF-1α levels decreased significantly in the patient group receiving metformin. However, there was no significant difference in terms of HIF-1α levels in the patients receiving pioglitazone.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Blood Glucose; Breast Neoplasms; Case-Control Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Metformin; Pioglitazone; Prognosis; Thiazolidinediones

Methylglyoxal (MGO) is a cytotoxic metabolite produced by in-vivo glycolysis that may result in diabetic complications. The aim of this study was to determine whether MGO and oxidative stress caused apoptosis of renal podocytes in the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes mellitus. Male ZDF rats aged 21 weeks developed marked hyperglycaemia with proteinuria and albuminuria. Immunohistochemical evaluation of sections of kidney demonstrated expression of MGO and 8-hydroxydeoxyguanosine (8-OHdG) in the podocytes of both normoglycaemic and diabetic rats. Podocyte apoptosis was shown through application of the TUNEL method. These findings suggest that expression of MGO and 8-OHdG is caused by hyperglycaemia, and that this expression is associated with the observed apoptosis of podocytes and is related to diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Apoptosis; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA Damage; Hyperglycemia; In Situ Nick-End Labeling; Kidney; Male; Oxidative Stress; Podocytes; Pyruvaldehyde; Rats; Rats, Zucker

Diabetic nephropathy is characterized by abnormal angiogenesis, and this is driven by several factors, including hyperglycaemia and ischaemia. We investigated the role of vascular endothelial growth factor receptor-2 (VEGFR-2) blockade and its effects on diabetic nephropathy.. Male db/db and db/m mice received long-term treatment with dRK6, an arginine-rich anti-VEGF hexapeptide, for 12 weeks or short-term treatment for only the first 4 weeks, starting from 8 weeks of age.. The urinary albuminuria and VEGF excretion varied according to the duration of diabetes, and the urinary VEGF levels were strongly correlated with the levels of albuminuria. Diabetes increased the VEGFR-2 expression in the kidneys. At the end of the 12-week study, compared with the db/db control mice, the db/db mice with long-term dRK6 treatment, which selectively inhibited VEGFR-2, had more albuminuria, related to weak nephrin signalling and advanced renal phenotypes, which were associated with hypoxia-oxidative stress, and an increased number of apoptotic endothelial cells. Interestingly, these changes were related to a decrease in phospho-Akt/eNOS-NO bioavailability. On the in vitro study, dRK6 increased the number of apoptotic human umbilical vein endothelial cells (HUVECs) in the high glucose media by blocking phospho-Akt/eNOS-NO signalling, and this was related to the increased oxidative stress. The short-term inhibition of VEGFR-2 neither improved the albuminuria nor the renal phenotype induced by diabetes.. Long-term selective blockade of VEGFR-2 by dRK6 had deleterious renal effects, and this was associated with downregulation of the Akt/eNOS-NO axis in db/db mice. Short-term VEGFR-2 blockade did not improve the renal phenotypes and the albuminuria. These findings suggest that VEGF-A-VEGFR-2 inhibition, regardless of how long it may be, does not ameliorate diabetic nephropathy in type 2 diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Animals; Apoptosis; Blotting, Western; Cell Proliferation; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelium, Vascular; Immunoenzyme Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide; Nitric Oxide Synthase Type III; Obesity; Oligopeptides; Proto-Oncogene Proteins c-akt; Renal Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Because oxidative stress may contribute to increased diabetes risk, the common variant of the MUTYH gene (AluYb8MUTYH) was investigated for its possible role in type 2 diabetes mellitus (T2DM). A total of 565 T2DM patients and 565 healthy subjects from China were enrolled in a case-control study. The distribution of AluYb8MUTYH differed in diabetic patients from controls, with a moderately increased percentage of the mutant allele (P) (44.7% versus 40.3%, P = 0.033, OR = 1.199). However, this distribution was similar between the diabetic early-onset and late-onset subgroups. Another 66 T2DM patients were further evaluated for 8-hydroxy-2'deoxyguanosine (8-OHdG) levels in leukocytic DNA. The average value of 8-OHdG/10(6) dG was 10.4 in patients with the wild-type genotype, 15.9 in heterozygotes, and 22.3 in homozygotes with the variation (P < 0.001, compared with the wild-type). Therefore, the AluYb8MUTYH polymorphism could be a novel genetic risk factor for T2DM, and accumulated 8-OHdG could contribute to this disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Asian People; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA; DNA Glycosylases; Female; Genetic Predisposition to Disease; Humans; Leukocytes; Male; Middle Aged; Mutagenesis, Insertional; Polymorphism, Genetic; Risk Factors

This study illustrates the relationship between oxidative DNA damage and obesity in patients with prediabetes and type 2 diabetes compared with controls.. Participants attended the School of Community Health, Diabetes Screening Clinic, Charles Sturt University, Australia, between February 2006 and June 2008. A total of 162 participants (35 type 2 diabetic patients; eight prediabetic subjects; and 119 age-, gender-, and weight-matched controls) were investigated. All patients were selected on clinical grounds.. Serum 8-hydroxy 2'-deoxy-guanosine (8-OHdG) level was significantly greater in the prediabetic subjects (671.3±140 pg/ml) compared with controls (210.1±166 pg/ml; P<0.01). The diabetic group (1979.6±1209 pg/ml) had the highest level of 8-OHdG. There was a significant increase in serum 8-OHdG in obese subjects (848.5±103 pg/ml; P<0.001) and overweight subjects (724±102 pg/ml; P=0.005) compared with the lean subjects (196.5±327 pg/ml).. Our results indicate that serum 8-OHdG is increased already in prediabetes suggesting oxidative DNA damage to be present with minor elevation of blood glucose levels (BGLs). The statistically significant positive correlation between serum 8-OHdG and body mass index in the diabetic group indicates that obesity has an additive effect to increased BGL contributing to oxidative DNA damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Antioxidants; Biomarkers; Blood Glucose; Body Mass Index; Cholesterol, HDL; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Female; Free Radicals; Glycated Hemoglobin; Humans; Lipids; Male; Middle Aged; Multivariate Analysis; Obesity; Oxidative Stress; Prediabetic State; Sex Characteristics

Several studies have shown increased oxidative stress in patients with pre-diabetes and newly diagnosed Type 2 diabetes mellitus (T2DM). It has been proposed that oxidative stress initiates insulin resistance in genetically predisposed individuals. The aim of this study was to evaluate the markers of oxidative stress in the offspring of patients with T2DM.. We examined 60 lean normoglycemic offspring of Type 2 diabetics, and 52 age, sex and body mass index matched subjects without family history of T2DM as controls. Anthropometric, biochemical and carotid intima media thickness (IMT) measurements and oral glucose tolerance test (OGTT) were performed. Erythrocyte superoxide dismutase and glutathione peroxidase activities, serum nitric oxide, plasma total sulfhydryl (tSH) groups, plasma total antioxidant status, plasma malondialdehyde and serum 8-hydroxydeoxy-guanosine (8-OHdG) levels were compared between 2 groups.. 2 groups were similar for the measurements of anthropometric, blood pressure, lipids, fasting glucose, HOMA-IR and carotid IMT. Glucose levels during OGTT were significantly higher in the offspring of Type 2 diabetics than controls (p=0.035). The offspring of Type 2 diabetics showed a significant increase in serum 8-OHdG level (p=0.005) and plasma tSH groups (p=0.032) when compared to the controls. Significant differences were not obtained in other oxidative stress marker levels between 2 groups.. Main finding of our study was the presence of increased oxidative DNA damage in lean normoglycemic offspring of Type 2 diabetic patients. There is a need for further clinical studies in order to explain whether oxidative stress is present in genetically predisposed subjects and induces the insulin resistance.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Blood Glucose; Body Mass Index; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Family Health; Female; Genetic Predisposition to Disease; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Oxidative Stress; Parents; Prediabetic State; Sulfhydryl Compounds; Thinness; Young Adult

Type 2 diabetes is a heterogeneous metabolic disease characterized by insulin resistance and β-cell dysfunction leading to hyperglycaemia and dyslipidaemia. Dietary intervention seems to improve some of these cellular complications, namely insulin resistance. Our aim was to evaluate the effects of dietary restriction on systemic and skeletal muscle oxidative stress and insulin resistance in normal Wistar rats and Goto-Kakizaki (GK) rats, a non-obese type 2 diabetic animal model. Four-month-old normal and diabetic rats were separated in four groups. One group of each strain was maintained with ad libitum standard diet, and the other group was submitted to a dietary restriction (50% of control animals daily food intake), during 2 months. Metabolic profile, insulin resistance indexes and muscle lipids were determined. Oxidative stress parameters were also measured at systemic and muscle levels: protein carbonyl, 8-hydroxy-2'-deoxyguanosine and free 8-isoprostane. Dietary restriction improved lipid profile in both strains and urinary free 8-isoprostane and plasma carbonyl compounds in diabetic rats. An improvement of muscle triglycerides accumulation and 8-isoprostane concentration and a reduction of insulin resistance were also observed in GK rats. Our data show that dietary restriction ameliorates systemic and skeletal muscle oxidative stress state in type 2 diabetes, which is associated with improved insulin resistance.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Glucose; Cholesterol; Deoxyguanosine; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Dinoprost; Eating; Insulin Resistance; Male; Muscle, Skeletal; Oxidative Stress; Protein Carbonylation; Rats; Rats, Inbred OLETF; Rats, Wistar; Triglycerides

We analyzed data from a cohort of 1,381 newly diagnosed type 2 diabetic patients to test the hypothesis that urinary markers of nucleic acid oxidation are independent predictors of mortality.. We examined the relationship between urinary excretion of markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) and RNA oxidation (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and long-term mortality using Cox proportional hazards regression.. After multivariate adjustment, the hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.44 (1.12-1.85) and 1.54 (1.13-2.10), respectively. Conversely, no significant associations between 8-oxodG and mortality were found in the adjusted analyses.. Urinary excretion of the RNA oxidation marker 8-oxoGuo measured shortly after diagnosis of type 2 diabetes predicts long-term mortality independently of conventional risk factors. This finding suggests that 8-oxoGuo could serve as a new clinical biomarker in diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Denmark; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Guanosine; Humans; Oxidation-Reduction; Oxidative Stress; Prognosis; Proportional Hazards Models; RNA

The aim of this study is to assess the oxidative stress status in diabetes mellitus (DM) and diabetic nephropathy. The study group comprised 40 control subjects, 40 type 2 DM patients without complications and 37 diabetic nephropathies. Compared with control subjects, superoxide dismutase, glutathione peroxidase, catalase, vitamin C were decreased (P < 0.01). There was a significant increase in serum malondialdehyde (MDA), conjugated diene (CD), advanced oxidation protein products (AOPP), protein carbonyl (PC) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in diabetes patients when compared with normal subjects (P < 0.01). Moreover, these indexes were much higher in diabetic nephropathy than that of diabetic patients without vascular complications (P < 0.05, P < 0.01). There was a significant correlation between the serum glucose levels and PC, 8-OHdG (P < 0.05, P < 0.01). There were highly significant positive correlation of CD and MDA, AOPP and PC (P < 0.01). Plasma AOPP levels had a significant correlation with PC levels (P < 0.01). Our findings suggested that diabetes patients have more severe oxidative stress than normal persons and higher oxidative stress in diabetic nephropathy than those in patients without complications. Oxidative stress may play an important intermediary role in the pathogenesis of diabetes complications.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Case-Control Studies; Catalase; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glutathione; Glutathione Peroxidase; Humans; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Superoxide Dismutase

Several studies have shown that twice-daily injection of premixed insulin analog (MIX) therapy achieves glycemic control equivalent to that with basal-bolus (BB) therapy. However, glycemic fluctuations that lead to oxidative stress may be associated with the risk of diabetic complications. Therefore, in this study, we compared oxidative stress markers between MIX therapy and BB therapy.. In this cross-sectional study, we recruited a total of 37 patients (17 patients in the BB group and 20 patients in the MIX group) and compared urinary 8-isoprostane and urinary 8-hydroxydeoxyguanosine (8-OHdG) levels.. There were no significant differences in urinary 8-isoprostane (BB vs MIX: 199+/-92 pg/mg Cr vs 266+/-107 pg/mg Cr) or urinary 8-OHdG (4.7+/-1.6 ng/mg Cr vs 5.4+/-1.9 ng/mg Cr, respectively). Conclusion These results suggest that MIX is equivalent to BB in terms of glycemic fluctuations and oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Blood Glucose; Cross-Sectional Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; Dinoprost; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Injections; Insulin; Male; Middle Aged; Oxidative Stress

Rising levels of oxidative stress play an important role in the pathogenesis of type 2 diabetes mellitus. Therefore, we investigated the serum level of 8-hydroxy-2-deoxy-guanosine (8-OHdG) as an early oxidative stress marker in patients with prediabetes and with type 2 diabetes mellitus.. Convenience sampling from people attending a diabetes screening clinic. Participants at the rural diabetes screening clinic had their medical history recorded as well as body mass index, blood glucose, cholesterol, glutathione, malondialdehyde, fasting blood glucose and 8-OHdG measured. Statistical analysis was performed using ANOVA followed by Sheffe posthoc test for between-group differences.. The 8-OHdG level was significantly greater in the prediabetes (516.5 +/- 260 pg/ml) compared to control group (177.8 +/- 91 pg/ml; P < 0.01). The diabetes group (1926.9 +/- 1197 pg/ml) had the highest level of 8-OHdG, being approximately four times greater compared to the prediabetes group (P < 0.001). No significant change in the cholesterol profile, MDA level indicative of lipid peroxidation and antioxidant activity as measured by erythrocyte reduced glutathione was observed in the prediabetes group compared to the control group (P > 0.05).. 8-OHdG levels in both the prediabetes and diabetes group were increased from control values suggesting a role for 8-OHdG as an early disease marker that may be more sensitive compared to cholesterol, MDA and erythrocyte reduced glutathione levels, which were within normal limits. This is of clinical significance as 8-OHdG is a strong indicator of oxidative stress related DNA damage within blood vessel walls and other tissue that increases the risk of cardiovascular disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Case-Control Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Female; Humans; Male; Malondialdehyde; Middle Aged; Prediabetic State

The effect of glucose excursions on oxidative stress is an important topic in diabetes research. We investigated this relationship by analyzing markers of oxidative stress and glycemic data from a continuous glucose monitoring system (CGMS) in 30 individuals with normal glucose regulation (NGR), 27 subjects with impaired glucose regulation (IGR), and 27 patients with newly diagnosed type 2 diabetes (T2DM). We compared the mean amplitude of glycemic excursion (MAGE), mean postprandial glucose excursion (MPPGE), and mean postprandial incremental area under the curve (IAUC) with plasma levels of oxidative stress markers 8-iso-PGF2α, 8-OH-dG, and protein carbonyl content in the study subjects. Patients with T2DM or IGR had significantly higher glucose excursions and plasma levels of oxidative stress markers compared to normal controls (P < 0.01 or 0.05). Multiple linear regression analyses showed significant relationships between MAGE and plasma 8-iso-PGF2α, and between MPPGE and plasma 8-OH-dG in patients with IGR or T2DM (P < 0.01 or 0.05). Furthermore, 2h-postprandial glucose level and IAUC were related to plasma protein carbonyl content in the study cohort including T2DM and IGR (P < 0.01). We demonstrate that glucose excursions in subjects with IGR and T2DM trigger the activation of oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Blood Glucose; Cohort Studies; Deoxyguanosine; Diabetes Complications; Diabetes Mellitus, Type 2; Dinoprost; Female; Glucose Intolerance; Humans; Hyperglycemia; Hypoglycemia; Male; Middle Aged; Monitoring, Ambulatory; Oxidative Stress; Postprandial Period; Protein Carbonylation

Diabetic nephropathy is the most serious complication in diabetes mellitus. Oxidative stress via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and vascular endothelial growth factor (VEGF) pathway play critical roles in the development of diabetic nephropathy. We evaluated the effects of apocynin, NADPH oxidase inhibitor on diabetic nephropathy in a type 2 diabetic rat model. Sixteen Otsuka Long Evans Tokushima Fatty (OLETF) rats and 9 Long Evans Tokushima Otsuka (LETO) were divided into the following three groups: LETO rats (n=9), control OLETF rats (n=7) and apocynin-treated OLETF rats (n=9). We examined body weights, plasma glucose levels, urinary albumin-creatinine ratio (ACR) and protein-creatinine ratio (PCR). At 50 weeks, experimental rats were sacrificed and their kidneys were extracted for hematoxylin eosin stain, immunohistochemical VEGF stain and VEGF mRNA real-time RT-PCR. To examine oxidative stress, we checked 24h urinary 8-OHdG (8-hydroxy-2'-deoxyguanosine) and MDA (malondialdehyde). Urinary protein and albumin excretions were reduced after apocynin treatment, though apocynin could not significantly decrease serum glucose levels. There were improvements of glomerular and mesangial expansion in the apocynin-treated OLETF rats. Apocynin significantly decreased optical density of glomerular VEGF expression in immunohistochemical stain and reduced the concentration of 24h urinary 8-OHdG and MDA. From these results, it was suggested that apocynin may have the potential to protect against diabetic nephropathy via amelioration of oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetophenones; Animals; Cytoprotection; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Down-Regulation; Drug Evaluation, Preclinical; Enzyme Inhibitors; Hypoglycemic Agents; Kidney; Male; Malondialdehyde; NADPH Oxidases; Oxidative Stress; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Vascular Endothelial Growth Factor A

The aim of the present observational study was to investigate the relationships between glycaemic status and levels of oxidative stress and inflammation in well-controlled type 2 diabetes subjects. Metabolic variables (weight, BMI, waist circumference (waist), blood glucose, glycated Hb (HbA(1c)), insulin, blood lipids), biomarkers of oxidative stress (8-iso-PGF(2alpha), malondialdehyde, 8-oxo-7,8-dihydro-2'-deoxyguanosine, formamido pyrimidine glycosylase-sites, frequency of micronucleated erythrocytes, nitrotyrosine) and inflammatory markers (high sensitivity C-reactive protein (hsCRP), IL-6, cyclo-oxygenase-catalyzed PGF(2alpha)-metabolite) were measured. Fifty-six patients (thirty women and twenty-six men, age 62.3 (SD 7.0) years, HbA(1c) 6.1 (SD 0.9) %, BMI 28.3 (SD 3.8) kg/m(2), waist 99.6 (SD 11.1) cm) were included in the study. HbA(1c) (r 0.29, P=0.03) and blood glucose (r 0.33, P=0.01) correlated positively with 8-iso-PGF(2alpha). Positive correlations were also observed between HbA(1c) and nitrotyrosine (r 0.42, P=0.01), waist and hsCRP (r 0.37, P=0.005), hsCRP and IL-6 (r 0.61, P<0.0001) and between PGF(2alpha)-metabolite and 8-iso-PGF(2alpha) (r 0.27, P=0.048). The present study indicates that glycaemic status is associated with oxidative stress even in subjects with well-controlled type 2 diabetes. Furthermore, inflammation was more related to abdominal obesity than to glycaemic control. A large number of biomarkers of oxidative stress and inflammation were investigated, but only a few associations were found between the markers. This could be due to the fact that none of these biomarkers biosynthesises via similar pathways or simultaneously owing to their diverse nature and origin.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Blood Glucose; Body Mass Index; C-Reactive Protein; Deoxyguanosine; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Insulin; Interleukin-6; Lipids; Male; Malondialdehyde; Middle Aged; Obesity; Oxidative Stress; Probability; Statistics, Nonparametric; Tyrosine; Waist Circumference

Vascular endothelial growth factor (VEGF), which is associated with the stimulation of angiogenesis and collateral vessel synthase, is one of the crucial factors involved in cardiac remodeling in type 2 diabetes.. We investigated VEGF inhibition by dRK6 on the heart in an animal model of type 2 diabetes. Male db/db and db/m mice either were treated with dRK6 starting at 7 weeks of age for 12 weeks (db/db-dRK6 and db/m-dRK6) or were untreated.. Cardiac dysfunction and hypertrophy were noted by echocardiogram and molecular markers in the db/db-dRK6 mice. The presence of diabetes significantly suppressed the expression of VEGF receptor (VEGFR)-1 and VEGFR-2, phospho-Akt, and phospho-endothelial nitric oxide synthase (eNOS) in the heart. In db/db-dRK6 mice, dRK6 completely inhibited VEGFR-2, phospho-Akt, and phospho-eNOS expression, whereas no effect on VEGFR-1 was observed. Cardiac fibrosis, microvascular scarcity associated with an increase in apoptotic endothelial cells, and inflammation were prominent, as well as increase in antiangiogenic growth factors. Cardiac 8-hydroxy-deoxyguanine and hypoxia-inducible factor-1alpha expression were significantly increased. No such changes were found in the other groups, including the db/m-dRK6 mice. The number of apoptotic human umbilical vein endothelial cells was increased by dRK6 in a dose-dependent manner only at high glucose concentrations, and this was associated with a decrease in phospho-Akt and phospho-eNOS related to oxidative stress.. Our results demonstrated that systemic blockade of VEGF by dRK6 had deleterious effects on the heart in an animal model of type 2 diabetes; dRK6 induced downregulation of the VEGFR-2 and Akt-eNOS axis and enhancement of oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cardiomegaly; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Echocardiography; Endothelium, Vascular; Fibrosis; Heart Diseases; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Inbred Strains; Nitric Oxide Synthase Type III; Oligopeptides; Proto-Oncogene Proteins c-akt; Thrombospondin 1; Vascular Endothelial Growth Factor A

Diabetes mellitus is characterized by oxidative stress, which in turn determines endothelial dysfunction. Gliclazide is a sulphonylurea antidiabetic drug with antioxidant effects due to its azabicyclo-octyl ring. It has been reported to potentially protect the vasculature through improvements in plasma lipid levels and platelet function. We hypothesized that gliclazide has a beneficial effect on endothelial function in Goto-Kakizaki rats (GK), an animal model of type 2 diabetes fed an atherogenic diet for 4 months. We evaluated the influence of gliclazide on both metabolic and oxidative status and NO-mediated vasodilation. GKAD rats showed increased oxidative stress and impaired endothelium-dependent vasodilation. GKAD rats treated with gliclazide showed increased sensitivity to NO-mediated vasodilation, a significant decrease in fasting glycemia and insulinemia, and a significant decrease in systemic oxidative stress. In conclusion, our results suggest that gliclazide treatment improves NO-mediated vasodilation in diabetic GK rats with dyslipidemia probably due to its antioxidant effects, although we cannot rule out substantial benefits due to a reduction in fasting blood glucose. The availability of a compound that simultaneously decreases hyperglycemia, hyperinsulinemia, and inhibits oxidative stress is a promising therapeutic candidate for the prevention of vascular complications of diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcholine; Animals; Antioxidants; Body Weight; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dietary Fats; Disease Models, Animal; Dyslipidemias; Gliclazide; Hypoglycemic Agents; Nitric Oxide; Oxidative Stress; Rats; Rats, Mutant Strains; Rats, Wistar; Vasodilation; Vasodilator Agents

Oxidative stress (OS) has been implicated in the aetiology and progression of diabetic complications including diabetic foot ulcer. In this study, the levels of lipid peroxides (LPO) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as well as the enzymatic antioxidant activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in type 2 diabetes mellitus and diabetic foot ulcer subjects were assessed and compared with apparently healthy normal subjects to understand the involvement of OS in the subjects.. The above-mentioned OS markers were measured in 50 subjects for each of the following groups: type 2 diabetes mellitus (DM), diabetic foot ulcer (DF) and non-diabetic control (NC).. Significant elevated values of LPO (39.86%) and 8-OHdG (45.53%) were found in DM subjects compared with the NC subjects. This increase in both parameters was greater for DF subjects: 80.23% and 53.91% respectively. SOD activities were significantly reduced in DM (14.82%) and DF (4.09%) subjects in contrast with elevated activities of GPx observed in DM (21.87%) and DF (20.94%) subjects. Glycated haemoglobin/fasting plasma glucose (HbA1c/FPG) correlated positively with LPO, 8-OHdG and GPx, whereas a negative correlation was observed for SOD.. Increased oxidation subsequent to diabetic conditions induces an over-expression of GPx activity suggesting a compensatory mechanism by the body to prevent further tissue damage in the subjects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antioxidants; Blood Glucose; Case-Control Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Foot; Disease Progression; Female; Glutathione Peroxidase; Glycated Hemoglobin; Humans; Hyperglycemia; Lipid Peroxides; Male; Middle Aged; Oxidative Stress; Risk Factors; Superoxide Dismutase

Individuals with type 2 diabetes exhibit higher DNA damage and increased risk of cardiovascular disease (CVD). However, mechanisms underlying the association between DNA damage and development of type 2 diabetes and CVD are not understood. We sought to link peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PPARGC1A), a master transcriptional regulator of mitochondrial oxidative phosphorylation and cellular energy metabolism, with DNA damage, type 2 diabetes, and CVD.. We measured DNA damage as urinary 8-hydroxydeoxyguanosine (8-OHdG) concentration and examined the relationship between nine PPARGC1A genetic variants, DNA damage, type 2 diabetes, and self-reported CVD in 959 participants of the Boston Puerto Rican Health Study.. With respect to urinary 8-OHdG, PPARGC1A variants showed significant association, and PPARGC1A haplotypes exhibited significant association after correction for multiple testing. Two independent PPARGC1A variants associated significantly with type 2 diabetes (odds ratios [ORs] 1.35 and 2.46; P = 0.045 and <0.001). Carriers of minor alleles of two other PPARGC1A variants, both in strong linkage disequilibrium and associated with lower DNA damage, showed lower prevalence of CVD (ORs 0.53 and 0.65; P = 0.030 and 0.175). Moreover, we found that physical activity correlated negatively with DNA damage.. It is plausible that low physical activity combined with risk haplotyes contribute to the high prevalence of type 2 diabetes in this population. We propose that PPARGC1A influences development of type 2 diabetes and CVD via DNA damage. Increasing physical activity, which induces PPARGC1A expression, is a potential strategy to slow DNA damage, thereby decreasing the risk of CVD for individuals with type 2 diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Boston; Cardiovascular Diseases; Deoxyguanosine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Angiopathies; DNA Damage; Exons; Female; Gene Frequency; Genetic Variation; Heat-Shock Proteins; Humans; Introns; Male; Middle Aged; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polymorphism, Single Nucleotide; Puerto Rico; Risk Factors; Transcription Factors

The purpose of this study was to determine whether moderate-intensity exercise training reduces oxidative stress in patients with type 2 diabetes mellitus over 12 months. The patients were divided into 3 groups: aerobic training combined with the use of a fitness center (group A, n = 43), aerobic training only (group B, n = 44), or controls (group C, n = 16). The subjects in groups A and B were instructed to exercise at 50% of peak oxygen uptake for more than 30 minutes on at least 3 days per week over a 12 month period. In addition, the subjects in group A were instructed to use a fitness center and were taught how to perform aerobic training in the indicated manner by certified fitness instructors. We measured the levels of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a parameter of oxidative stress. Serum glycated albumin levels were reduced significantly after 6 and 12 months in groups A and B and after 12 months in group C. Urinary 8-OHdG levels decreased after 12 months in groups A and B, but remained unchanged in group C. There was a significant positive linear association between percentage changes in urinary 8-OHdG and glycated albumin levels over the 12 months. In conclusion, aerobic exercise training improved glycemic control and reduced oxidative stress in patients with type 2 diabetes mellitus. Furthermore, improvement in glycemic control was associated with a reduction in oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Deoxyguanosine; Diabetes Mellitus, Type 2; Electrocardiography; Exercise; Exercise Test; Female; Fitness Centers; Glycated Serum Albumin; Glycation End Products, Advanced; Heart Rate; Humans; Male; Middle Aged; Oxidative Stress; Oxygen Consumption; Serum Albumin

To assess the therapeutic effect of losartan on type 2 diabetes mellitus (DM2) with gas chromatography (GC)-based metabonomics.. DM2 patients were dosed with losartan (100 mg/d) and urines were collected at week 8 and 12. The biochemical criteria (blood pressure, urinary albumen, urinary 8-hydroxy-2'-deoxyguanosine and blood creatinine) were analyzed. Urine samples were derivatived and analyzed by GC. Multivariate metabonomics analysis was performed after peak alignment.. After 8-12 weeks, losartan showed little curative effect and no remarked changes of biochemical criteria were observed. However, metabonomics analysis revealed that some biomarkers such as glucitol and inositol changed.. GC-based metabonomics analysis enables the rapid identification of metabolic differences and provides information concerning therapeutic effect of losartan.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Biomarkers; Chromatography, Gas; Creatinine; Deoxyguanosine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Monitoring; Humans; Hypoglycemic Agents; Inositol; Losartan; Metabolome; Sorbitol

Recent studies have uncovered various pleiotrophic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase-inhibiting drugs (statins). Several studies have identified a beneficial effect of statins on diabetic nephropathy; however, the molecular mechanisms are unclear. In this study, we show that statin ameliorates nephropathy in db/db mice, a rodent model of type 2 diabetes, via downregulation of NAD(P)H oxidase NOX4, which is a major source of oxidative stress in the kidney. Pitavastatin treatment for 2 weeks starting at 12 weeks of age significantly reduced albuminuria in the db/db mice concomitant with a reduction of urinary 8-hydroxy-2'-deoxyguanosine and 8-epi-prostaglandin F(2alpha). Immunohistochemical analysis found increased amounts of 8-hydroxy-2'-deoxyguanosine and NOX4 protein in the kidney of db/db mice. Quantitative reverse transcription-polymerase chain reaction also showed increased levels of NOX4 mRNA. Pitavastatin normalized all of these changes in the kidneys of diabetic animals. Additionally, 12-week treatment with the statin completely normalized the levels of transforming growth factor-beta1 and fibronectin mRNA as well as the mesangial expansion characteristic of diabetic nephropathy. Our study demonstrates that pitavastatin ameliorates diabetic nephropathy in db/db mice by minimizing oxidative stress by downregulating NOX4 expression. These findings may provide insight into the mechanisms of statin therapy in early stages of diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Animals; Blood Glucose; Body Weight; Cell Proliferation; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Models, Animal; Down-Regulation; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Mesangial Cells; Mice; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Quinolines; RNA, Messenger; Time Factors; Transforming Growth Factor beta1

To detect the oxidative DNA damage in diabetic patients and to investigate the relationship of oxidative DNA damage with diabetes and diabetic nephropathy.. Single cell gel electrophoresis (SCGE) was used to detect the DNA strand breaks in peripheral blood lymphocytes, and oxidative DNA damage product and serum 8-OHdG were determined by a competitive ELISA in 47 cases, including 25 patients without diabetic complications, 22 patients with diabetic nephropathy and 25 normal control subjects.. Diabetic patients showed greater oxidative damage to DNA. The percentage of comet cells and the length of DNA migration (comet tail length) of peripheral blood lymphocytes were significantly increased in patients with diabetes, and significantly higher in patients with diabetic nephropathy than in diabetic patients without vascular complications (P < 0.05). There was a significant increase in serum 8-OHdG in diabetic patients compared with normal subjects (P < 0.05). Moreover, serum 8-OHdG was much higher in patients with diabetic nephropathy than in diabetic patients without vascular complications (P < 0.05).. There is severe oxidative DNA damage in diabetic patients. Enhanced oxidative stress may be associated with diabetes, especially in patients with diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Case-Control Studies; Comet Assay; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA Damage; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lymphocytes; Male; Middle Aged; Oxidative Stress

To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine- and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; AMP-Activated Protein Kinases; Deoxyguanosine; Diabetes Mellitus, Type 2; Female; Gene Expression; Glucose; Glutathione; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Multienzyme Complexes; Oxidative Stress; Protein Serine-Threonine Kinases; Time Factors; Tyrosine

This study was undertaken to reveal the role of NAD(P)H oxidase in increased oxidative stress in islets of Type 2 diabetes. Immunostaining analysis showed that staining intensities of NAD(P)H oxidase components, gp91phox and p22phox, significantly increased in islets of animal models of Type 2 diabetes, OLETF rats (60 weeks of age) and db/db mice (14 weeks of age), compared with age-matched controls, respectively, correlating with increased levels of oxidative stress marker, 8-hydroxy-deoxyguanosine or 4-hydroxy-2-nonenal modified protein. In db/db mice, oral administration of angiotensin II Type 1 receptor antagonist valsartan (5 mg/kg) for 4 weeks significantly attenuated the increased expression of gp91phox and p22phox together with inhibition of oxidative stress and partially restored decreased insulin contents in islets. Angiotensin II-related increased expression of NAD(P)H oxidase may play an important role in increased oxidative stress in islets of Type 2 diabetes. This mechanism may be a novel therapeutic target for preventing beta-cell damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Aldehydes; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensins; Animals; Body Weight; Deoxyguanosine; Diabetes Mellitus, Type 2; Disease Models, Animal; Insulin; Islets of Langerhans; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Phosphoproteins; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Tetrazoles; Time Factors; Valine; Valsartan

Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Oxykine is the cantaloupe melon extract rich in vegetal superoxide dismutase covered by polymeric films of wheat matrix gliadin. In this study, we examined whether chronic oral administration of oxykine could prevent the progression of diabetic nephropathy induced by oxidative stress using preclinical rodent model of type 2 diabetes. We used female db/db mice and their non-diabetic db/m littermates. The mice were divided into the following three groups: non-diabetic db/m; diabetic db/db, and diabetic db/db treated with oxykine. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were preformed on 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the oxykine-treated group and the non-treated db/db group, however both groups kept significantly high levels rather than db/m mice. The relative mesangial area calculated by mesangial area/total glomerular area ratio was significantly ameliorated in the oxykine treated group compared with non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with oxykine. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than that of oxykine-treated db/db mice. In this study, treatment of oxykine ameliorated the progression and acceleration of diabetic nephropathy for rodent model of type 2 diabetes. These results indicated that the oxykine reduced the diabetes-induced oxidative stress and renal mesangial cell injury. In conclusion, oxykine might be a novel approach for the prevention of diabetes nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Glucose; Body Weight; Cucumis melo; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glucose Tolerance Test; Kidney; Mice; Oxidative Stress; Phytotherapy; Plant Extracts; Superoxide Dismutase

Carbonyl stress is one of the important mechanisms of tissue damage in vascular complications of diabetes. In the present study, we observed that the plasminogen activator inhibitor-1 (PAI-1) levels in serum and its gene expression in adipose tissue were up-regulated in aged OLETF rats, model animals of obese type 2 diabetes. To study the mechanism of PAI-1 up-regulation, we examined the effect of advanced glycation end products (AGEs) and the product of lipid peroxidation (4-hydroxy-2-nonenal (HNE)), both of which are endogenously generated under carbonyl stress. Stimulation of primary white adipocytes by either AGE or HNE resulted in the elevation of PAI-1 in culture medium and at mRNA levels. The up-regulation of PAI-1 was also observed by incubating the cells in high glucose medium (30 mm, 48 h). The stimulatory effects by AGE or high glucose were inhibited by antioxidant, pyrrolidine dithiocarbamate, and reactive oxygen scavenger, probucol, suggesting a pivotal role of oxidative stress in white adipocytes. We also found that the effect by HNE was inhibited by antioxidant, N-acetylcysteine and that a specific inhibitor of glutathione biosynthesis, l-buthionine-S,R-sulfoximine, augmented the effect of subthreshold effect of HNE. Bioimaging of reactive oxygen species (ROS) by a fluorescent indicator, 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, revealed ROS production in white adipocytes treated with AGE or HNE. These results suggest that cellular carbonyl stress induced by AGEs or HNE may stimulate PAI-1 synthesis in and release from adipose tissues through ROS formation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcysteine; Adipocytes; Aldehydes; Animals; Antioxidants; Buthionine Sulfoximine; Cells, Cultured; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Free Radical Scavengers; Glycation End Products, Advanced; Lipid Peroxidation; Male; NF-kappa B; Oxidative Stress; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred OLETF; Reactive Oxygen Species; RNA, Messenger; Up-Regulation

Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Astaxanthin, which is found as a common pigment in algae, fish, and birds, is a carotenoid with significant potential for antioxidative activity. In this study, we examined whether chronic administration of astaxanthin could prevent the progression of diabetic nephropathy induced by oxidative stress in mice. We used female db/db mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into three groups as follows: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with astaxanthin. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the astaxanthin-treated group showed a lower level of blood glucose compared with the non-treated db/db group; however, both groups had a significantly high level compared with the db/m mice. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the astaxanthin-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with astaxanthin. The 8-OHdG immunoreactive cells in glomeruli of non-treated db/db mice were more numerous than in the astaxanthin-treated db/db mice. In this study, treatment with astaxanthin ameliorated the progression and acceleration of diabetic nephropathy in the rodent model of type 2 diabetes. The results suggested that the antioxidative activity of astaxanthin reduced the oxidative stress on the kidneys and prevented renal cell damage. In conclusion, administration of astaxanthin might be a novel approach for the prevention of diabetes nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Animals; beta Carotene; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Female; Kidney; Mice; Mice, Mutant Strains; Reference Values; Regression Analysis; Tissue Distribution; Xanthophylls

Increased oxidative stress induced by hyperglycemia may contribute to the pathogenesis of diabetic complications. Urinary 8-hydroxydeoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative DNA damage and also of oxidative stress. This article studied oxidative DNA damage in patients with diabetic nephropathy and in healthy control subjects by urinary 8-OHdG evaluations. Contents of 8-OHdG in urine were analyzed by capillary electrophoresis with end-column amperometric detection (CE-AD) after a single-step solid-phase extraction (SPE). Levels of urinary 8-OHdG in diabetic nephropathy patients with macroalbuminuria was significant higher than in control subjects (5.72 +/- 6.89 micromol/mol creatinine versus 2.33 +/- 2.83 micromol/mol creatinine, P = 0.018). A significant difference of 24 h urinary 8-OHdG excretions exists between the patients with macroalbuminuria and the patients with normoalbuminuria (19.2 +/- 16.8 microg/24 h versus 8.1 +/- 1.7 microg/24 h, P = 0.015). There was a positive correlation between urinary excretion of 8-OHdG and glycosylated hemoglobin (HbA1c) (r = 0.287, P = 0.022). A weak correlation exists between the levels of 8-OHdG and triglyceride (r = 0.230, P = 0.074). However, the urinary 8-OHdG contents are not correlated with blood pressure and total cholesterol. The increased excretion of urinary 8-OHdG is seen as indicating an increased systemic level of oxidative DNA damage in diabetic nephropathy patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA Damage; Electrophoresis, Capillary; Female; Humans; Male; Middle Aged

To evaluate the association between the C242T polymorphism of the p22 phox gene, an essential component of NAD(P)H oxidase in the vasculature, with intima-media thickness (IMT) of the carotid artery and risk factors for atherosclerosis in type 2 diabetic subjects.. C242T polymorphism of the p22 phox gene was detected by polymerase chain reaction-restriction fragment-length polymorphism in 200 Japanese type 2 diabetic subjects and 215 nondiabetic subjects. We examined the association with this mutation and carotid atherosclerosis as well as the patients' clinical characteristics and the level of 8-hydroxy-2'deoxyguanosine (8-OHdG) as an index of oxidative DNA damage.. The diabetic subjects with the TC+TT genotypes displayed a significantly lower average IMT (1.13 +/- 0.31 vs. 1.31 +/- 0.34 mm; P = 0.0099) and a not significantly lower serum 8-OHdG level than those with the CC genotype, despite no difference in the risk factors. Stepwise multiple regression analysis showed that the risk factors for increased IMT in the diabetic subjects were systolic blood pressure (P = 0.0042) and p22 phox CC genotype (P = 0.0151). In nondiabetic subjects, the average IMT of the TC+TT group was not different from that of the CC group (0.85 +/- 0.14 vs. 0.94 +/- 0.30 mm, P = 0.417). Fasting plasma insulin concentration (41.4 +/- 15.6 vs. 64.2 +/- 59.4 pmol/l, P = 0.0098) and insulin resistance index of homeostasis model assessment (HOMA-R) (1.58 +/- 0.66 vs. 2.60 +/- 2.56, P = 0.0066) were significantly lower in the TC+TT group than in the CC group.. These results show that the C242T mutation in the p22 phox gene is associated with progression of asymptomatic atherosclerosis in the subjects with type 2 diabetes and is also associated with insulin resistance in nondiabetic subjects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Asian People; Carotid Arteries; Carotid Artery Diseases; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Insulin; Insulin Resistance; Japan; Male; Membrane Transport Proteins; Middle Aged; NADPH Dehydrogenase; NADPH Oxidases; Phosphoproteins; Polymorphism, Genetic; Risk Factors; Tunica Intima; Tunica Media; Ultrasonography

To evaluate urinary 8-hydroxydeoxyguanosine (8-OHdG) as a marker for the progression of diabetic macroangiopathic complications.. The content of urinary 8-OHdG, common carotid intima-media thickness (IMT), the coronary heart disease (CHD) risk score, the severity of diabetic retinopathy, and urinary albumin excretion were examined in 96 patients with type 2 diabetes, including 32 patients who had been nominated for the Kumamoto Study [Shichiri M, et al. Diabetes Care 23 (Suppl 2):B21-B29, 2000]. In addition, the patients from the Kumamoto Study were further evaluated regarding the effect of intensive insulin therapy on urinary 8-OHdG excretion.. The urinary 8-OHdG:creatinine ratio (U8-OHdG) was 2.5-fold higher in patients with increased HbA(1c) than in those with normal HbA(1c) (P < 0.05). In addition, U8-OHdG was 2.3-fold higher in patients with increased IMT (P < 0.005). A similar result was observed between U8-OHdG and CHD risk score (P < 0.01). U8-OHdG was significantly higher in patients with simple retinopathy (P < 0.05) and those with advanced retinopathy (P < 0.01) than in patients without retinopathy. Similarly, U8-OHdG was significantly higher in patients with albuminuria (P < 0.01). Furthermore, in the Kumamoto Study, U8-OHdG was significantly lower in the multiple insulin injection therapy group compared with the conventional insulin injection therapy group (P < 0.01).. Hyperglycemia independently increases 8-OHdG in patients with type 2 diabetes. 8-OHdG is a useful biomarker of not only microvascular but also macrovascular complications in patients with type 2 diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albuminuria; Biomarkers; Carotid Artery, Common; Creatinine; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Retinopathy; Drug Administration Schedule; Female; Humans; Insulin; Male; Middle Aged; Risk Factors; Tunica Intima; Tunica Media

Considering that increased oxidative stress induced by hyperglycaemia plays a possible role in the pathogenesis of diabetic complications and that mitochondrial DNA (mDNA) is thought to be more vulnerable than nuclear DNA, we investigated what somatic mutations actually occur in the mDNA of diabetic patients. We also studied the relations between those mutations and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) which is known to increase considerably in people with diabetes.. We identified somatic mutations by subcloning and sequencing two segments of mDNA [control region (nt 15996-16401) and the segment encompassing t-RNA(Leu(UUR))(nt 3149-3404)] in the peripheral blood cells of six diabetic women and control subjects matched for age and sex. This was done in 20 colonies each. In each case we also assayed urinary 8-OHdG.. No difference in the aggregate somatic mutational burden of mDNA was found between patients and control subjects. However, the incidence of somatic transversion mutations in mDNA was significantly higher in diabetic patients than in control subjects (13.93+/-4.57 x 10(-5) vs 1.27+/-1.27 x 10(-5) mutations per base pair; p=0.031, according to Mann-Whitney U-test). There was no significant difference in transition mutations. A correlation was found between the transversion mutational burden and HbA(1)c values, but not between it and 8-OHdG content in the urine.. We showed that somatic transversion point mutations of mDNA increase in diabetic patients. Such transversion mutations can become a new biomarker for mDNA damage associated with hyperglycaemia and possibly caused by oxidative stress but not reflected by urinary 8-OHdG.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Base Sequence; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Female; Guanine; Humans; Hyperglycemia; Middle Aged; Mutation; Polymerase Chain Reaction; Reference Values

Seven clinically healthy, nondiabetic (ND) and four Type II diabetic (D) men were assessed for circadian rhythms in oxidative "stress markers." Blood samples were collected at 3h intervals for approximately 27 h beginning at 19:00h. Urine samples were collected every 3 h beginning with the 16:00h-19:00h sample. The dark (sleep) phase of the light-dark cycle extended from 22:30h to 06:30h, with brief awakening for sampling at 01:00h and 04:00h. Subjects were offered general hospital meals at 16:30h, 07:30h, and 13:30h (2400 cal in total/24h). Serum samples were analyzed for uric acid (UA) and nitrite (NO) concentrations, and urine samples were assayed for 8-hydroxydeoxyguanosine (8-OHdG), malondialdehyde (MDA), and 8-isoprostane (ISP). Data were analyzed statistically both by the population multiple-components method and by the analysis of variance (ANOVA). The 24h mean level of UA and NO was greater in D than in ND subjects (424 vs. 338 micromol/L and 39.2 vs. 12.7 microM, respectively). A significant circadian rhythm in UA (p = 0.001) and NO (p = 0.048) was evident in ND but not in D (p = 0.214 and 0.065). A circadian rhythm (p = 0.004, amplitude = 8.6 pmol/kgbw/3h urine vol.) was also evident in urine 8-OHdG of ND but not of D. The 24h mean levels of ND and D were comparable (76.8 vs. 65.7 pmol/kgbw/3h urine vol.). No circadian rhythm by population multiple-components was evident in MDA and ISP levels of ND subjects, or in 8-OHdG, MDA, and ISP in D. However, a significant time-effect was demonstrated by ANOVA in all variables and groups. The 24h mean of MDA and ISP in D was significantly greater than in ND (214 vs. 119 nmol/3h urine vol. and 622 vs. 465 ng/3h urine vol.). The peak concentrations of the three oxidative "stress markers" in urine, like those of serum NO, occurred early in the evening in both groups of men. This observation suggests a correlation between increased oxidative damage and increased rate of anabolic-catabolic events as evidenced by similarities in the timing of peak NO production and in parameters relevant to metabolic functions.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Case-Control Studies; Circadian Rhythm; Deoxyguanosine; Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Humans; Male; Malondialdehyde; Middle Aged; Nitrates; Nitrites; Oxidative Stress; Uric Acid

Reactive oxygen species are involved in a diversity of biological phenomena such as inflammation, carcinogenesis, aging, and atherosclerosis. We and other investigators have shown that the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker for oxidative stress, is increased in either the urine or the mononuclear cells of the blood of type 2 diabetic patients. However, the association between type 2 diabetes and oxidative stress in the pancreatic beta-cells has not been previously described. We measured the levels of 8-OHdG and 4-hydroxy-2-nonenal (HNE)-modified proteins in the pancreatic beta-cells of GK rats, a model of nonobese type 2 diabetes. Quantitative immunohistochemical analyses with specific antibodies revealed higher levels of 8-OHdG and HNE-modified proteins in the pancreatic beta-cells of GK rats than in the control Wistar rats, with the levels increasing proportionally with age and fibrosis of the pancreatic islets. We further investigated whether the levels of 8-OHdG and HNE-modified proteins would be modified in the pancreatic beta-cells of GK rats fed with 30% sucrose solution or 50 ppm of voglibose (alpha-glucosidase inhibitor). In the GK rats, the levels of 8-OHdG and HNE-modified proteins, as well as islet fibrosis, were increased by sucrose treatment but reduced by voglibose treatment. These results indicate that the pancreatic beta-cells of GK rats are oxidatively stressed, and that chronic hyperglycemia might be responsible for the oxidative stress observed in the pancreatic beta-cells.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Blood Glucose; Deoxyguanosine; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Hyperglycemia; Immunohistochemistry; Inositol; Insulin; Islets of Langerhans; Oxidative Stress; Proteins; Rats; Rats, Inbred Strains; Solutions; Sucrose

Augmented oxidative stress induced by hyperglycaemia possibly contributes to the pathogenesis of diabetic complications. Oxidative stress is known to increase the conversion of deoxyguanosine to 8-oxo, 2'-deoxyguanosine in DNA. To investigate the possible contribution of oxidative DNA damage to the pathogenesis of diabetic complications, we measured the content of 8-oxo, 2'-deoxyguanosine in the urine and the blood mononuclear cells of Type II (non-insulin-dependent) diabetic patients.. We studied 53 Type II diabetic patients and 39 age-matched healthy control subjects. We assayed 8-oxo, 2'-deoxyguanosine by HPLC-electrochemical detection method.. The content of 8-oxo, 2'-deoxyguanosine in the urine and the mononuclear cells of the Type II diabetic patients was much higher than that of the control subjects. Urinary 8-oxo, 2'-deoxyguanosine excretion and the 8-oxo, 2'-deoxyguanosine content in the mononuclear cells from the diabetic patients with complications were higher than those from the diabetic patients without complications. Urinary excretion of 8-oxo, 2'-deoxyguanosine was significantly correlated with the 8-oxo, 2'-deoxyguanosine content in the mononuclear cells. The 8-oxo, 2'-deoxyguanosine content in the urine and mononuclear cells was correlated with the haemoglobin A1c value.. This is the first report of a direct association between oxidative DNA damage and the complications of diabetes. The augmented oxidative DNA damage in diabetes is speculated to contribute to the pathogenesis of diabetic complications.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Analysis of Variance; Biomarkers; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; DNA Damage; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Oxidative Stress; Reference Values; Smoking

Increased oxidative stress induced by hyperglycemia may contribute to the pathogenesis of diabetic complications. Oxidative stress is known to increase the conversion of deoxyguanosine (dG) to 8-hydroxydeoxyguanosine (8-OHdG) in DNA, which is linked to increased mitochondrial DNA (mtDNA) deletions. We investigated mtDNA deletions and 8-OHdG in the muscle DNA of non-insulin-dependent diabetes mellitus (NIDDM) patients. mtDNA deletion of 4977 bp (delta mtDNA4977) and the content of 8-OHdG in the muscle DNA of the NIDDM patients were much higher than those of the control subjects. There was a significant correlation between delta mtDNA4977 and the 8-OHdG content (P < 0.0001). Both delta mtDNA4977 and the 8-OHdG content were also correlated with the duration of diabetes. Delta mtDNA4977 and the 8-OHdG content in muscle DNA increased in proportion to the severity of diabetic nephropathy and retinopathy. This is the first report that an increase in delta mtDNA4977 and 8-OHdG is proportional to the severity of diabetic complications. Oxidative mtDNA damage is speculated to contribute to the pathogenesis of diabetic complications though a defect in mitochondrial oxidative phosphorylation or other mechanisms. 8-OHdG and delta mtDNA4977 are useful markers to evaluate oxidative mtDNA damage in the diabetic patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; DNA, Mitochondrial; Humans; Muscle, Skeletal; Polymerase Chain Reaction; Reference Values; Regression Analysis; Sequence Deletion

The Goto-Kakizaki (GK) rat is a spontaneously diabetic animal model of non-insulin-dependent diabetes mellitus, which is characterized by progressive loss of beta cells in the pancreatic islets with fibrosis. In the present study, we examined the effects of sucrose feeding on the islet pathology in this model. Six-week-old GK rats were fed with 30% sucrose for 6 weeks to induce severe hyperglycemia, and their condition was compared with that of nontreated rats. Age-matched normal Wistar rats were also given sucrose for the same periods and used for comparison. The sucrose-treated GK rats showed elevated blood glucose levels on oral glucose tolerance tests at 60 minutes and 120 minutes, representing 123% and 127% of values in untreated GK rats, respectively. At the end of the study, the mean beta-cell volume density in GK rats was 50% less than that in untreated Wistar rats. Sucrose feeding further reduced the volume densities of beta cells to only 50% of the levels of age-matched GK rats. Apoptotic cells were found in islet beta cells only in GK rats fed sucrose (mean 0.067%). There appeared to be more islets that immunohistochemically stained strongly positive with 8-hydroxy-deoxyguanosine as a marker of oxidative damage of DNA in GK rats fed sucrose compared with those not given sucrose. GK rats not fed sucrose showed significantly lower proliferative activity of beta cells measured by 5-bromo-2'-deoxyuridine uptake and intensified expression of Bcl-2 immunoreactivities at 6 weeks of age compared with those in age-matched Wistar rats. These two indices were reduced in both GK and Wistar rats with increasing age and were not affected by sucrose feeding in either group. The present study thus indicated that sucrose feeding promoted the apoptosis of beta cells in GK rats through increased oxidative stress without altering their proliferative activity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Age Factors; Animals; Apoptosis; bcl-2-Associated X Protein; Blood Glucose; Body Weight; Cell Division; Deoxyguanosine; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Tolerance Test; Immunohistochemistry; In Situ Hybridization; Insulin; Islets of Langerhans; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Inbred Strains; Rats, Wistar; Sucrose; Time Factors

1. The role of oxidative stress in the pathogenesis of the diabetic state is being investigated extensively. Although oxidative stress has been reported in terms of glycoxidation, protein oxidation and DNA oxidation in diabetes mellitus, oxidation parameters have not been determined in parallel on the same study population.2. We studied 24 patients with diabetes mellitus (14 patients with Type I diabetes with a mean age of 62.3+/-6.3 years and 10 patients with Type II diabetes aged 67.3+/-5.9 years) and compared them with age-matched non-diabetic controls. Urinary o-tyrosine, 8-hydroxy-2'-deoxyguanosine and pentosidine measurements by HPLC were made on two occasions (t1 and t2).3.A clear statistical difference was found between diabetic patients and controls at t1 or t2 for 8-hydroxy-2'-deoxyguanosine and pentosidine, but not for o-tyrosine. No significant correlations were found between clinical and other laboratory parameters except high-density lipoprotein and uric acid. We revealed significantly increased glycoxidation and DNA oxidation in patients with Type I and Type II diabetes, but protein oxidation was not different from controls.4. The finding of increased glycoxidation reflects increased oxidation of the carbohydrate moiety, whereas the increased levels of oxidized DNA may also be interpreted as due to increased DNA repair. The increased 8-hydroxy-2'-deoxyguanosine does not indicate the generation of an individual active oxygen species, but DNA could have been oxidized simply by alkenals from lipid peroxidation, as e.g. malondialdehyde. As no difference in protein oxidation (i.e. o-tyrosine) between diabetics and controls could be revealed, the oxidation of DNA by hydroxyl radical attack is unlikely, as o-tyrosine was proposed as a marker for hydroxyl radical attack. Therefore, the message is that increased glycoxidation can be confirmed, protein oxidation does not appear to take place and increased DNA oxidation is still not proven, as increased 8-hydroxy-2'-deoxyguanosine may simply reflect repair.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Arginine; Biomarkers; Case-Control Studies; Chromatography, High Pressure Liquid; Deoxyguanosine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Lysine; Middle Aged; Oxidative Stress; Statistics, Nonparametric; Tyrosine

Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative DNA damage and also of oxidative stress. We have investigated oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus (NIDDM) by urinary 8-OHdG assessments. We determined the total urinary excretion of 8-OHdG from 24 h urine samples of 81 NIDDM patients 9 years after the initial diagnosis and of 100 non-diabetic control subjects matched for age and gender. The total 24 h urinary excretion of 8-OHdG was markedly higher in NIDDM patients than in control subjects (68.2 +/- 39.4 microg vs. 49.6 +/- 37.7 microg, P = 0.001). High glycosylated hemoglobin was associated with a high level of urinary 8-OHdG. The increased excretion of urinary 8-OHdG is seen as indicating an increased systemic level of oxidative DNA damage in NIDDM patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Blood Glucose; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Oxidative Stress; Sex Factors; Smoking

Increased production of reactive oxygen species (ROS) and lipid peroxidation may contribute to vascular complications in diabetes. to test whether DNA is also oxidatively damaged in diabetes, we measured 8-hydroxydeoxyguanosine (8-OHdG), an indicator of oxidative damage of DNA, in mononuclear cells.. For this laboratory-based study, 12 patients with insulin-dependent diabetes mellitus (IDDM) and 15 patients with non-insulin-dependent diabetes mellitus (NIDDM) were matched by age with ten healthy volunteers each. DNA was extracted from mononuclear cells from whole blood. 8-OHdG was assayed by high-pressure liquid chromatography, and ROS were assayed by chemiluminescence.. IDDM and NIDDM patients had significantly higher median concentrations (p , 0.001, U test) of 8-OHdG in their mononuclear cells than their corresponding controls (in fmol/micrograms DNA): 128.2 (interquartile range 96.0-223.2) and 95.2 (64.0-133.5) vs 28.2 (21.7-43.4) and 21.9 (18.0-24.4), respectively. ROS generation by mononuclear cells was also significantly greater (p < 0.01) in diabetic patients than in their controls (in mV): 238.0 (107.0-243.0) and 101.3 (66.0-134.0) vs 69.5 (49.8-91.9) and 56.0 (38.8-62.5), respectively.. IDDM and NIDDM patients showed greater oxidative damage to DNA, with increased generation of ROS, than controls. Such changes might contribute to accelerated aging and atherogenesis in diabetes and to the microangiopathic complications of the disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Case-Control Studies; Chromatography, High Pressure Liquid; Deoxyguanosine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; DNA; DNA Damage; Humans; Leukocytes, Mononuclear; Lipid Peroxidation; Luminescent Measurements; Middle Aged; Reactive Oxygen Species