dinoprost and Diabetes-Mellitus--Type-2

Topics: Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dinoprost; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Oxidative Stress

Mild hypoglycemia is common in clinical practice. Severe hypoglycemia results in heat shock protein and associate co-chaperone changes. Whether mild prolonged hypoglycemia elicits a similar response with inflammatory and oxidative-stress responses compared with a severe hypoglycemic event is unclear; therefore, this pilot exploratory study was undertaken. We performed a case-control induced hypoglycemia clamp study, maintaining blood glucose at 2.8 mmol/L (50 mg/dL) for 1 h in 17 subjects (T2D (

Topics: Adult; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Dinoprost; Female; Heat-Shock Proteins; Heat-Shock Response; Humans; Hypoglycemia; Inflammation; Male; Middle Aged; Oxidative Stress; Protein Interaction Mapping; Proteins; Ubiquitin-Conjugating Enzymes

Patients with type 2 diabetes mellitus (T2DM) have been known to be suffering from coenzyme Q10 (CoQ10) deficiency which results in some complications in them. The purpose of this clinical trial study was to evaluate the effects of CoQ10 supplementation on serum values of adiponectin (A), leptin (L), 8-isoprostane, malondialdehyde (MDA), the A/L ratio in women with T2DM. Sixty-eight women with T2DM were enrolled in the current study and were randomly divided into drug (n = 34) and placebo (n = 34) groups who were consuming 100 mg CoQ10 and 100 mg cellulose acetate per day for 12 weeks, respectively. Measurements were performed at the beginning and after the intervention. Serum values of adiponectin (p = .001) and the A/L ratio (p = .001) were increased while values of leptin (p = .041), MDA (p = .023), 8-isoprostane (p = .004) were decreased significantly in drug group after intervention. This study had shown that CoQ10 supplementation in women with T2DM was effective in elevation of adiponectin and the A/L ratio and reduction of leptin, MDA and 8-isoprostane which could result in improving insulin resistance and modulating oxidative stress situation.. 摘要 患有2型糖尿病（T2DM）的患者伴有辅酶Q10（CoQ10）缺乏, 这将导致一系列并发症。该临床试验研究的目的是评估补充CoQ10对2型糖尿病（T2DM）女性患者的脂联素（A）, 瘦素（L）, 8-异前列烷, 丙二醛（MDA）, A/L比值的影响。本研究纳入了68名T2DM女性, 随机分为药物组（n = 34）和安慰剂组（n = 34）, 每天服用100mg辅酶Q10和100mg醋酸纤维素, 共12周。在开始时和干预后对观察指标进行测量。干预后药物组患者的脂联素（p = .001）和A/L比（p = .001）的血清值增加, 瘦素（p = .041）, MDA（p = .023）, 8-异前列烷（p = .004）显著下降。本研究表明补充CoQ10对T2DM女性有效, 可提高脂联素和A/L比值, 减少瘦素, MDA和8-异前列烷, 从而改善胰岛素抵抗, 调节氧化应激状态。.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Dietary Supplements; Dinoprost; Double-Blind Method; Female; Humans; Leptin; Malondialdehyde; Middle Aged; Ubiquinone; Vitamins

To evaluate the impact to oxidative stress, atherosclerosis and macrovascular disease by two proprietary herbal medicines including Ginkgo Leaf Tablets and Liuwei Dihuang Pills in type 2 diabetes.. The recruited 140 type 2 diabetes were randomly divided into the treatment group and control group which were both received basic diabetic management including anti-hyperglycemia, anti-hypertension, life style adjustment and health education etc. Additionally, the treatment group was given both Ginkgo Leaf Tablets and Liuwei Dihuang Pills while the control group was given placebos of Ginkgo Leaf Tablets and Liuwei Dihuang Pills. The relative clinical indexes about macrovascular events occurrence, atherosclerosis degree(IMT levels), oxidative stress in vivo(plasma carboxymethyl lysine(CML) and 8-isoprostane(8-IsoP) levels), plasma glucose, plasma lipid, blood pressure, other drugs usage situations and so on of two groups before and after consecutive 36-month treatment were accurately collected and statistically analyzed.. There were no significant differences of cardiovascular disease, cerebrovascular disease, IMT levels, plasma CML and 8-IsoP levels between the two groups before treatment. After 36-month treatment, the plasma CML and 8-IsoP levels of treatment group were both significantly lower than control group (CML: 312.4 ± 90.4 ng/ml versus 463.5 ± 97.2 ng/ml, P < 0.0001; 8-IsoP: 23.7 ± 9.5 pg/ml versus 62.6 ± 16.1 pg/ml, P < 0.0001) although this improvement was not shared with IMT and macrovascular events.. Ginkgo Leaf Tablets and Liuwei Dihuang Pills are beneficial to oxidative stress which plays important role in diabetic atherosclerosis and macrovascular complications. The preventive and therapeutic values of herbal medicines will be proved in further diabetic complication researches.

Topics: Aged; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 2; Dinoprost; Drugs, Chinese Herbal; Female; Ginkgo biloba; Humans; Lysine; Male; Middle Aged; Oxidative Stress; Plant Extracts

To compare the effects of either vildagliptin or glimepiride on glycemic variability, oxidative stress, and endothelial parameters in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone.. In this randomized, open-label, parallel study, 34 patients with T2DM being treated with metformin having an HbA1c of 7.0-10.0% were allocated into either the vildagliptin or glimepiride group. A mixed-meal tolerance test and 72-hour continuous glucose monitoring were conducted, and urinary 8-iso-prostaglandinF. Similar significant improvements in HbA1c level were shown in both vildagliptin (-0.8%) and glimepiride (-0.9%) groups after treatment (Ps<0.001). The mean amplitude of glycemic excursions (MAGE) and the mean of daily differences (MODD) were significantly decreased by vildagliptin (P = 0.044 and P = 0.031, respectively) but not by glimepiride. Glimepiride was significantly associated with a higher incidence of hypoglycemia than vildagliptin (P = 0.005). There were no significant differences in urinary 8-iso-PGF. Vildagliptin effectively improved glucose level with a significantly greater reduction in glycemic variability and hypoglycemia than glimepiride in patients with T2DM ongoing metformin therapy. The two drugs showed no significant differences in urinary 8-iso-PGF. NCT01404676.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dinoprost; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nitriles; Pyrrolidines; Sulfonylurea Compounds; Treatment Outcome; Vildagliptin

Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Oxidative Stress

The present study describes the effects of atorvastatin on whole body synthesis of nitric oxide (NO), prostacyclin (PGI2), and thromboxane A2 (TxA2), on oxidative stress and nitrite/nitrate-related renal carbonic anhydrase (CA) activity in patients with type 2 diabetes mellitus (T2DM). A double-blind, randomized, placebo-controlled parallel-group trial (the DALI study group) on 217 patients with T2DM and dyslipidemia was performed. Urinary samples were collected before and after administration of a standard dose (10 mg/d, n=73), a maximal dose atorvastatin (80 mg/d, n=72) or placebo (n=72) for 30 weeks. Urinary nitrite and nitrate were measured to assess whole body NO synthesis. The urinary molar ratio of nitrate to nitrite (UNOxR) served as a measure of renal CA activity. Free radical- and cyclooxygenase (COX)-catalyzed lipid peroxidation was estimated by measuring urinary 8-iso-prostaglandin F2α (8-iso-PGF2α). In subgroups, systemic PGI2 and TxA2 synthesis was assessed by measuring their major urinary metabolites 2,3-dinor-6-keto-prostaglandin F1α and 2,3-dinor-thromboxane B2, respectively. All biochemical parameters were measured by GC-MS and GC-MS/MS methods. T2DM patients had elevated levels of nitrate, nitrite, UNOxR, and 8-iso-PGF2α compared to healthy non-diabetic and normolipidemic subjects. Thirty-week treatment with atorvastatin (10 or 80 mg/d) did not significantly alter NO, PGI2, TxA2 and 8-iso-PGF2α synthesis and did not improve the renal reabsorption of nitrite which is considered an important reservoir of NO. Our study suggests that atorvastatin (10 or 80 mg/d) does not provide cardiovascular benefit beyond its cholesterol lowering effect in patients with T2DM.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Atorvastatin; Creatinine; Diabetes Mellitus, Type 2; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Prostaglandins I; Thromboxanes

The primary goals were to re-examine whether sevelamer carbonate (SC) reduces advanced glycation end products (AGEs) (methylglyoxal and carboxymethyllysine [CML]), increases antioxidant defenses, reduces pro-oxidants, and improves hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Secondary goals examined albuminuria, age, race, sex, and metformin prescription.. This two-center, randomized, intention-to-treat, open-label study evaluated 117 patients with T2DM (HbA1c >6.5%) and stages 2-4 DKD (urinary albumin/creatinine ratio ≥200 mg/g) treated with SC (1600 mg) or calcium carbonate (1200 mg), three times a day, without changing medications or diet. Statistical analyses used linear mixed models adjusted for randomization levels. Preselected subgroup analyses of sex, race, age, and metformin were conducted.. SC lowered serum methylglyoxal (95% confidence interval [CI], -0.72 to -0.29; P<0.001), serum CML (95% CI, -5.08 to -1.35; P≤0.001), and intracellular CML (95% CI, -1.63 to -0.28; P=0.01). SC increased anti-inflammatory defenses, including nuclear factor like-2 (95% CI, 0.58 to 1.29; P=0.001), AGE receptor 1 (95% CI, 0.23 to 0.96; P=0.001), NAD-dependent deacetylase sirtuin-1 (95% CI, 0.20 to 0.86; P=0.002), and estrogen receptor α (95% CI, 1.38 to 2.73; P ≤0.001). SC also decreased proinflammatory factors such as TNF receptor 1 (95% CI, -1.56 to -0.72; P≤0.001) and the receptor for AGEs (95% CI, -0.58 to 1.53; P≤0.001). There were no differences in HbA1c, GFR, or albuminuria in the overall group. Subanalyses showed that SC lowered HbA1c in women (95% CI, -1.71 to -0.27; P=0.01, interaction P=0.002), and reduced albuminuria in those aged <65 years (95% CI, -1.15 to -0.07; P=0.03, interaction P=0.02) and non-Caucasians (95% CI, -1.11 to -0.22; P=0.003, interaction P≤0.001), whereas albuminuria increased after SC and calcium carbonate in Caucasians.. SC reduced circulating and cellular AGEs, increased antioxidants, and decreased pro-oxidants, but did not change HbA1c or the albumin/creatinine ratio overall in patients with T2DM and DKD. Because subanalyses revealed that SC may reduce HbA1c and albuminuria in some patients with T2DM with DKD, further studies may be warranted.

Topics: Adiponectin; Age Factors; Aged; Albuminuria; Chelating Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Estrogen Receptor alpha; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Intention to Treat Analysis; Lysine; Male; Metformin; Middle Aged; NF-E2-Related Factor 2; Pyruvaldehyde; Receptor for Advanced Glycation End Products; Receptors, Tumor Necrosis Factor, Type I; RNA, Messenger; Sevelamer; Sex Factors; Single-Blind Method; Sirtuin 1; White People

Platelets from patients with type 2 diabetes are characterised by hyperactivation and high level of oxidative stress. Docosahexaenoic acid (DHA) may have beneficial effects on platelet reactivity and redox status. We investigated whether moderate DHA supplementation, given as a triglyceride form, may correct platelet dysfunction and redox imbalance in patients with type 2 diabetes. We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (n=11 post-menopausal women with type 2 diabetes) to test the effects of 400 mg/day of DHA intake for two weeks on platelet aggregation, markers of arachidonic acid metabolism, lipid peroxidation status, and lipid composition. Each two week-period was separated from the other by a six-week washout. Daily moderate dose DHA supplementation resulted in reduced platelet aggregation induced by collagen (-46.5 %, p< 0.001), and decreased platelet thromboxane B2 (-35 %, p< 0.001), urinary 11-dehydro-thromboxane B2 (-13.2 %, p< 0.001) and F2-isoprostane levels (-19.6 %, p< 0.001) associated with a significant increase of plasma and platelet vitamin E concentrations (+20 % and +11.8 %, respectively, p< 0.001). The proportions of DHA increased both in plasma lipids and in platelet phospholipids. After placebo treatment, there was no effect on any parameters tested. Our findings support a significant beneficial effect of low intake of DHA on platelet function and a favourable role in reducing oxidative stress associated with diabetes.

Topics: Administration, Oral; alpha-Tocopherol; Antioxidants; Arachidonic Acid; Blood Platelets; Collagen; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Supplements; Dinoprost; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Double-Blind Method; F2-Isoprostanes; Fatty Acids; Female; Humans; Lipid Peroxidation; Lipids; Membrane Lipids; Middle Aged; Oxidative Stress; Phospholipids; Platelet Aggregation; Postmenopause; Thromboxane B2

Oxidative stress plays an essential role in the pathogenesis of type 2 diabetes. Anthocyanin, a natural antioxidant, has been reported to reduce oxidative stress and to attenuate insulin resistance and diabetes in animal models; however, the translation of these observations to humans has not been fully tested.. This study was designed to investigate the effects of purified anthocyanins on dyslipidemia, oxidative status, and insulin sensitivity in patients with type 2 diabetes.. A total of 58 diabetic patients were given 160 mg of anthocyanins twice daily or placebo (n = 29/group) for 24 wk in a randomized, placebo-controlled, double-blind trial. Participants and investigators were masked to treatment allocation.. Anthocyanin supplementation significantly decreased serum LDL cholesterol (by 7.9%; P < 0.05), triglycerides (by 23.0%; P < 0.01), apolipoprotein (apo) B-48 (by 16.5%; P < 0.05), and apo C-III (by 11.0%; P < 0.01) and increased HDL cholesterol (by 19.4%; P < 0.05) compared with placebo after the 24-wk intervention. In addition, patients in the anthocyanin group showed higher total radical-trapping antioxidant parameter and ferric ion reducing antioxidant power values than did patients in the placebo group (both P < 0.05). Serum concentrations of 8-iso-prostaglandin F2α, 13-hydroxyoctadecadienoic acid, and carbonylated proteins in patients in the anthocyanin group were significantly less than in patients in the placebo group (23.4%, 25.8%; P < 0.01 and 20%; P = 0.022, respectively). Furthermore, supplementation with anthocyanin lowered fasting plasma glucose (by 8.5%; P < 0.05) and homeostasis model assessment for insulin resistance index (by 13%; P < 0.05), and elevated serum adiponectin (by 23.4%; P < 0.01) and β-hydroxybutyrate (by 42.4%; P = 0.01) concentrations compared with placebo supplementation.. These findings demonstrate that anthocyanin supplementation exerts beneficial metabolic effects in subjects with type 2 diabetes by improving dyslipidemia, enhancing antioxidant capacity, and preventing insulin resistance. This trial was registered at www.clinicaltrials.gov as NCT02317211.

Topics: 3-Hydroxybutyric Acid; Aged; Anthocyanins; Antioxidants; Apolipoprotein B-48; Apolipoprotein C-III; Blood Glucose; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dietary Supplements; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; Dyslipidemias; Female; Humans; Insulin; Insulin Resistance; Linoleic Acids; Male; Middle Aged; Nutrition Assessment; Oxidative Stress; Triglycerides

To test the hypothesis that the simultaneous administration of GLP-1 and insulin may increase their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes.. In two groups of persons with type 2 diabetes, two sets of experiments were performed. The first group had two normoglycemic-normoinsulinemic clamps with or without GLP-1 and two normoglycemic-hyperinsulinemic clamps with or without GLP-1. The second group had two hyperglycemic-normoinsulinemic clamps and two hyperglycemic-hyperinsulinemic clamps with or without GLP-1.. During the normoglycemic-hyperinsulinemic clamp, flow-mediated dilatation (FMD) increased, while soluble intercellular adhesion molecule (sICAM-1), plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), nitrotyrosine, and interleukin (IL)-6 decreased compared with normoglycemic-normoinsulinemic clamp. Similar results were obtained with the infusion of GLP-1 during the normoglycemic-normoinsulinemic clamp. The combination of hyperinsulinemia and GLP-1 in normoglycemia was accompanied by a further FMD increase and sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 decrease. During the hyperglycemic-normoinsulinemic clamp, FMD significantly decreased, while sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 significantly increased. When hyperglycemia was accompanied by hyperinsulinemia or by the simultaneous infusion of GLP-1, these phenomena were attenuated. The simultaneous presence of hyperinsulinemia and GLP-1 had an increased beneficial effect.. Our results show that the combination of insulin and GLP-1 is more effective than insulin or GLP-1 alone in improving endothelial dysfunction, inflammation, and oxidative stress in type 2 diabetes.

Topics: Anti-Inflammatory Agents; Antioxidants; Diabetes Mellitus, Type 2; Dinoprost; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Interleukin-6; Male; Middle Aged; Oxidative Stress; Vasodilator Agents

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing cardiovascular disease, largely as a result of defective production of cardioprotective nitric oxide and a concomitant rise in oxidative stress. Dietary interventions that could reverse this trend would be extremely beneficial. Here we investigated whether dietary n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation positively affected platelet nitroso-redox imbalance.. We randomized hypertensive T2DM patients (T2DM HT; n = 22) and age-and-sex matched hypertensive study participants without diabetes (HT alone; n = 23) in a double-blind, crossover fashion to receive 8 weeks of n-3 PUFAs (1.8 g eicosapentaenoic acid and 1.5 g docosahexaenoic acid) or identical olive oil capsules (placebo), with an intervening 8-week washout period. Platelet nitrite and superoxide were measured and compared before and after treatment; 8-isoprostane was determined by ELISA and subcellular compartmentalization of the NAD(P)H oxidase subunit p47-phox examined by Western blotting.. The n-3 PUFA supplementation reduced 8-isoprostane and superoxide levels in platelets from T2DM HT, but not HT alone, participants, without effect on nitrite production. This coincided with a significant decrease in p47-phox membrane localization and a similar reduction in superoxide to that achieved with apocynin. At baseline, a subcohort of T2DM HT and HT alone participants showed evidence of nitric oxide synthase (NOS)-derived superoxide production, indicating defective enzymatic activity. This was reversed significantly in T2DM HT participants after treatment, demonstrating improved NOS function.. Our finding that n-3 PUFAs diminish platelet superoxide production in T2DM HT patients in vivo suggests a therapeutic role for these agents in reducing the vascular-derived oxidative stress associated with diabetes.

Topics: Aged; Blood Platelets; Cross-Over Studies; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Fatty Acids, Omega-3; Female; Humans; Hypertension; Male; Middle Aged; Oxidation-Reduction; Superoxides

It is well accepted that glycemic control in patients with diabetes mellitus (DM) is affected by systemic inflammation and oxidative stress. The effect of periodontal therapy on these systemic factors may be related to improvement on glycemic status. The aim of the present study is to assess over a period of 6 months the effect of non-surgical periodontal therapy on serum levels of high-sensitivity C-reactive protein (hsCRP), d-8-iso prostaglandin F2a (d-8-iso) as a marker of oxidative stress, and matrix metalloproteinase (MMP)-2 and MMP-9 on patients with type 2 DM.. Sixty participants with type 2 DM and moderate to severe periodontal disease were randomized into intervention (IG) and control (CG) groups. IG received scaling and root planing, whereas CG received supragingival cleaning at baseline and scaling and root planing at 6 months. Participants of both groups were evaluated at baseline and 1, 3, and 6 months. Periodontal data recorded at each visit included probing depth, clinical attachment loss, bleeding on probing, and gingival index. Blood was collected at each visit for the assay of serum glycated hemoglobin A1c (A1c), hsCRP, d-8-iso, MMP-2, and MMP-9.. Although there was a trend to a reduction in hsCRP, d-8-iso and MMP-9 it did not reach statistical significance. MMP-2 levels remained unchanged after periodontal treatment.. Effective non-surgical periodontal treatment of participants with type 2 DM and moderate to severe periodontal disease improved significantly A1c levels but did not result in a statistically significant improvement in hsCRP, d-8-iso, MMP-2, and MMP-9 levels.

Topics: Adult; Aged; C-Reactive Protein; Chi-Square Distribution; Dental Scaling; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycated Hemoglobin; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Oxidative Stress; Periodontal Diseases; Periodontal Index; Prospective Studies; Statistics, Nonparametric

To determine whether pioglitazone 30 mg daily reduces levels of ADMA in adult patients with diabetes, and whether there is improvement in markers of oxidative stress.. Prospective randomized cross-over placebo-controlled study of 36 adults age 40-75 years with type 2 diabetes recruited from a single academic health center. Intervention was for 12 weeks, followed by a 4-week wash-out period, followed by a second 12-week cross-over treatment period. The main outcome was comparison of the change in ADMA levels in the two treatment periods. Secondary outcomes included change in NOx and F2-isoprostanes.. Thirty-six patients were enrolled in the study, 31 completed the protocol; the study enrollment met the sample size required to detect a change of 18% in levels. There were no differences in ADMA, NOx and F2-isoprostanes levels in the two treatment periods. Non-study medication changes or changes in dose were infrequent, and a statin was added during the study period in only one patient.. Despite previous animal data that showed an effect of pioglitazone on ADMA, the current study in human patients did not demonstrate any differences in ADMA, NOx, or F2-isoprostane levels. The results do not favor that pioglitazone has a significant impact on ADMA levels in human patients with diabetes.

Topics: Academic Medical Centers; Arginine; Biomarkers; Cross-Over Studies; Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Nitrates; Nitrites; Oxidative Stress; Pioglitazone; Prospective Studies; South Carolina; Thiazolidinediones; Time Factors; Treatment Outcome

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

Increased inflammation and oxidative stress may be caused by proteins and lipids modified by cytotoxic advanced glycation end products (AGEs) in food. Restricting food containing elevated AGEs improves these risk factors in diabetic CKD. Because diet adherence can be problematic, this study aimed to remove cytotoxic AGEs from food already ingested and to determine whether sevelamer carbonate sequesters cytotoxic AGEs in the gut, preventing their uptake and thereby reducing AGE-induced abnormalities.. This single-center, randomized, 2-month, open-label, intention-to-treat, crossover study compared sevelamer carbonate with calcium carbonate treatment in stage 2-4 diabetic CKD. Participants received 2 months of treatment with one drug, had a 1-week washout, and then received the opposite drug for 2 months.. Sevelamer carbonate reduced HbA1c, serum methylglyoxal, serum (ε)N-carboxymethyl-lysine, triglycerides, and 8-isoprostanes. Total cholesterol and fibroblast growth factor 23 were reduced by sevelamer carbonate, relative to calcium carbonate. AGE receptor 1 and sirtuin 1 mRNA were increased and PMNC TNFα levels were decreased by sevelamer carbonate, but not calcium carbonate. Medications and caloric and AGE intake remained unchanged. Sevelamer carbonate reversibly bound AGE-BSA at intestinal, but not stomach, pH.. Sevelamer carbonate significantly reduces HbA1c, fibroblast growth factor 23, lipids, and markers of inflammation and oxidative stress, and markedly increases antioxidant markers, independently of phosphorus in patients with diabetes and early kidney disease. These novel actions of sevelamer carbonate on metabolic and inflammatory abnormalities in type 2 diabetes mellitus may affect progression of early diabetic CKD.

Topics: Aged; Biomarkers; Calcium; Calcium Carbonate; Chelating Agents; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Inflammation; Inflammation Mediators; Kidney; Leukocytes; Lipids; Male; Middle Aged; New York City; Oxidative Stress; Phosphorus; Polyamines; Sevelamer; Severity of Illness Index; Time Factors; Treatment Outcome

We aimed to evaluate whether 4-week of dietary treatment with rice containing resistant starch reduces blood glucose and oxidative stress as well as improves endothelial function.. Patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes (n = 90) were randomly assigned to either a group ingesting rice containing 6.51 g resistant starch daily or a control rice group for 4-weeks. We assessed fasting and postprandial levels of glucose and insulin, oxidative stress markers and endothelial function using reactive hyperemia peripheral arterial tonometry (RH-PAT).. The diet containing rice with resistant starch reduced fasting insulin and insulin resistance, postprandial glucose (P = 0.010) and insulin levels at 30 min, and glucose and insulin areas under the response curve after the standard meal. Rice with resistant starch also decreased urinary 8-epi-PGF(2α) and plasma malondialdehyde (MDA) and increased the RH-PAT index (P < 0.001) and total nitric oxide (NO). Postprandial changes in glucose at 60 and 120 min and areas under the glucose response curve, MDA, RH-PAT, and total NO of the test group differed significantly from those in the control even after adjusting for baseline values. Overall, changes in the RH-PAT index correlated positively with changes in total NO (r = 0.336, P = 0.003) and superoxide dismutase activity (r = 0.381, P = 0.001) and negatively with changes in MDA (r = -0.358, P = 0.002) and 8-epi-PGF(2α).. In patients with IFG, IGT or newly diagnosed type 2 diabetes, 4-weeks of dietary treatment with rice containing resistant starch was associated with improved endothelial function with reduction of postprandial glucose and oxidative stress compared with control.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Digestion; Dinoprost; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hydrolysis; Hyperemia; Insulin; Insulin Resistance; Male; Malondialdehyde; Manometry; Middle Aged; Nitric Oxide; Oryza; Oxidative Stress; Plants, Genetically Modified; Postprandial Period; Prediabetic State; Republic of Korea; Starch; Superoxide Dismutase; Time Factors; Treatment Outcome

As two novel adipocytokines, chemerin and apelin play a key role in the pathological process of insulin resistance (IR), glucose metabolism and obesity, researchers have found that the levels of chemerin and apelin changed significantly in type 2 diabetic patients with obesity, however, the underlying mechanism involved remains unclear. The aim of this study was to investigate whether chemerin and apelin play an important role in the pathophysiologic proceeding of diabetes.. This study enrolled 81 newly diagnosed obese type 2 diabetes mellitus (T2DM) patients (T2DM group, n = 81). All the patients were randomly assigned to DM1 group treated with metformin (n = 41) and DM2 group treated with pioglitazone (n = 40). After hypoglycemic agents treatment, patients under better blood glucose control were chosen to be given antioxidant treatment. Another 79 subjects without T2DM were recruited as normal control group (NC group), including 40 subjects (NC1 group) with normal body mass index (BMI) and 39 obese subjects (NC2 group). Levels of chemerin, apelin, BMI, tumor necrosis factor-α (TNF-α), homeostasis model assessment of IR (HOMA-IR) and 8-isoprotaglandim F2α (8-iso-PGF2α) were examined at baseline and post-treatment. The relationship between chemerin, apelin and BMI, TNF-α, HOMA-IR, 8-iso-PGF2α was analyzed.. The baseline levels of chemerin, apelin, TNF-α, HOMA-IR and 8-iso-PGF2α in T2DM group were significantly higher than normal control group (P < 0.001). All indices mentioned above were significantly decreased after treatment (P < 0.05). In T2DM patients treated with pioglitazone, indices mentioned above except for HOMA-IR, were decreased significantly compared with patients treated with metformin (P < 0.05). After antioxidant treatment using lipoic acid, levels of chemerin, apelin, TNF-α and 8-iso-PGF2α were further significantly decreased (P < 0.05). Correlation analysis showed that the levels of chemerin and apelin correlated positively with BMI, TNF-α, HOMA-IR and 8-iso-PGF2α before and after treatment with hypoglycemic agents (P < 0.01). The levels of chemerin and apelin also had positive correlation with TNF-α and 8-iso-PGF2α after antioxidant treatment (P < 0.05).. The levels of chemerin and apelin in obese T2DM patients are closely related to IR. The increased levels may be a result of compensatory response to IR, and also may be the causative factor of IR. The levels of chemerin and apelin correlate closely with oxidative stress and inflammation. The two adipokines may be inflammatory factors playing important roles in the initiation and development of obese T2DM. Chemerin and apelin are related to the pathophysiology of IR, oxidative stress and inflammation.

Topics: Apelin; Blood Glucose; Body Mass Index; Chemokines; Diabetes Mellitus, Type 2; Dinoprost; Humans; Hypoglycemic Agents; Inflammation; Intercellular Signaling Peptides and Proteins; Metformin; Pioglitazone; Thiazolidinediones; Tumor Necrosis Factor-alpha

This study was designed to determine the effect of exenatide on inflammatory and oxidative stress markers in type 2 diabetes mellitus (T2DM) patients who were suboptimally controlled with metformin and/or sulfonylurea.. Twenty-three patients with T2DM with inadequate glucose control were randomly divided into two groups: exenatide group (E group) (12 patients, 5 μg b.d. × 4 weeks followed by 10 μg b.d. × 12 weeks) and placebo group (P group) (11 patients). Glycosylated hemoglobin (HbA1c), the seven-point glucose profile, daily mean glucose, and glycemic excursion were determined. The effects of exenatide on 8-iso-prostaglandin F2α (PGF2α), monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-CRP) were investigated.. Exenatide treatment reduced body weight and body mass index (BMI) and improved HbA1c, the seven-point glucose profile, and daily mean glucose compared with placebo (P < 0.05). Limited glycemic excursion was found in the E group compared with the P group (P < 0.05), including a smaller SD and postprandial glucose excursion. In addition, the oxidative stress maker PGF2α was significantly reduced by exenatide treatment (P < 0.05). The inflammatory markers hs-CRP and MCP-1 were also significantly reduced in the E group compared with the P group (P < 0.05). PGF2α was significantly correlated with glycemic excursion (P < 0.05), whereas MCP-1 was significantly correlated with body weight, BMI, glycemic excursion, and HbA1c (P < 0.05 for all).. Exenatide treatment reduced patient body weight and BMI, improved HbA1c and the seven-point glucose profile, reduced daily mean glucose, limited glycemic excursion, and reduced oxidative stress and inflammatory markers in patients of T2DM having inadequate glucose control.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Chemokine CCL2; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin Resistance; Male; Middle Aged; Oxidative Stress; Peptides; Pilot Projects; Venoms

A strong relationship between glycemic variability and oxidative stress in poorly regulated type 2 diabetes (T2DM) on oral medication has been reported. However, this relationship was not seen in type 1 diabetes. The purpose of this study is to reexamine the relation between glycemic variability and oxidative stress in a cohort of T2DM patients on oral medication.. Twenty-four patients with T2DM on oral glucose lowering treatment underwent 48 hours of continuous glucose monitoring (CGMS® System GoldTM, Medtronic MiniMed) and simultaneous collection of two consecutive 24-hour urine samples for determination of 15(S)-8-iso-prostaglandin F2α (PGF2α) using high-performance liquid chromatography tandem mass spectrometry. Standard deviation (SD) and mean amplitude of glycemic excursions (MAGE) were calculated as markers of glycemic variability.. Included in the study were 66.7% males with a mean age (range) of 59 (36-76) years and a mean (SD) HbA1c of 6.9% (0.7). Median [interquartile range (IQR)] urinary 15(S)-8-iso-PGF2α excretion was 176.1 (113.6-235.8) pg/mg creatinine. Median (IQR) SD was 31 (23-40) mg/dl and MAGE 85 (56-106) mg/dl. Spearman correlation did not show a significant relation for SD (ρ = 0.15, p = .49) or MAGE (ρ = 0.23, p = .29) with 15(S)-8-iso-PGF2α excretion. Multivariate regression analysis adjusted for age, sex, HbA1c, and exercise did not alter this observation.. We did not find a relevant relationship between glucose variability and 15(S)-8-iso-PGF2α excretions in T2DM patients well-regulated with oral medication that would support an interaction between hyperglycemia and glucose variability with respect to the formation of reactive oxygen species.

Topics: Adult; Aged; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dinoprost; Fasting; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Observer Variation; Oxidative Stress; Postprandial Period; Treatment Outcome

Glycemic excursion is significantly associated with oxidative stress, which plays a role in the development of chronic complications in type 2 diabetes mellitus (T2DM). Acarbose has been reported to reduce cardiovascular risk in patients with impaired glucose tolerance and T2DM. We hypothesize that treatment with acarbose could attenuate glycemic excursions and reduce oxidative stress in patients with T2DM.. This study aimed to evaluate the effects of acarbose versus glibenclamide on mean amplitude of glycemic excursions (MAGE) and oxidative stress in patients with T2DM who are insufficiently controlled by metformin.. T2DM outpatients aged 30 to 70 years who were taking single or dual oral antidiabetic drugs for ≥3 months and had a glycosylated hemoglobin (HbA(1c)) value between 7.0% and 11.0% were eligible. Patients were treated with metformin monotherapy (1500 mg daily) for 8 weeks, followed by randomization to either acarbose or glibenclamide add-on for 16 weeks. The dosage of acarbose and glibenclamide was 50 mg TID and 2.5 mg TID, respectively, for the first 4 weeks. In the following 12 weeks, the dosage was doubled in both groups. Continuous glucose monitoring (CGM) for 72 hours and a meal tolerance test (MTT) after a 10-hour overnight fast were conducted before randomization and at the end of study. MAGE was calculated from CGM data. β-cell response to postprandial glucose increments was assessed by the ratio between incremental AUC of insulin and glucose during MTT. Oxidative stress was estimated by plasma oxidized LDL (ox-LDL) and urinary excretion rates of 8-iso prostaglandin F(2α) (8-iso PGF(2α)). The primary outcomes included changes in MAGE, plasma ox-LDL, and urinary excretion of 8-iso PGF(2α). Adverse events, including hypoglycemia, were recorded.. A total of 55 patients were randomized (mean age, 54 years; males, 47%; mean body mass index, 25.9 kg/m(2); mean duration of diabetes, 6.9 years; mean HbA(1c), 8.3%) and 51 patients completed this study (acarbose, n = 28; glibenclamide, n = 23). HbA(1c) decreased significantly in both treatment groups (acarbose: 8.2 [0.8]% to 7.5 [0.8]% [P < 0.001]; glibenclamide: 8.6 [1.6]% to 7.4 [1.2]% [P < 0.001]). MAGE did not change significantly in glibenclamide-treated patients (6.2 [2.8] mmol/L to 6.3 [2.3] mmol/L; P = 0.82), whereas ox-LDL (242.4 [180.9] ng/mL to 470.7 [247.3] ng/mL; P = 0.004) and urinary excretion of 8-iso PGF(2α) (121.6 [39.6] pmol/mmol creatinine to 152.5 [41.8] pmol/mmol creatinine; P = 0.03) increased significantly. Acarbose decreased MAGE (5.6 [1.5] mmol/L to 4.0 [1.4] mmol/L; P < 0.001) without significant change in ox-LDL levels (254.4 [269.1] ng/mL to 298.5 [249.8) ng/mL; P = 0.62) or 8-iso PGF(2α) excretion rates (117.9 [58.1] pmol/mmol creatinine to 137.8 [64.4] pmol/mmol creatinine; P = 0.12). Body weight and serum triglycerides (fasting and 2-hour postprandial) decreased (all, P < 0.01) and serum adiponectin increased (P < 0.05) after treatment with acarbose, whereas HDL-C decreased (P < 0.01) after treatment with glibenclamide. β-cell response to postprandial glucose increments was negatively correlated with MAGE (r = 0.570, P < 0.001) and improved significantly with acarbose (35.6 [32.2] pmol/mmol to 56.4 [43.7] pmol/mmol; P = 0.001) but not with glibenclamide (27.9 [17.6] pmol/mmol to 36.5 [24.2] pmol/mmol; P = 0.12).. In this select population of adult Taiwanese patients with T2DM who were inadequately controlled by metformin, add-on acarbose or glibenclamide significantly reduced HbA(1c). However, treatment with acarbose decreased MAGE, body weight, and serum triglyceride and increased serum adiponectin without significant effect on oxidative stress. Treatment with glibenclamide had no statistically significant effect on MAGE but increased oxidative stress and decreased HDL-C. ClinicalTrials.gov identifier: NCT00417729.

Topics: Acarbose; Adult; Aged; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dinoprost; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Lipoproteins, LDL; Male; Medication Adherence; Metformin; Middle Aged; Outpatients; Oxidative Stress; Regression Analysis; Taiwan; Time Factors; Treatment Outcome

Chronic hyperglycemia is a major contributor to in vivo platelet activation in diabetes mellitus.. To evaluate the effects of acarbose, an alpha-glucosidase inhibitor, on platelet activation and its determinants in newly diagnosed type 2 diabetic patients.. Forty-eight subjects (26 males, aged 61 +/- 8 years) with early type 2 diabetes (baseline hemoglobin A(1c) < or = 7% and no previous hypoglycemic treatment) were randomly assigned to acarbose up to 100 mg three times a day or placebo, and evaluated every 4 weeks for 20 weeks. The main outcome measures were urinary 11-dehydro-thromboxane (TX)B(2) (marker of in vivo platelet activation) and 8-iso-prostaglandin (PG)F(2alpha) (marker of in vivo lipid peroxidation) excretion rate, 2-h postprandial plasma glucose (PPG) after a test meal, and assessment of glucose fluctuations by mean amplitude of glycemic excursions (MAGE).. Baseline measurements revealed biochemical evidence of enhanced lipid peroxidation and platelet activation. As compared with the placebo group, patients treated with acarbose had statistically significant reductions in urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) excretion rate as early as after 8 weeks and at each subsequent time point (between-group P < 0.0001 at 12, 16 and 20 weeks), following earlier decreases in PPG and MAGE. Multiple regression analyses in the acarbose group revealed that PPG was the only significant predictor of 11-dehydro-TXB(2) urinary excretion rate (beta = 0.39, P = 0.002) and MAGE the only predictor of 8-iso-PGF(2alpha) urinary excretion rate (beta = 0.42, P = 0.001).. Postprandial hyperglycemia is associated with enhanced lipid peroxidation and platelet activation in early type 2 diabetes. A moderate decrease in PPG achieved with acarbose causes time-dependent downregulation of these phenomena, suggesting a causal link between early metabolic abnormalities and platelet activation in this setting.

Topics: Acarbose; Aged; Arginine; Biomarkers; Blood Glucose; C-Reactive Protein; CD40 Ligand; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Enzyme Inhibitors; Female; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Italy; Lipid Peroxidation; Male; Middle Aged; P-Selectin; Platelet Activation; Postprandial Period; Thromboxane B2; Time Factors; Treatment Outcome

Coffee consumption is associated with a decreased risk of type 2 diabetes. Suggested mechanisms underlying the association have included attenuation of subclinical inflammation and a reduction in oxidative stress.. The aim was to investigate the effects of daily coffee consumption on biomarkers of coffee intake, subclinical inflammation, oxidative stress, glucose, and lipid metabolism.. Habitual coffee drinkers (n = 47) refrained for 1 mo from coffee drinking; in the second month they consumed 4 cups of filtered coffee/d and in the third month 8 cups of filtered coffee/d (150 mL/cup). Blood samples were analyzed by gas chromatography-mass spectrometry, bead-based multiplex technology, enzyme-linked immunosorbent assay, or immunonephelometry.. Coffee consumption led to an increase in coffee-derived compounds, mainly serum caffeine, chlorogenic acid, and caffeic acid metabolites. Significant changes were also observed for serum concentrations of interleukin-18, 8-isoprostane, and adiponectin (medians: -8%, -16%, and 6%, respectively; consumption of 8 compared with 0 cups coffee/d). Serum concentrations of total cholesterol, HDL cholesterol, and apolipoprotein A-I increased significantly by 12%, 7%, and 4%, respectively, whereas the ratios of LDL to HDL cholesterol and of apolipoprotein B to apolipoprotein A-I decreased significantly by 8% and 9%, respectively (8 compared with 0 cups coffee/d). No changes were seen for markers of glucose metabolism in an oral-glucose-tolerance test.. Coffee consumption appears to have beneficial effects on subclinical inflammation and HDL cholesterol, whereas no changes in glucose metabolism were found in our study. Furthermore, many coffee-derived methylxanthines and caffeic acid metabolites appear to be useful as biomarkers of coffee intake.

Topics: Adiponectin; Adult; Anti-Inflammatory Agents; Apolipoproteins; Biomarkers; Blood Glucose; Caffeic Acids; Caffeine; Chlorogenic Acid; Cholesterol; Coffee; Diabetes Mellitus, Type 2; Dinoprost; Female; Humans; Inflammation; Interleukin-18; Lipids; Male; Middle Aged; Plant Preparations; Risk Factors; Single-Blind Method

We investigated changes in serum biomarkers of vascular function after short-term, continuous sildenafil dosing in men with type 2 diabetes with erectile dysfunction.. Men with erectile dysfunction associated with type 2 diabetes mellitus were randomized to receive continuous, daily sildenafil (50 mg for 1 week run-in and 100 mg for 3 weeks) (148), or placebo (144) for 4 weeks (phase I) and then sildenafil (25, 50 or 100 mg) on demand for 12 weeks (phase II). Blood draws at baseline and after phases I and II were analyzed for cyclic guanosine monophosphate (endothelial function marker), 8-isoprostane (oxidative stress marker), and interleukin-6 and interleukin-8 (inflammatory cytokines). Primary and secondary erectile function outcome variables were affirmative responses on Sexual Encounter Profile question 3 (ability to maintain erection sufficient for sexual intercourse) and Erection Hardness Score, respectively.. Serum cyclic guanosine monophosphate levels were increased in the sildenafil group relative to the placebo group at 4 (p <0.01) and 16 (p <0.05) weeks, correlating with affirmative responses to Sexual Encounter Profile question 3 at the 4-week interval only (p <0.05). Serum 8-isoprostane levels were decreased to a nonsignificant degree in the sildenafil group at 4 weeks with no further change at 16 weeks, whereas interleukin-6 and interleukin-8 levels were unchanged at either interval, and these levels were unassociated with erectile function outcomes.. These data suggest that short-term, continuous sildenafil treatment causes systemic endothelial function to be enhanced and remain so for a duration after its discontinuation. However, they do not indicate any influence of this treatment on systemic oxidative stress or inflammation, or an effect on long-term erectile function improvement.

Topics: Adult; Aged; Biomarkers; Cyclic GMP; Diabetes Complications; Diabetes Mellitus, Type 2; Dinoprost; Endothelium, Vascular; Erectile Dysfunction; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Oxidative Stress; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Rosuvastatin, a strong statin, and colestimide, a new anion exchange resin, are both clinically beneficial drugs for treatment of hypercholesterolemia. The main purpose of the study was to compare the effects of rosuvastatin and colestimide on metabolic parameters, adipokines, and markers of oxidative stress and diabetic nephropathy in patients with type 2 diabetes complicated by hyperlipidemia.. A total of 40 patients with type 2 diabetes complicated by hyperlipidemia were recruited prospectively and consecutively. The patients were assigned randomly in equal numbers to rosuvastatin (2.5 mg/day) and colestimide (3.0 g/day) groups. Blood and urine tests were performed at the beginning of the study and after 12 weeks.. Rosuvastatin significantly decreased the level of serum retinol-binding protein (RBP)-4, an insulin-resistant adipokine, in a subgroup of patients with poor glycemic control, in addition to exerting a strong low-density lipoprotein (LDL-C)-lowering effect. Colestimide significantly decreased HbA1c, even in patients treated with a sulfonylurea at a more than moderate dose, without influencing insulin resistance or adiponectin (an insulin-sensitive adipokine) and RBP4. Colestimide also significantly decreased the levels of urinary 8-iso-prostaglandin (PG) F2alpha (a marker of oxidative stress) and urinary monocyte chemoattractant protein-1 (MCP-1) (a marker of diabetic nephropathy).. Our results show that rosuvastatin and colestimide exert different beneficial effects in type 2 diabetic patients complicated by hyperlipidemia. Therefore, concomitant use of these drugs may be useful for prevention of progression of diabetic complications.

Topics: C-Reactive Protein; Chemokine CCL2; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Enzyme-Linked Immunosorbent Assay; Epichlorohydrin; Female; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Imidazoles; Male; Middle Aged; Oxidative Stress; Peptide Fragments; Prospective Studies; Pyrimidines; Resins, Synthetic; Retinol-Binding Proteins; Rosuvastatin Calcium; Sulfonamides

To investigate the effect of glucose excursion on oxidative stress that is expressed by plasma 8-iso prostaglandin F2alpha (8-iso) level.. Continuous glucose monitor system (CGMS) was used to calculate the mean amplitude of glycemic excursion (MAGE), mean blood glucose (MBG) and its standard deviation (SDBG), mean 1 h preprandial glucose value (1 h-prePG) and 3 h post-prandial glucose value (3 h PPG) over 24 h period, area under the ROC curve when the blood glucose within 24 h > 5.6 mmol/L (AUC 5.6), mean of daily differences (MODD), and mean postprandial glucose excursion (MPPGE) on 33 individuals with normal glucose regulation (NGR), 25 subjects with impaired glucose regulation (IGR), and 25 patients with newly diagnosed type 2 diabetes mellitus (T2DM) for 3 days. Plasma 8-iso level was determined by EIA.. The plasma 8-iso level of the T2DM patients was 230 ng/L, significantly higher than that of the subjects with IGR (199 ng/L, P < 0.05) and that of the NGR subjects (156 ng/L, P < 0.01). Patients with T2DM also had higher levels of glycated hemoglobin (HbA1c), MBG, SDBG, 1 h pre-PG and 3 h PPG, MAGE, and MODD than those of the NGR and IGR subjects (P < 0.05 or 0.01). The plasma 8-iso level and parameters of glucose excursion of the IGR subjects were all significantly higher than those of the NGR individuals (P < 0.05 or 0.01). Plasma 8-iso level was positively correlated with MAGE, MBG, SDBG, 1 h pre-PG, 3 h PPG, MODD, and HbA1c in all groups. Further analysis showed that the relationship between plasma 8-iso level and MAGE remained significant after adjustment for the other parameters of glucose excursion in multiple linear regression analysis (multiple R(2) = 0.55 for the model including MAGE). Standardized regression coefficients were 0.694 (P = 0.000) for MAGE.. Glucose excursion exhibits a stronger triggering effect on oxidative stress than chronic sustained hyperglycemia in the subjects with IGR and T2DM.

Topics: Adolescent; Adult; Aged; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Dinoprost; Female; Glucose Metabolism Disorders; Humans; Middle Aged; Oxidative Stress; Young Adult

Fatty acids (FA) can impair glucose metabolism to a varying degree depending on time of exposure and also of type of FA. Here we tested for acute effects of marine n-3 FA on insulin sensitivity, insulin secretion, energy metabolism, and oxidative stress. This was a randomized, double-blind, crossover study in 11 subjects with type 2 diabetes mellitus. A 4-hour lipid infusion (Intralipid [Fresenius Kabi, Halden, Norway], total of 384 mL) was compared with a similar lipid infusion partly replaced by Omegaven (Fresenius Kabi) that contributed a median of 0.1 g fish oil per kilogram body weight, amounting to 0.04 g/kg of marine n-3 FA. Insulin sensitivity was assessed by isoglycemic hyperinsulinemic clamps; insulin secretion (measured after the clamps), by C-peptide glucagon tests; and energy metabolism, by indirect calorimetry. Infusion of Omegaven increased the proportion of n-3 FA in plasma nonesterified fatty acids (NEFA) compared with Intralipid alone (20:5n-3: median, 1.5% [interquartile range, 0.6%] vs -0.2% [0.2%], P = .001; 22:6n-3: 0.8% [0.4%] vs -0.7% [0.2%], P = .001). However, glucose utilization was not affected; neither was insulin secretion or total energy production (P = .966, .210, and .423, respectively, for the differences between the lipid clamps). Omegaven tended to lower oxidation of fat (P = .062) compared with Intralipid only, correlating with the rise in individual n-3 NEFA (r = 0.627, P = .039). The effects of clamping on phospholipid FA composition, leptin, adiponectin, or F(2)-isoprostane concentrations were not affected by Omegaven. Enrichment of NEFA with n-3 FA during a 4-hour infusion of Intralipid failed to affect insulin sensitivity, insulin secretion, or markers of oxidative stress in subjects with type 2 diabetes mellitus.

Topics: Adult; Aged; Biomarkers; Body Composition; C-Peptide; Calorimetry, Indirect; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Dinoprost; Double-Blind Method; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Fatty Acids, Omega-3; Female; Glucagon; Glucose Clamp Technique; Humans; Infusions, Intravenous; Insulin; Insulin Resistance; Isoprostanes; Male; Middle Aged; Oxidative Stress

Renin-angiotensin system blockade reduces proteinuria and prevents nephropathy progression in patients with type 2 diabetes mellitus (T2D). Experimental evidence demonstrates that angiotensin receptor blockers (ARBs) possess anti-inflammatory potential, which might contribute to reducing proteinuria and providing renoprotection.. We conducted a multicentre, double-blind, prospective, parallel-group non-inferiority study of 885 hypertensive [systolic blood pressure/diastolic blood pressure (SBP/DBP) >130/80 mmHg] patients with T2D, proteinuria (> or =900 mg/24 h) and serum creatinine (< or =3.0 mg/dl) who were randomized to once-daily telmisartan 80 mg or valsartan 160 mg; additional antihypertensive therapy was permitted. The primary endpoint was the change from baseline in the 24-h proteinuria after 12 months. Secondary endpoints included changes in 24-h albuminuria, estimated glomerular filtration rate (eGFR) and inflammatory parameters asymmetrical dimethylarginine (ADMA), high-sensitivity C-reactive protein (CRP) and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)).. Telmisartan and valsartan produced comparable reductions in 24-h urinary protein excretion rates: geometric mean reduction (95% confidence interval) [telmisartan, 33% (27-39%); valsartan, 33% (27-38%)]. No significant differences between treatments were seen in changes from baseline in 24-h urinary albumin excretion rate and eGFR at 12 months. With both treatments, greater renoprotection was seen among patients with better blood pressure control. No significant changes in ADMA or CRP were noted in either group after 12 months, but urinary 8-iso-PGF(2alpha) levels decreased by 14% with telmisartan and by 7% with valsartan (P = 0.040).. In patients with T2D, hypertension and overt nephropathy, the renoprotection afforded by telmisartan and valsartan appears similar, and the study was unable to show any effect beyond that due to blood pressure control. At doses used to treat hypertension, there is no evidence of inflammatory parameters being modified by ARBs in patients with more advanced kidney disease due to T2D.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Arginine; Benzimidazoles; Benzoates; Blood Pressure; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Proteinuria; Renin-Angiotensin System; Telmisartan; Tetrazoles; Valine; Valsartan

It has been shown that angiotensin-converting enzyme inhibition or angiotensin receptor blockade may improve endothelial dysfunction, an early manifestation of atherosclerosis, in patients with diabetes. Whether this protective effect is mediated through blood pressure-lowering effects or other specific mechanisms such as a reduction in oxidative stress is not clear. We investigated the influence of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension.. Thirteen patients were included in this randomized, double-blind, crossover study; they received losartan 50 mg twice daily for 4 weeks followed by atenolol 50 mg twice daily or vice versa. Concomitant medication with renin-angiotensin blocking agents or beta-blockers was withdrawn, whereas other medication remained unchanged. At baseline and after each treatment period, flow-mediated dilation of the brachial artery and oxidative stress were measured in serum samples.. Flow-mediated dilation was increased significantly after 4 weeks' treatment with losartan (3.4 +/- 0.44%) compared with atenolol (2.58 +/- 0.42%; P = 0.01). 8-Isoprostanes, a marker of oxidative stress, were significantly reduced in the losartan group compared with baseline (0.039 +/- 0.007 versus 0.067 +/- 0.006 ng/ml; P = 0.01), but did not differ from baseline with atenolol. Glucose, hemoglobin A1c, highly sensitive C-reactive protein, lipids and systolic blood pressure remained unaltered, whereas diastolic blood pressure tended to be lower in the atenolol group.. This study demonstrates that losartan significantly improved endothelial function in type 2 diabetes patients with hypertension compared with atenolol. This must be independent of the blood pressure-lowering effect of losartan and is probably caused by an antioxidative effect of the angiotensin receptor blocker.

Topics: Antihypertensive Agents; Atenolol; Blood Pressure; Brachial Artery; Cross-Over Studies; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Insulin Resistance; Losartan; Male; Middle Aged; Oxidative Stress; Regional Blood Flow; Research Design; Treatment Outcome; Vasodilation

The goals of this study were to characterize the platelet contribution to soluble CD40 ligand (sCD40L), to correlate its formation with the extent of oxidative stress and platelet activation, and to investigate the effects of improved metabolic control and low-dose aspirin on these processes.. Inflammation, oxidative stress, and platelet activation are involved in the pathogenesis of type 2 diabetes (T2DM) and its complications. The CD40-CD40L interactions result in inflammatory and pro-thrombotic responses.. Urinary 8-iso-prostaglandin (PG)F2alpha and 11-dehydro-thromboxane (TX)B2, in vivo markers of oxidative stress and platelet activation, respectively, plasma CD40L, and C-reactive protein (CRP) were measured in 114 T2DM patients and 114 control patients. A randomized, parallel group, 17-day study of aspirin (30, 100, or 325 mg/day) was performed in 18 T2DM patients. A similar study was performed in six healthy volunteers (aspirin, 100 mg/day). Twenty poorly controlled T2DM patients were studied before and after improved metabolic control.. Compared with control patients, diabetic patients showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, sCD40L, and CRP. On multiple regression analysis, 11-dehydro-TXB2 and 8-iso-PGF2alpha excretion rates predicted sCD40L levels. Soluble CD40L linearly correlated with 11-dehydro-TXB2 (rho = 0.67, p < 0.0001), and both were reduced after one week of aspirin (p < 0.0026), with slow recovery over 10 days after aspirin withdrawal. Improved metabolic control was associated with a reduction in sCD40L, 8-iso-PGF2alpha, and 11-dehydro-TXB2.. This study provides several lines of evidence for the dependence of sCD40L release on TXA(2)-dependent platelet activation in T2DM and provides novel mechanistic insight into the amplification loops of persistent platelet activation in this setting.

Topics: Aged; Aspirin; CD40 Ligand; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dinoprost; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Platelet Activation; Platelet Aggregation Inhibitors; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Aldosterone causes organic impairment by enhancement of oxidative stress and subsequent induction of proinflammatory cytokines and chemokines.. This study was designed to investigate the effect of spironolactone, an aldosterone blocker, on oxidative stress and the level of urinary monocyte chemoattractant protein (MCP)-1, a cysteine-cysteine chemokine that may contribute to progression of various nephropathies in type 2 diabetic patients with diabetic nephropathy. DESIGN, SETTING, PATIENTS AND OTHER PARTICIPANTS, AND INTERVENTION: The patients were randomly assigned to two groups in which they received either spironolactone (50 mg/d; n = 23) or amlodipine (2.5 mg/d; n = 14).. Urinary 8-iso-prostaglandin (PG) F2alpha (a marker of oxidative stress), urinary MCP-1, and urinary albumin excretion (UAE) were measured at the start of administration (0 months) and after 3 months in each group. Baseline levels of these variables were also measured in 25 age-matched healthy subjects.. There were significant positive correlations between log(10)-transformed (log) 8-iso-PGF2alpha and log MCP-1 levels in control and diabetic subjects and all subjects combined, but no correlations between log UAE and log 8-iso-PGF2alpha or log MCP-1 were found in any group. Significant decreases in 8-iso-PGF2alpha, MCP-1, and UAE were observed with spironolactone (P = 0.0001, P = 0.0041, and P = 0.0037, respectively), and systolic blood pressure significantly decreased after both spironolactone and amlodipine therapy (P = 0.00011 and P = 0.0051, respectively).. Our data suggest that urinary MCP-1 is correlated with oxidative stress as measured by urinary 8-iso-PGF2alpha and that spironolactone can decrease urinary MCP-1 and oxidative stress.

Topics: Chemokine CCL2; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Humans; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Spironolactone

Increased (intra)renal activity of the renin-angiotensin system may cause a persistent increase in renovascular resistance and intraglomerular pressure in patients with diabetes, thus contributing to the development of diabetic renal damage. The effect of chronic angiotensin II subtype 1 receptor blockade on (intra)renal hemodynamics in patients with type 2 diabetes was examined in a double-blind parallel group study. Patients were treated with 40 mg of olmesartan (n = 19) or placebo (n = 16), and renal hemodynamics were assessed before and after 12 wk of treatment using inulin and para-aminohippurate clearance techniques. Olmesartan significantly reduced 24-h ambulatory systolic and diastolic BP (both P < 0.05). In parallel, effective renal plasma flow increased significantly from 602 +/- 76 to 628 +/- 87 ml/min per 1.73 m(2), whereas filtration fraction and renovascular resistance decreased significantly (all P < 0.05). With placebo treatment, effective renal plasma flow decreased and filtration fraction increased significantly (both P < 0.05). GFR was not affected by both treatments. Active plasma renin concentration increased considerably (P < 0.05) with olmesartan therapy but remained unchanged with placebo treatment. Nitric oxide metabolism (plasma nitrate and nitrite) and asymmetric dimethylarginine blood levels were not affected by olmesartan and placebo therapy. In contrast, plasma 8-isoprostane 15(S)-8-iso-prostaglandin F(2a) concentration, a biochemical marker of oxidative stress, decreased significantly (P < 0.05) with olmesartan treatment. Chronic angiotensin II subtype 1 receptor blockade decreases (intra)renal vascular resistance and increases renal perfusion despite significant BP reduction. In addition, it significantly reduces oxidative stress. These effects of angiotensin II receptor antagonists may contribute to their beneficial long-term renal effects in patients with type 2 diabetes.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Drug Administration Schedule; Female; Humans; Imidazoles; Kidney; Male; Middle Aged; Olmesartan Medoxomil; Oxidative Stress; Renal Circulation; Renin; Tetrazoles; Vascular Resistance

We investigated the effect of glimepiride, a third-generation sulfonylurea hypoglycemic agent, on insulin resistance in elderly patients with type 2 diabetes, in connection with plasma adiponectin and 8-epi-prostagrandin F2alpha (8-epi-PGF2alpha), an oxidative stress marker.. A total of 17 elderly patients with type 2 diabetes received 12 weeks of treatment with glimepiride. Homeostasis assessment model of insulin resistance (HOMA-IR), homeostasis assessment model of beta-cell function, HbA(1c), C-peptide in 24-h pooled urine (urine CPR), and plasma concentrations of 8-epi-PGF2alpha, tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor type 1, and adiponectin were measured at various times. The metabolic clearance rate of glucose (MCR-g) was also assessed by a hyperinsulinemic-euglycemic clamp.. After 8 weeks of glimepiride treatment, significant reductions were observed in HbA(1c) (from 8.4 +/- 1.9 to 6.9 +/- 1.0%), HOMA-IR (from 2.54 +/- 2.25 to 1.69 +/- 0.95%), and plasma TNF-alpha concentrations (from 4.0 +/- 2.0 to 2.6 +/- 2.5 pg/ml). MCR-g was significantly increased from 3.92 +/- 1.09 to 5.73 +/- 1.47 mg. kg(-1). min(-1). Plasma adiponectin increased from 6.61 +/- 3.06 to 10.2 +/- 7.14 micro g/ml. In control subjects, who maintained conventional treatment, no significant changes were observed in any of these markers.. Glimepiride remarkably improved insulin resistance, suggested by a significant reduction in HOMA-IR, an increase in MCR-g, and a reduction in HbA(1c) without changing extrapancreatic beta-cell function and urine CPR. Increased plasma adiponectin and decreased plasma TNF-alpha may underlie the improvement of insulin resistance with glimepiride.

Topics: Adiponectin; Aged; Diabetes Mellitus, Type 2; Dinoprost; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Osmolar Concentration; Plasminogen Activator Inhibitor 1; Proteins; Sulfonylurea Compounds; Tumor Necrosis Factor-alpha

Type II diabetes is characterized by increased oxidative stress, endothelial dysfunction and hypertension. We investigated whether short-term treatment with oral vitamin C reduces oxidative stress and improves endothelial function and blood pressure in subjects with Type II diabetes. Subjects ( n =35) received vitamin C (1.5 g daily in three doses) or matching placebo for 3 weeks in a randomized, double-blind, parallel-group design. Plasma concentrations of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)), a non-enzymically derived oxidation product of arachidonic acid, were used as a marker of oxidative stress. Endothelial function was assessed by measuring forearm blood flow responses to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine (with nitroprusside as an endothelium-independent control) and by the pulse wave responses to systemic albuterol (endothelium-dependent vasodilator) and glyceryl trinitrate (endothelium-independent vasodilator). Plasma concentrations of vitamin C increased from 58+/-6 to 122+/-10 micromol/l after vitamin C, but 8-epi-PGF(2alpha) levels (baseline, 95+/-4 pg/l; after treatment, 99+/-5 pg/l), blood pressure (baseline, 141+/-5/80+/-2 mmHg; after treatment, 141+/-5/81+/-3 mmHg) and endothelial function, as assessed by the systemic vasodilator response to albuterol and by the forearm blood flow response to acetylcholine, were not significantly different from baseline or placebo. Thus treatment with vitamin C (1.5 g daily) for 3 weeks does not significantly improve oxidative stress, blood pressure or endothelial function in patients with Type II diabetes.

Topics: Acetylcholine; Antioxidants; Ascorbic Acid; Blood Pressure; Diabetes Mellitus, Type 2; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; F2-Isoprostanes; Female; Forearm; Humans; Male; Middle Aged; Oxidative Stress; Regional Blood Flow; Vasodilation; Vasodilator Agents

Despite the reported benefits associated with omega3 fatty acids for cardiovascular disease, there remains concern that increased intake may lead to increased lipid peroxidation. To date, however, the data, particularly in vivo, are inconclusive. This report describes two interventions, one providing daily fish meals and the other eicosapentaenoic acid (EPA, 20:5 omega3) or docosahexaenoic acid (DHA, 22:6 omega3), the two principal omega3 fatty acids in marine oils, in which in vivo lipid peroxidation was assessed by measurement of urinary excretion of F2-isoprostanes. In both trials, urinary F2-isoprostanes were significantly reduced by 20-27%. Therefore, in contrast with previous reports in the literature, these results demonstrate that omega3 fatty acids reduce in vivo oxidant stress in humans.

Topics: Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Fatty Acids, Omega-3; Fish Oils; Gas Chromatography-Mass Spectrometry; Humans; Male; Oxidative Stress

To determine whether raxofelast, a new water soluble antioxidant decreases oxidative stress and improves endothelial function in men with Type II (non-insulin dependent) diabetes mellitus.. We treated ten normotensive, normocholesterolaemic men with Type II diabetes and as controls ten healthy men matched with them for age with raxofelast (600 mg twice daily) for 1 week. Plasma 8-epi-PGF(2a), a non-enzymic oxidation product of arachidonic acid was measured by gas chromatography/mass spectrometry as an index of oxidative stress. Forearm vasodilator responses to brachial artery infusion of acetylcholine (7.5, 15 and 30 microg min(-1)) and of the nitric oxide donor nitroprusside (1, 3 and 10 microg min(-1)) were measured by strain gauge plethysmography.. Plasma concentrations of 8-epi-PGF(2a), were greater in diabetic than in control men (0.99 +/- 0.20 vs 0.18 +/- 0.01 nmol 1(-1), means +/- SEM, p < 0.001) and fell after raxofelast (from 0.99 +/- 0.20 to 0.47 +/- 0.07 nmol 1(-1), p < 0.05) in diabetic men but not in control men. Blood flow responses to acetylcholine were lower (p < 0.05) in diabetic than in control men (7.4 +/- 1.0 vs 12.9 +/- 2.3 ml min(-1) x 100 ml(-1) for the highest dose). In diabetic men, but not in control men, raxofelast increased (p < 0.05) blood flow responses to acetylcholine (from 7.4 +/- 1.0 m x min(-1) x 100 ml(-1) to 11.3 +/- 2.3 ml x min(-1) x 100 ml(-1) at highest dose). Blood flow responses to nitroprusside were similar in control and diabetic men and in both groups were similar before and after raxofelast.. Oral treatment with raxofelast for 1 week reduces oxidative stress and improves endothelial function in men with Type II diabetes.

Topics: Acetylcholine; Administration, Oral; Antioxidants; Benzofurans; Biomarkers; Brachial Artery; Diabetes Mellitus, Type 2; Dinoprost; Endothelium, Vascular; Female; Forearm; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Nitric Oxide Donors; Nitroprusside; Oxidative Stress; Reference Values; Vasodilation; Vitamin E

Despite the potential benefits of dietary treatment with marine omega3 fatty acids in cardiovascular disease, there remains concern with respect to their potential for increased lipid peroxidation. Thus far, data from in vivo studies are inconclusive. Increased lipid peroxidation has also been associated with acute exercise in some studies, but the methods have been nonspecific. The quantitation of F2-isoprostanes provides a more reliable and useful assessment of in vivo lipid peroxidation. We therefore aimed to assess the independent and combined effects of dietary omega3 fatty acids and aerobic exercise training on urinary F2-isoprostane levels in dyslipidemic non-insulin-dependent diabetic (NIDDM) patients. In a randomized controlled trial, 55 untrained, sedentary, dyslipidemic NIDDM patients were randomly assigned to a low-fat diet (30% of daily energy) with or without one daily fish meal (3.6 g omega3 fatty acids per day) and further randomized to either a moderate (55% to 65% maximal oxygen consumption [VO2max]) or light (heart rate <100 bpm) exercise training program for 8 weeks. Twenty-four-hour urine samples from 49 subjects were collected for measurement of urinary F2-isoprostanes by gas chromatography-mass spectrometry before and after intervention. The fish diets reduced urinary F2-isoprostanes by 830+/-321 pmol/24 h (20%, P = .013) relative to the low-fat diet alone. This effect was independent of age, gender, and body weight change. Moderate exercise training did not alter F2-isoprostanes. These findings show that, at least in the short-term, exercise had no effect, whereas the inclusion of regular fish meals as part of a low-fat diet reduced in vivo lipid peroxidation in dyslipidemic NIDDM patients. This response could further complement the known benefits of omega3 fatty acids and exercise favoring a reduced cardiovascular risk in diabetic patients.

Topics: Adult; Aged; Animals; Diabetes Mellitus, Type 2; Dietary Fats; Dinoprost; Exercise; Female; Fishes; Humans; Hyperlipidemias; Male; Middle Aged; Treatment Outcome

Oxidant species is reported as a major determinant in the pathophysiology of diabetic kidney disease. However, reactive oxygen species (ROS) formation in the initial phase and progressing phase of diabetic kidney disease remains unclear. Therefore, we conducted this study to find out what ROS and their modified product are associated with eGFR in type 2 diabetes mellitus (T2DM) patients. A cross-sectional study was performed on 227 T2DM patients. The study subjects were divided into three groups based on their eGFR stage (Group 1, eGFR > 89 ml/min/1.73 m2; Group 2, eGFR = 60-89 ml/min/1.73 m2; and Group 3, eGFR < 60 ml/min/1.73 m2). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum oxLDL/β2GPI complex and urinary 8-iso-PGF2α, while ferrous ion oxidation xylenol orange method 1 (FOX-1) was used to measure urinary hydrogen peroxide (H2O2). H2O2 significantly decreased across the groups, whereas OxLDL/β2GPI complex increased, but not significant, and there was no trend for 8-iso-PGF2α. Consistently, in the total study population, only H2O2 showed correlation with eGFR (r = 0.161, p = 0.015). Multiple linear regression analysis showed that significant factors for increased eGFR were H2O2, diastolic blood pressure, and female. Whereas increased systolic blood pressure and age were significant factors affecting the decrease of eGFR. We also found that urinary H2O2 had correlation with serum oxLDL/β2GPI complex in total population. This finding could lead to further research on urinary H2O2 for early detection and research on novel therapies of diabetic kidney disease.

Topics: Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Female; Humans; Hydrogen Peroxide; Lipoproteins, LDL; Reactive Oxygen Species

Several investigations revealed the association between ApoA2 concentration and lipid profile, inflammation and oxidative stress markers. Dietary habits also play a major role in the health status of individuals with type 2 diabetes mellitus (T2DM). This study aimed to investigate the interaction of ApoA2-256T > C with dietary indexes on ghrelin and leptin hormones together with biochemical markers among individuals with T2DM. A cross-sectional study was conducted on 726 randomly selected individuals with T2DM. A validated FFQ was used to evaluate Healthy Eating Index, Dietary Quality Index-International (DQI-I) and Dietary Phytochemical Index (DPI). ApoA2-256T > C genotypes were detected by real-time-PCR. Ghrelin, leptin and biochemical markers were also assessed. ANCOVA was used for the interaction between the polymorphism and dietary indexes. A significant interaction was observed between ApoA2-256T > C and DQI-I on high-sensitivity C-reactive protein (hs-CRP) level and superoxide dismutase (SOD) activity. Besides, the interaction of the SNP and DPI significantly affected hs-CRP and 8-isoprostane F2

Topics: Apolipoprotein A-II; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diet, Healthy; Dinoprost; Ghrelin; Humans; Leptin; Phytochemicals; Superoxide Dismutase

This work aims to examine the interaction between apo A2 (Apo A-II) -265T > C SNP and dietary total antioxidant capacity (DTAC) on inflammation and oxidative stress in patients with type 2 diabetes mellitus. The present cross-sectional study included 180 patients (35-65 years) with identified Apo A-II genotype. Dietary intakes were assessed by a FFQ. DTAC was computed using the international databases. IL-18 (IL18), high-sensitivity C-reactive protein (hs-CRP), pentraxin (PTX3), serum total antioxidant capacity (TAC), superoxide dismutase (SOD) activity and 8-isoprostaneF2

Topics: Antioxidants; Apolipoprotein A-II; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dinoprost; Humans; Interleukin-18; Obesity; Oxidative Stress; Superoxide Dismutase

Few research was reported to explore oxidative stress in individuals with latent autoimmune diabetes in adults (LADA). Therefore, our goal is to study oxidative stress and related factors in LADA patients.. In this study, 250 Chinese inpatients were diagnosed with LADA (. Compared with patients with type 2 diabetes, individuals with LADA have better oxidative stress and worse oxidative stress than healthy volunteers. After multiple regression analyses, systolic blood pressure, HbA. Our results show that compared with type 2 diabetes, LADA means less oxidative stress, and compared with healthy volunteers, it means more oxidative stress. Systolic blood pressure, HbA

Topics: Adult; Diabetes Mellitus, Type 2; Dinoprost; Female; Follow-Up Studies; Healthy Volunteers; Hospitalization; Humans; Latent Autoimmune Diabetes in Adults; Male; Middle Aged; Oxidative Stress; Regression Analysis; Superoxide Dismutase

This study aimed to investigate the differences in oxidative stress (OS) levels represented by 8-iso-prostaglandin F. We recruited a total of 160 eligible subjects. According to the blood glucose levels and the T2DM duration, subjects were divided into three groups: Type 2 Diabetes (T2DM) group, Prediabetic group, and Normal glucose-tolerance (NC) group, containing 66, 41, 53 patients, respectively. T2DM groups were additionally divided into a new-onset T2DM group including 29 patients and a non-new-onset T2DM group including 37 patients. General clinical data and biochemical indicators were collected. Intra-abdominal fat (IAF) was measured by MRI. 8-iso-PGF. Compared with the NC group, levels of systolic blood pressure (SBP), waist-to-hip ratio (WHR), FBG, 2 h postprandial glycemia(2hPG), 2 h insulin (2 h INS), IAF area, HOMA-IR, and 8-iso-PGF. In various glycometabolism populations, 8-iso-PGF2α is significantly correlated with FBG and IAF, this suggests that high blood glucose and abdominal obesity can increase the damage related to the OS in vivo.

Topics: Abdominal Fat; Aged; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Dinoprost; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Oxidative Stress; Prediabetic State

Oxidative stress is believed to play an important role in the pathophysiology of type 2 diabetes, but the few cohort studies that have assessed the association of oxidative stress biomarkers with type 2 diabetes incidence were small and reported inconclusive results.. We examined the associations of urinary oxidized guanine/guanosine (OxGua) levels (a biomarker of DNA/RNA oxidation) and urinary 8-isoprostane levels (a biomarker of lipid peroxidation) with type 2 diabetes incidence in 7,828 individuals initially without diabetes from a population-based German cohort study with 14 years of follow-up. Hazard ratios (HRs) (95% CIs) per 1 SD were obtained using multivariable-adjusted Cox proportional hazards regression models.. In the total population, weak but statistically significant associations with type 2 diabetes incidence were observed for OxGua levels (HR [95% CI] per 1 SD 1.05 [1.01; 1.09]) and 8-isoprostane levels (1.04 [1.00; 1.09]). Stratified analyses showed that associations of both biomarkers with type 2 diabetes incidence were absent in the youngest age-group (50-59 years) and strongest in the oldest age-group (65-75 years) of the cohort, with HR of OxGua levels 1.14 (1.05; 1.23) per 1 SD and of 8-isoprostane levels 1.22 (1.02; 1.45) per 1 SD.. These results from a large cohort study support suggestions that an imbalanced redox system contributes to the development of type 2 diabetes but suggest that this association becomes clinically apparent at older ages only, possibly as a result of reduced cellular repair capacity.

Topics: Age of Onset; Aged; Aging; Biomarkers; Cohort Studies; Diabetes Mellitus, Type 2; Dinoprost; DNA; DNA Damage; Female; Follow-Up Studies; Germany; Humans; Incidence; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; RNA

Postprandial hyperglycemia was reported to play a key role in established risk factors of coronary artery diseases (CAD) and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of short-term postprandial glucose (PPG) excursions. Low serum 1,5-AG levels have been associated with occurrence of CAD. However, the relationship between 1,5-AG levels and coronary plaque rupture has not been fully elucidated. The aim of this study was to evaluate 1,5-AG as a predictor of coronary plaque rupture in diabetic patients with acute coronary syndrome (ACS).. A total of 144 diabetic patients with ACS were included in this study. All patients underwent intravascular ultrasound examination, which revealed 49 patients with plaque rupture and 95 patients without plaque rupture in the culprit lesion. Fasting blood glucose (FBG), hemoglobin A. Serum 1,5-AG may identify high risk for coronary plaque rupture in diabetic patients with ACS, which suggests PPG excursions are related to the pathogenesis of plaque rupture in diabetes.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Blood Glucose; Coronary Artery Disease; Coronary Vessels; Deoxyglucose; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Predictive Value of Tests; Prospective Studies; Rupture, Spontaneous; Ultrasonography, Interventional

To evaluate serum concentration of 8-isoprostane, nitrotyrosine (NT), and total antioxidant capacity (TAC) in pregnant women with diabetes mellitus (DM) considering preconception planning and method of diabetes correction in 11-14 and 30-34 weeks.. The study included 130 women: T1DM (n = 40), T2DM (n = 35), gestational diabetes (GDM, n = 40) and the control group (n = 15). The serum concentrations of NT, 8-isoprostane, and TAC were measured by ELISA methods.. Elevated 8-isoprostane levels were observed in all patients with DM, but this biomarker's maximum values have been seen in T1DM and T2DM on insulin groups. A similar tendency was observed for the concentration of NT in both the 1st and 3rd trimesters. TAC levels showed a statistically relevant decrease in all DM groups compared to the control. The correlation analysis showed a direct correlation between HbA1c and serum 8-isoprostane levels in the 1st (r = .27) and 3rd (r = .3) pregnancy trimesters as well as inverse correlation with TAC level (r = -.48). Direct (NT, 8-isoprostane) and inverse correlations (TAC) were fixated for this biomarker concentration and preeclampsia rates.. DM in pregnancy is related to oxidative stress activation, which might lead to the development of adverse perinatal outcomes.

Topics: Adult; Antioxidants; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; Dinoprost; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Pregnancy Outcome; Russia; Tyrosine

Diabetic retinopathy (DR) is the most frequent microvascular complications of diabetes and the leading cause of blindness in adults worldwide. Non-proliferative DR (NPDR) is the first stage of DR but currently has few recommended intervention. Eicosanoids play important roles in maintaining vessel homeostasis. However, the functions of eicosanoids in NPDR are still unknown. In this study, we investigated the eicosanoids profile difference in plasma between type 2 diabetes with NPDR or not. A total of 50 patients with type 2 diabetes were recruited and divided into non-DR (NDR) group and NPDR group based on fundus photographs. The eicosanoids profiles in plasma were determined by LC-MS/MS. Adhesion and transwell assay were used to detect the adhesion and migration effects of metabolites on primary bovine retinal pericyte cells (BRPC), respectively. Streptomycin (STZ)-induced diabetic mouse model was used to test the protective effects of selected metabolites according to retinal immunofluorescence staining and fluorescence confocal microscopy. Prostaglandin 2α (PGF2α) was decreased significantly in NPDR group compared to NDR group and negatively correlated with NPDR. In vitro, PGF2α was found to accelerate adhesion and migration by activating prostaglandin F receptor (FP receptor) and subsequent increasing RhoA activity in primary bovine retinal pericyte. Administration of PGF2α analogue diminished the damage on retinal capillary in an STZ-induced diabetic mouse model. Our results suggested that PGF2α may be a protective factor in the progression of NPDR in T2D patients. The protective mechanism of PGF2α was to increase pericyte mobility through FP receptor/RhoA pathway.

Topics: Animals; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Dinoprost; Disease Progression; Eicosanoids; Female; Humans; Male; Metabolome; Mice; Middle Aged

We tested the hypothesis that the cumulative effects of common genetic variants related to elevated fasting glucose are collectively associated with oxidative stress. Using 25 single nucleotide polymorphisms (SNPs), a weighted genetic risk score (wGRS) was constructed by summing nine risk alleles based on nominal significance and a consistent effect direction in 1,395 controls and 718 patients with impaired fasting glucose (IFG) or newly diagnosed type 2 diabetes. All the participants were divided into the following three groups: low-wGRS, middle-wGRS, and high-wGRS groups. Among the nine SNPs, five SNPs were significantly associated with IFG and type 2 diabetes in this Korean population. wGRS was significantly associated with increased IFG and newly diagnosed type 2 diabetes (p = 6.83 × 10

Topics: Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Dinoprost; Female; Genetic Predisposition to Disease; Glycated Hemoglobin; Humans; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Polymorphism, Single Nucleotide; Prediabetic State; Risk Factors

Renal dysfunction is a common complication in type 2 diabetes mellitus patients associated with oxidative damage which could be characterized by 8-iso-prostaglandin F2α and hydrogen peroxide level as oxidative stress markers.. The aim of our study is to determine if there is a difference in 8-iso-prostaglandin F2α and hydrogen peroxide levels between sulfonylurea and combination of metformin-sulfonylurea in diabetic patients. We also wanted to determine if these oxidative stress markers correlate with the estimated Glomerular Filtration Rate (eGFR).. We conducted a cross-sectional study with inclusion of 55 patients with type 2 diabetes mellitus in Dr. Sitanala Tangerang Hospital, Indonesia with purposive sampling. The value of eGFR was obtained by serum creatinine levels, while the level of 8-iso-prostaglandin F2α was measured by ELISA and urinary hydrogen peroxide using FOX-1 (Ferrous Ion Oxidation Xylenol Orange 1).. There was no difference in 8-iso-prostaglandin F2α and hydrogen peroxide level between the two groups (p=0.088 and p=0.848). Moreover, there was no difference in eGFR values between the two groups, measured by Cockroft-Gault, MDRD, and CKD-EPI. 8-iso-prostaglandin F2α (n=55) was positively correlated with eGFR based on Cockroft-Gault (r=0.382; p=0.009), whereas urinary hydrogen peroxide (n=47) also generate significant positive correlation with eGFR based on the MDRD equation (r=0.326; p=0.021). Linear regression analysis showed that 8-iso-prostaglandin F2α is the most predictive factor and the only significant factor for eGFR in Cockroft-Gault, MDRD and also CKDEPI, even after controlled by gender, age, BMI, HbA1c, systole, and H2O2.. The two treatments did not have any significant differences in antioxidant activity. However, an increase of urinary 8-iso-prostaglandin F2. and hydrogen peroxide which correlates with eGFR in the total sample may play a significant role in the pathophysiology of diabetic nephropathy.

Topics: Aged; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Female; Glomerular Filtration Rate; Humans; Hydrogen Peroxide; Hypoglycemic Agents; Linear Models; Male; Metformin; Middle Aged; Oxidative Stress; Sulfonylurea Compounds

To evaluate glycemic variability (GV) and oxidative stress in patients who achieved type 2 diabetes (T2DM) remission after bariatric surgery (BS).. Remission of T2DM after BS is characterized by high GV and high oxidative stress in the face of fasting blood glucose and HbA1c within the normal range.

Topics: Adult; Biomarkers; Blood Glucose; Case-Control Studies; Chi-Square Distribution; Diabetes Mellitus, Type 2; Dinoprost; Energy Intake; Female; Gastrectomy; Gastric Bypass; Glycated Hemoglobin; Humans; Insulin; Linear Models; Male; Middle Aged; Obesity; Oxidative Stress; Remission Induction; Time Factors; Treatment Outcome

Apolipoprotein A2 (APOA2) -265T>C polymorphism has been studied in relation to oxidative stress and various dietary fatty acids. Since the interaction between APOA2 polymorphism and dietary fatty acids on oxidative stress has not yet discussed, we aimed to investigate the interaction on oxidative stress in type 2 diabetes mellitus (T2DM) patients.. The subjects were 180 T2DM patients with known APOA2 genotype, either TT, TC or CC. Superoxide dismutase (SOD) activity was determined by colorimetric method. Total antioxidant capacity (TAC) and serum level of 8-isoprostane F2α were measured by spectrophotometry and ELISA, respectively. Dietary intake was collected through a food frequency questionnaire. Based on the median intake, fatty acids intake was dichotomized into high or low groups. The interaction between APOA2 polymorphism and dietary fatty acids intake was analyzed by ANCOVA multivariate interaction model.. Higher than median intake of omega-6 polyunsaturated fatty acids (n-6 PUFA) was associated with increased serum level of 8-isoprostane F2α in subjects with TT/TC genotype (p = 0.004), and higher than median intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) was associated with increased serum SOD activity in CC genotype (p < 0.001). There was a statistically significant interaction between APOA2 polymorphism and n-6 PUFA intake on 8-isoprostane F2α concentration as well as n-3 PUFA intake on serum SOD activity (p-interaction = 0.04 and 0.02, respectively).. The current study shows the interaction between APOA2 polymorphism and dietary fatty acids intake on oxidative stress. More investigations on different populations are required to confirm the interaction.

Topics: Adult; Aged; Anthropometry; Apolipoprotein A-II; Cholesterol; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diet; Dietary Fats; Dinoprost; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Gene-Environment Interaction; Genotyping Techniques; Humans; Male; Middle Aged; Oxidative Stress; Polymorphism, Single Nucleotide; Superoxide Dismutase; Triglycerides

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dinoprost; Fasting; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Estrogen; Republic of Korea

Adults with metabolic syndrome from different race/ethnicities are often predisposed to developing type 2 diabetes (T2D); however, growing evidence suggests that healthy diets and lifestyle choices can significantly slow or prevent progression to T2D. This poorly understood relationship to healthy dietary patterns and prevention of T2D motivated us to conduct a retrospective analysis to determine the potential impact of a minor dietary lifestyle change (daily mushroom consumption) on known T2D risk factors in racially diverse adults with confirmed features of the metabolic syndrome. Retrospectively, we studied 37 subjects who had participated in a dietary intervention focused on vitamin D bioavailability from white button mushrooms (WBM). All 37 had previously completed a 16-week study where they consumed 100 g of WBM daily and were then followed-up for one month during which no mushrooms were consumed. We analyzed differences in serum risk factors from baseline to 16-week, and from baseline to one-month follow-up. Measurement of serum diabetic risk factors included inflammatory and oxidative stress markers and the antioxidant component naturally rich in mushrooms, ergothioneine. Significant beneficial health effects were observed at 16-week with the doubling of ergothioneine from baseline, increases in the antioxidant marker ORAC (oxygen radical absorption capacity) and anti-inflammatory hormone, adiponectin and significant decreases in serum oxidative stress inducing factors, carboxymethyllysine (CML) and methylglyoxal (MG), but no change in the lipid oxidative stress marker 8-isoprostane, leptin or measures of insulin resistance or glucose metabolism. We conclude that WBM contain a variety of compounds with potential anti-inflammatory and antioxidant health benefits that can occur with frequent consumption over time in adults predisposed to T2D. Well-controlled studies are needed to confirm these findings and identify the specific mushroom components beneficial to health.

Topics: Adiponectin; Adult; Agaricus; Antioxidants; beta-Glucans; Biomarkers; Body Mass Index; Chitin; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diet; Dinoprost; Ergothioneine; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Linear Models; Lysine; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Oxidative Stress; Polyphenols; Pyruvaldehyde; Retrospective Studies; Risk Factors; Triglycerides; Vitamin D

Hyperglycemia, inflammation, and oxidative stress are thought to be involved in the pathogenesis of cognitive decline. Dipeptidyl peptidase-4 (DPP4) is a newly identified adipokine related to these risk factors. Hence, we aimed to investigate the association between plasma DPP4 activities and mild cognitive impairment (MCI) in elderly patients with type 2 diabetes.. We evaluated plasma DPP4 activity, inflammatory markers, and oxidative stress parameters in a cross-sectional sample of 1,160 patients with type 2 diabetes aged 60 years or older in China. MCI was diagnosed based on criteria established by the National Institute on Aging-Alzheimer's Association workgroups. Patients in the highest quartile of DPP4 activity had higher HbA1c, interleukin 6 (IL-6), CRP, nitrotyrosine, 8-iso-PGF2a, and lower Montreal Cognitive Assessment (MoCA) scores compared with subjects in the lowest quartile (P < 0.001). In the highest DPP4 quartile, MCI risk was higher (odds ratio 3.49; 95% CI 1.97-4.57) than in the lowest quartile after adjustment for potential confounders. The risk for MCI increased more with higher levels of DPP4 activity, IL-6, CRP, nitrotyrosine, and 8-iso-PGF2a (P < 0.05), but not with higher levels of HbA1c.. This study shows that increased DPP4 activities are independently associated with MCI in elderly patients with type 2 diabetes. The mechanisms might be partly explained by the effect of DPP4 on inflammation and oxidative stress. These observations raise further interest in DPP4 activity for its potential effect on these MCI-related risk factors as a biological marker or even a possible therapeutic target for MCI.

Topics: Aged; Biomarkers; C-Reactive Protein; China; Cognitive Dysfunction; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dinoprost; Dipeptidyl Peptidase 4; Female; Glycated Hemoglobin; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Odds Ratio; Oxidative Stress; Risk Factors; Tyrosine

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

Oxidative stress is one of the key mechanisms responsible for disease progression in non-alcoholic fatty liver disease. The aim of this study was to evaluate the serum levels of oxidative stress markers in patients with type 2 diabetes mellitus (DMT2) and non-alcoholic steatohepatitis (NASH) and test their relationships with clinical and biochemical patient characteristics, compared to patients with DMT2 without non-alcoholic fatty liver disease (NAFLD), and controls.. In all, 60 consecutive patients with DMT2 and NASH, 55 with DMT2 without NAFLD, and 50 age-and-gender-matched healthy subjects participated in the study. The serum levels of protein carbonyls and 8-isoprostane were determined by ELISA methods, while the serum levels of malondialdehyde (MDA) were detected by means of the spectrophotometric method. Clinical, demographic, and laboratory parameters were examined for all the subjects included in the study. Multivariate logistic regression was used to test the independent predictive factors in the relationships investigated here.. Patients with DMT2 and NASH displayed significantly higher serum levels of protein carbonyls (1.112 ± 0.42 nmol/dL), MDA (6.181 ± 1.81 ng/mL), and 8-isoprostane (338.6 ± 98.5 pg/mL) compared to patients with DMT2 without NAFLD, and controls. Results of multivariate logistic regression analyses indicate that in patients with DMT2 and NASH, the serum levels of oxidative stress markers were independently and positively associated with: HbA1c, duration of diabetes, the UKPDS cardiovascular risk score (for protein carbonyls); age, LDL-cholesterol (for 8-isoprostane); and triglycerides serum levels (for MDA).. Our findings indicate that the process of oxidative stress tends to increase in patients with DMT2 and NASH, compared to patients with DMT2 without NAFLD, and controls. This evidence suggests that an antioxidant therapy might prove useful in the treatment of patients with DMT2 and NASH.

Topics: Adult; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Dinoprost; Female; Humans; Male; Malondialdehyde; Middle Aged; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Protein Carbonylation; Risk Factors

Even though diabetes patients exhibit an increased oxidative stress, its correlation with diabetic nephropathy is not fully understood. The purpose of this study was to determine whether lipid peroxidation marker correlates well with eGFR and UACR in type 2 diabetes mellitus patients.. We collected urine and serum samples of Indonesian type 2 diabetes mellitus outpatients with normo- and microalbuminuria at a Local Government Clinic (from ages: 39-74 years). Urinary 8-iso-PGF2α was measured by ELISA, the serum malondialdehyde by TBARS assay, and urinary albumin by BCG albumin assay. eGFR was calculated using the corrected-Cockcroft-Gault (CG), MDRD, and CKD-EPI equation. Other necessary data were obtained through questionnaires.. The results showed that the increasing level of malondialdehyde was mildly correlated with the decline in eGFR (MDRD). In contrary, there was a significant positive correlation between 8-iso-PGF2α concentration and eGFR based on the corrected-CG, MDRD study, and CKD-EPI equation (r=0.457, p<0.001; r=0.424, p<0.001; r=0.443, p<0.001). This relationship still persisted in the normoalbuminuric subjects (n=43) (r=0.491, p=0.001; r=0.461, p=0.002; r=0.455, p=0.002). The multivariate analysis showed that 8-iso-PGF2α together with fasting plasma glucose was the most predictive factor for the high 2-quantile eGFR (adjusted OR 1.001, (95% CI, 1.000-1.001)). However, there was no significant correlation between UACR with malondialdehyde (r=0.268, p=0.050) and 8-iso-PGF2α(r=-0.030, p=0.808). UACR itself was inversely correlated with eGFR based on the corrected-CG, the MDRD, and CKD-EPI (r=-0.232, p<0.05; r=-0.228, p<0.05; r=-0.232, p<0.05).. Increased 8-iso-PGF2α and malondialdehyde in type 2 diabetes mellitus patients may play a role in the pathophysiologic significance of diabetic nephropathy, even while considering the effect of potential confounders.

Topics: Adult; Aged; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Enzyme-Linked Immunosorbent Assay; Female; Glomerular Filtration Rate; Humans; Indonesia; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Prevalence; Spectrophotometry

We sought to investigate whether enhanced oxidation contributes to unfavorable fibrin clot properties in patients with diabetes.. We assessed plasma fibrin clot permeation (K s , a measure of the pore size in fibrin networks) and clot lysis time induced by recombinant tissue plasminogen activator (CLT) in 163 consecutive type 2 diabetic patients (92 men and 71 women) aged 65 ± 8.8 years with a mean glycated hemoglobin (HbA1c) of 6.8%. We also measured oxidative stress markers, including nitrotyrosine, the soluble form of receptor for advanced glycation end products (sRAGE), 8-iso-prostaglandin F2α (8-iso-PGF2α ), oxidized low-density lipoprotein (oxLDL), and advanced glycation end products (AGE).. There were inverse correlations between K s and nitrotyrosine, sRAGE, 8-iso-PGF2α , and oxLDL. CLT showed a positive correlation with oxLDL and nitrotyrosine but not with other oxidation markers. All these associations remained significant for K s after adjustment for fibrinogen, disease duration, and HbA1c (all P < 0.05), while oxLDL was the only independent predictor of CLT.. Our study shows that enhanced oxidative stress adversely affects plasma fibrin clot properties in type 2 diabetic patients, regardless of disease duration and glycemia control.

Topics: Aged; Aged, 80 and over; Blood Coagulation; Blood Glucose; Diabetes Mellitus, Type 2; Dinoprost; Female; Fibrin; Fibrinolysis; Glomerular Filtration Rate; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Kinetics; Lipoproteins, LDL; Male; Middle Aged; Oxidative Stress; Oxygen; Permeability; Receptor for Advanced Glycation End Products; Recombinant Proteins; Surveys and Questionnaires; Tissue Plasminogen Activator; Tyrosine

Oxidative stress has been implicated in the development of coronary artery calcification (CAC). However, there are few reports on this issue in Japanese patients with diabetes. In this study, we examined the association of the CAC score (CACS) with oxidative stress markers.. The study subjects were 163 Japanese patients with type 2 diabetes (75 men and 88 women). The CACS (Agatston unit: AU) was measured by multi-detector computed tomography (MDCT), and the oxidative stress markers, such as the urinary 8-isoprostane and 8-hydroxydeoxyguanosine (8-OHdG) and serum malondialdehyde (MDA)-LDL cholesterol were measured. The relationships between CACS and oxidative stress markers were statistically analyzed.. Compared with the CACS 0-400 AU group (n=132), the age, duration of diabetes, urinary 8-isoprostane levels, serum MDA-LDL-C/LDL-C and maximum intima media thickness (IMT) were higher, and body mass index and HbA1c level were lower, in the CACS >400 AU group (n=31). The multiple logistic regression analysis showed that a CAC >400 AU was independently associated with the urinary 8-isoprostane (>median) (OR=2.54, 95% CI=1.03-6.32, p=0.044), MDA-LDL-C/LDL-C (>median) (OR=2.62, 95% CI=1.07-6.40, p=0.035) and HbA1c (>median) (OR=0.32, CI=0.12-0.87, p<0.025). Focusing on oxidative stress, a higher MDA-LDL-C/LDL-C (p=0.026) and a higher urinary 8-isoprostane level (p=0.074) were associated with the CACS.. The CACS was found to be independently associated with the MDA-LDL-C/LDL-C and urinary 8-isoprostane levels in Japanese patients with type 2 diabetes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Calcinosis; Carotid Intima-Media Thickness; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus, Type 2; Dinoprost; Female; Follow-Up Studies; Humans; Incidence; Japan; Male; Malondialdehyde; Middle Aged; Multidetector Computed Tomography; Oxidative Stress; Prevalence; Retrospective Studies; Tomography, X-Ray Computed; Young Adult

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Female; Glomerular Mesangium; Hypercholesterolemia; Hypertriglyceridemia; Hypertrophy; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Kidney; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Piperidines; PPAR alpha; Propionates

The aim of this study was to determine the long-term effects of a moderate protein diet (MPD) on renal function, low-grade inflammation, and oxidative stress in older adults with type 2 diabetes, which to date are unclear.. Seventy-four older adults with type 2 diabetes and chronic kidney disease (stage G3b-G4) were enrolled in the study. During the 4-wk baseline period (T0), all patients were asked to follow a normal protein diet regimen, providing 1.1 g/kg daily. Successively, all patients were asked to follow an MPD, for 36 mo, providing 0.7 g/kg daily, for only 6 d/wk. Patients who refused to follow an MPD treatment were included in the control (NPD [normal protein diet] group). During the 36 mo of the study, creatinine clearance, blood urea nitrogen, proteinuria, blood pressure, glycated hemoglobin (Hb)A1c, fat-free mass, low-grade inflammation (interleukin-6 and C-reactive protein) were evaluated monthly and oxidative stress (urinary 8-epiprostaglandin [Epi-PG]F2α) was evaluated every 3 mo.. During T0, mean creatinine clearance, proteinuria, blood urea nitrogen, blood pressure, HbA1c, fat free mass, low-grade inflammation, and oxidative stress were similar in both groups. After 36 mo, a significant reduction in decline of renal function was observed in the MPD group but not in controls (2.4 ± 0.2 versus 5.7 ± 0.5 mL·min·y, respectively; P < 0.05 versus control). Similarly, a significant reduction in proteinuria, serum interleukin-6, serum C-reactive protein, and urinary 8-Epi-PGF2α excretion, was observed in the MPD group (P < 0.05 versus NPD).. In older adults with type 2 diabetes, long-term effects of an MPD regimen are associated with a significant decline of renal function, proteinuria, low-grade inflammation, and oxidative stress without a change in fat-free mass.

Topics: Aged; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet; Diet, Protein-Restricted; Dietary Proteins; Dinoprost; Female; Humans; Inflammation; Interleukin-6; Kidney; Male; Oxidative Stress; Patient Compliance; Proteinuria; Renal Insufficiency, Chronic; Time Factors

Because alterations in blood fatty acid (FA) composition by dietary lipids are associated with insulin resistance and related metabolic disorders, we hypothesized that serum phospholipid FA composition would reflect the early alteration of fasting glycemic status, even in people without metabolic syndrome (MetS). To examine this hypothesis, serum phospholipid FA, desaturase activities, fasting glycemic status, and cardiometabolic parameters were measured in study participants (n = 1022; 30-69 years; male, n = 527; female, n = 495; nondiabetics without disease) who were stratified into normal fasting glucose (NFG) and impaired fasting glucose (IFG) groups. Total monounsaturated FA (MUFA), oleic acid (OA; 18:1n-9), dihomo-γ-linolenic acid (DGLA; 20:3n-6), Δ-9-desaturase activity (D9D; 18:1n-9/18:0), and DGLA/linoleic acid (20:3n-6/18:2n-6) in serum phospholipids were significantly higher in IFG subjects than NFG controls. Study subjects were subdivided into 4 groups, based on fasting glucose levels and MetS status. Palmitoleic acid (16:1n-7) was highest in IFG-MetS and lowest in NFG-non-MetS subjects. Oleic acid and D9D were higher in IFG-MetS than in the other 3 groups. Dihomo-γ-linolenic acid and DGLA/linoleic acid were higher in MetS than in non-MetS, regardless of fasting glucose levels. The high-sensitivity C-reactive proteins (hs-CRPs) and 8-epi-prostaglandin-F2α were higher in IFG than in NFG, regardless of MetS status. Oxidized low-density lipoproteins were higher in IFG-MetS than in the other 3 groups. Total MUFAs, OA, and D9D were positively correlated with homeostasis model assessment of insulin resistance, fasting glucose, triglyceride, hs-CRP, and 8-epi-prostaglandin-F2α. Palmitoleic acid was positively correlated with triglyceride and hs-CRP. Lastly, total MUFA, OA, palmitoleic acid, and D9D were associated with early alteration of fasting glycemic status, therefore suggesting that these may be useful markers for predicting the risk of type 2 diabetes and cardiometabolic diseases.

Topics: 8,11,14-Eicosatrienoic Acid; Biomarkers; Blood Glucose; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dinoprost; Fasting; Fatty Acids, Monounsaturated; Female; Humans; Insulin; Insulin Resistance; Linoleic Acid; Lipoproteins, LDL; Male; Metabolic Syndrome; Middle Aged; Oleic Acid; Phospholipids; Stearoyl-CoA Desaturase; Triglycerides

To investigate the changes of serum anti-aging protein Klotho and neutrophil gelatinase-associated lipocalin (NGAL) levels and their correlation in type 2 diabetes mellitus (T2DM) patients at different stages of diabetic kidney disease (DKD) determined by urinary albuminuria.. 462 cases with T2DM were divided into three groups: normoalbuminuric [N-UAlb; urinary albumin to creatinine ratio (UACR) < 30 mg/g, n=180], microalbuminuric [M-UAlb; UACR 30-300 mg/g, n = 158], macroalbuminuric [L-UAlb; UACR > 300 mg/g, n = 124]. The levels of serum soluble-Klotho (sKlotho), NGAL, 8-isoprostane prostaglandin F2α (8-iso-PGF2α), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) were determined by enzyme-linked immunosorbent assay (ELISA) in all cases and 160 control subjects.. Compared with control, serum sKlotho levels were significantly decreased (P < 0.001), and serum NGAL levels increased significantly (P < 0.001) in T2DM patients. Furthermore, serum sKlotho and NGAL levels were significantly negatively correlated (P < 0.001). Serum sKlotho levels negatively correlated with UACR, TG, CHO, LDL, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-β1 (P < 0.001), but positively correlated with LDL (P < 0.001). Serum NGAL levels positively correlated with UACR, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-β1 (P < 0.001). In addition, serum NGAL levels and LDL were significantly positively correlated (P = 0.005), and HDL was significantly negatively correlated (P < 0.001).. Serum Klotho and NGAL levels may become new biomarkers of the early diagnosis of DKD in T2DM. Klotho may participate in the development of DKD pathological mechanism such as oxidative stress related to inflammation, renal fibrosis, lipid metabolic disorders, modulating the pathological process of diabetic kidney tissue. NGAL may play a part in these mechanisms.

Topics: Acute-Phase Proteins; Adult; Albuminuria; Biomarkers; Case-Control Studies; Chemokine CCL2; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Female; Glucuronidase; Humans; Klotho Proteins; Lipocalin-2; Lipocalins; Male; Middle Aged; Proto-Oncogene Proteins; Serum Albumin; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The aim of the present study was to evaluate the protective effect of catalpol on vascular endothelial function in STZ-induced type 2 diabetes mellitus (T2DM) rats. 40 high-fat diet with STZ-induced diabetes rats were randomly divided into model group, catalpol low-dose, middle-dose and high-dose group (10, 50, 100 mg x kg(-1) x d(-1)), 10 normal Wistar rats were used as the normal group. The normal and model groups were given an equivalent amount of saline. All reagents were administered by oral gavage for 6 weeks. After 6 weeks, blood glucose and lipids were detected by an automatic biochemical analyzer. The endothelium-dependent vasodilation response of thoracic aortar was detected. The pathological changes of the thoracic aorta were observed by HE staining. Ser- um nitric oxide (NO), 8-iso prostaglandin F2α (8-iso-PGF2α) and superoxide dismutase (SOD) were detected by ELISA. Reactive oxygen species (ROS) level of thoracic aorta was detected by fluorescence method. The expression of Nox4 and p22phox mRNA and protein in aortic tissue were detected by RT-PCR and Western-blot respectively. After catalpol treatment, endothelial damage of thoracic aorta was attenuated significantly; ROS level of thoracic aorta and serum level of 8-iso-PGF2α were decreased significantly; serum NO and SOD levels were remarkably elevated; expression of Nox4, p22phox mRNA and protein in thoracic aorta were significantly reduced (P < 0.05). Therefore, catalpol has protective effect on endothelial of T2DM, its mechanism may be associated with the down-regulation of Nox4 and p22phox expression, inhibiting oxidative stress reaction response.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Endothelium, Vascular; Enzyme Inhibitors; Gene Expression Regulation; Iridoid Glucosides; Male; NADPH Oxidase 4; NADPH Oxidases; Nitric Oxide; Rats; Rats, Wistar; Reactive Oxygen Species; RNA, Messenger; Superoxide Dismutase

8-iso-PGF2α is a family of PGF2α that could be offered as a non-invasive tool to represent in vivo oxidation status, as a link between oxidative milieus and vascular dysfunction.. A total of 45 patients with type 2 diabetes and 45 healthy adults were studied in this cross-sectional analysis. Blood samples were collected to measure the level of lipid profile, oxidative stress, and glycemic control indices. The sensitivity and specificity of 8-iso-PGF2α as a screening test were analyzed in the cut-off range 252 - 377.5 pg/mL and the corresponding receiver operating characteristics (ROC) were plotted to assess performance of the test.. 8-iso-PGF2α level was significantly higher in the diabetic group (439.11 pg/mL ± 181.13 vs. 380.93 pg/mL ± 146.52). After adjustments for age, gender, and body mass index (BMI), linear regression analysis revealed that homeostasis model assessment of insulin resistance (HOMA-IR), blood pressure, fasting blood sugar (FBS), serum creatinine, insulin, oxLDL, and CRP levels are directly correlated with 8-iso-PGF2α in the 25% - 75% quartiles. Moreover, their mean levels were higher in quartiles with greater 8-iso-PGF2α levels. The cut-offs showing the best equilibrium between sensitivity and specificity approached 269.5 pg/mL with 83% and 62.5% sensitivity and specificity, respectively.. Our study provides evidence for the application of serum 8-isoPGF2α in the 25 - 75% quartile ranges to screen for the severity of oxidative reactions and glycemic control in vivo without need for any further in vitro enzymatic reactions, with higher levels, reflecting more severe oxidation and poor glycemic control.

Topics: Aged; Area Under Curve; Biomarkers; Blood Glucose; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycated Hemoglobin; Humans; Inflammation Mediators; Insulin; Linear Models; Lipids; Male; Middle Aged; Oxidative Stress; Predictive Value of Tests; ROC Curve

To investigate the relationship between oxidative stress and biochemical parameters and the expression of TXNIP, IL-6, IL-1β and TNF-α in peripheral mononuclear cells (PMCs) from type-2 diabetic patients.. We studied 60 males: 20 normal-weight type- 2 diabetic patients (NW), 20 obese diabetic patients (OB) and 20 controls (C). Biochemical and oxidative stress parameters were evaluated. PMCs were isolated and total RNA was extracted in order to determine the expression of TXNIP, IL-6, IL-1β and TNF-α by qRT-PCR.. OB had higher weight, BMI and abdominal circumference (One way ANOVA, p<0.0001). NW had higher fasting glycemia (One way ANOVA, p=0.0034) however OB had higher HbA1c (One way ANOVA, p<0.0001). OB also had higher hsCRP (One way ANOVA, p=0.0158). TBARS and AGES were elevated in both NW and OB (One way ANOVA, p<0.0001 and p=0.0008, respectively). Compared to OB and C participants, the expression of TXNIP was significantly higher in NW (Kruskal Wallis, p=0.0074); IL-1β, IL-6 and TNF-α transcripts were higher in NW and OB (Kruskal Wallis, p<0.0001, for all). In NW patients, the expression of TXNIP was positively correlated with fasting glycemia and AGES and negatively correlated with HOMA-β (r=0.72; r=0.59; r=-0.44, respectively, for all p<0.05), in OB there was correlation only with 8-Isoprostanes (r=0.42, p=0.046).. Our results suggest that fasting glycemic control, independent of adiposity and nutritional status, represents a risk factor for β-cell dysfunction, increases oxidative stress markers and it is related with an elevation of TXNIP expression.. Objetivo: Investigar la relación existente entre parámetros bioquímicos y de estrés oxidativo y la expresión de TXNIP, IL-6, IL-1y TNF-en células mononucleares periféricas (CMPs) de sujetos diabéticos. Material y métodos: Se estudió 60 sujetos hombres: 20 con peso normal y diabetes tipo 2 (NW), 20 sujetos obesos con diabetes (OB) y 20 sujetos controles (C). Se evaluaron parámetros bioquímicos y de estrés oxidativo. Además se aislaron CMPs para la extracción de RNA total y se determinó la expresión de los genes TXNIP, IL-6, IL- 1y TNF-mediante PCR de tiempo real cuantitativo. Resultados: Los OB presentaron mayor IMC y circunferencia abdominal que los NW y los C (ANOVA de una vía, p.

Topics: Adult; Anthropometry; Blood Glucose; Body Mass Index; Body Weight; Carrier Proteins; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Inflammation; Insulin; Interleukin-1beta; Interleukin-6; Lipids; Male; Middle Aged; Overweight; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Effect of high-dose insulin analog initiation therapy was evaluated on lipid peroxidation and oxidative stress markers in type 2 diabetes mellitus (T2DM). Twenty-four T2DM patients with HbA1c levels above 10% despite ongoing therapy with sulphonylurea and metformin were selected. Former treatment regimen was continued for the first day followed by substitution of sulphonylurea therapy with different insulin analogs. Glycemic profiles were determined over 72 hours by Continuous Glucose Monitoring System (CGMS), and blood/urine samples were collected at 24 and 72 hours. Insulin analog plus metformin treatment significantly reduced glucose variability. Plasma and urine lipid peroxidation were markedly decreased following insulin analog plus metformin treatment. No correlation existed between glucose variability and levels of plasma and urine oxidative stress markers. Likewise, changes in mean blood glucose from baseline to end point showed no significant correlation with changes in markers of oxidative stress. On the contrary, decreased levels of oxidative stress markers following treatment with insulin analogs were significantly correlated with mean blood glucose levels. In conclusion, insulin plus metformin resulted in a significant reduction in oxidative stress markers compared with oral hypoglycemic agents alone. Data from this study suggests that insulin analogs irrespective of changes in blood glucose exert inhibitory effects on free radical formation.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dinoprost; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Insulin; Lipid Peroxidation; Male; Metformin; Middle Aged; Nitrates; Nitrites; Oxidative Stress; Protein Carbonylation; Sulfonylurea Compounds; Tyrosine

Urinary 8-iso-PGF2α, a marker of oxidative stress, is influenced by the activation of NOX2. It is unclear if platelets 8-iso-PGF2α contribute to urinary 8-iso-PGF2α.. In a cross-sectional study, platelet, urinary, and serum 8-iso-PGF2α were determined in subjects with downregulation (X-linked chronic granulomatous disease [X-CGD], n=25) and upregulation (type II diabetic patients [T2D], n=121) of NOX2 and 153 controls matched for sex and age. In diabetic patients (n=18), the above variables were repeated before and after 7 days treatment with 100 mg/day aspirin or 100 mg/day aspirin plus 40 mg/day atorvastatin. In vitro study was performed to see the contribution of blood cells to serum 8-iso-PGF2α. Compared with controls, X-CGD patients had lower platelet, serum, and urinary 8-iso-PGF2α values; conversely, diabetic patients had higher values of 8-iso-PGF2α compared with controls. Urinary 8-iso-PGF2α significantly correlated with both platelet and serum 8-iso-PGF2α in the 2 cohorts. A parallel increase of platelet, serum, and urinary 8-iso-PGF2α by aspirin and a parallel decrease by aspirin plus atorvastatin were detected in the interventional study. In vitro study demonstrated that platelets contribute to 37% of serum 8-iso-PGF2α and that only 13% of it is of extravascular origin.. The study suggests that NOX2 contributes to the formation of 8-iso-PGF2α in both platelets and urine. The direct correlation between platelet and urinary 8-iso-PGF2α suggests that, at least partly, urinary 8-iso-PGF2α reflects platelet 8-iso-PGF2α production. Analysis of serum 8-iso-PGF2α may represent a novel tool to investigate the production of 8-iso-PGF2α by blood cells including platelets.. URL: ClinicalTrials.gov. Unique Identifier: NCT01250340.

Topics: Aged; Blood Platelets; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dinoprost; Female; Granulomatous Disease, Chronic; Humans; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases

The present study investigated whether endothelial nitric oxide synthase (eNOS) activation may be dysregulated in cardiac tissue of patients suffering from type 2 diabetes (T2D). We performed immunohistochemical measurements of translocated eNOS activation as well as eNOS phosphorylation at Ser1177, Thr495, Ser 635, Ser114, and of the protein kinase B (Akt) in isolated right atrial trabeculae of patients undergoing cardiac bypass or valve surgery with (n = 12, 68.1 ± 2.5 yr) and without T2D (n = 12, 64.7 ± 2.7 yr). In addition, we investigated oxidative (8-isoprostane) and nitrosative stress markers (nitrotyrosine) as well as the effect of pharmacological stimulation of angiotensin (AT)-receptors on eNOS-phosphorylation. Translocation-dependent eNOS activation was similar in both groups. The same holds true for eNOS phosphorylation at Ser114. eNOS phosphorylation at Ser635 was significantly increased, whereas eNOS phosphorylation of Ser1177 was significantly decreased in the diabetic group paralleled by a decrease in phosphorylation of Akt and Thr495. These alterations were accompanied by a significant decrease in nitrotyrosine. After application of angiotensin II (10 μM, 2 min) for investigation of the AT-receptor-dependent eNOS stimulation, we did not find differences between the increases in eNOS Ser1177-phosphorylation in the nondiabetic (+39.7 ± 23.5%) and in the diabetic group (32.22 ± 11.45%). A simultaneous increase in Akt phosphorylation could not be observed. The present study indicates that T2D goes along with a decrease in eNOS phosphorylation at Ser1177 under basal conditions in cardiac tissue. Whether this may be attributed to the insulin resistance of cardiac muscle has to be further investigated. Receptor-stimulated eNOS activation still works at least for angiotensin II-dependent eNOS activation.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II; Diabetes Mellitus, Type 2; Dinoprost; Humans; Middle Aged; Myocardium; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-akt; Tyrosine

Epidemiological evidence suggests that whole grain intake is associated with reduced risk of type 2 diabetes. However, studies of individual whole grains on the prevention of type 2 diabetes are lacking. The objective of the present study was to examine the effect of different whole grains on type 2 diabetes in an animal model of type 2 diabetes, the Goto-Kakisaki (GK) rat. GK rats were fed either a basal diet or a whole grain-containing diet for 5 months. Whole grain diets contained 65 % whole grain flours of wheat, barley, oats or maize. After 2 months of feeding, fasting plasma glucose concentrations were lower in the wheat, barley and oats groups, compared with the basal group, whereas glycated Hb was significantly greater in the wheat group compared with other groups. Feeding of whole barley and maize increased plasma C-peptide concentrations compared with whole wheat at 2 months. There was a trend in the improvement of insulin resistance with a consumption of barley and oats diets at 2 months (P = 0·06) compared with the basal diet. Oxidative stress markers, urinary thiobarbituric acid-reactive substances and 8-isoprostane, did not improve with whole grain intake at 2 months. At 5 months, whole grain diets did not differ from the basal diet in glycaemic control, insulin secretion, oxidative stress and preservation of pancreatic β-cell mass. These results suggest that the consumption of whole grains may offer modest benefit early in the development of type 2 diabetes, but this benefit is lost with further development of the disease.

Topics: Animals; Antioxidants; Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Dietary Fiber; Dinoprost; Disease Progression; Edible Grain; Food Handling; Functional Food; Glycated Hemoglobin; Hyperglycemia; Insulin Resistance; Insulin-Secreting Cells; Male; Oxidative Stress; Random Allocation; Rats; Rats, Mutant Strains; Rats, Wistar; Thiobarbituric Acid Reactive Substances

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

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

Because pharmacotherapies in type 2 diabetes exert complex effects, we examined the different anti-diabetic strategies, especially the influence of insulin doses, on the activation of oxidative stress, a key player in atherosclerosis, ageing and the risk of cancer.. This observational study included 122 persons with type 2 diabetes, 61 treated with oral hypoglycaemic agents alone (group I), 61 treated with a combination of oral hypoglycaemic agents and insulin at either a low dose (<0.40 unit/kg/day, group IIa, n = 30) or high dose (≥0.40 unit/kg/day, group IIb, n = 31) of insulin. Oxidative stress was estimated from 24-h urinary excretion rates of 8-iso-prostaglandin F2α. Haemoglobin A(1c) (%) was also measured to assess overall diabetic control.. The 24-h excretion rates of 8-iso-prostaglandin F2α [median (range) pmol/mmol of creatinine] were much lower in group IIa [68 (32-220)] than in either group I [120 (26-329) p < 0.001] or group IIb [101 (30-289) p = 0.026]. Considering groups IIa and IIb as a whole, a significant and positive relationship (p = 0.021) was observed between insulin dose and 8-iso-prostaglandin F2α. Haemoglobin A(1c) was comparable in the three groups.. The main benefit of insulin therapy is the restoration and maintenance of near normal glycaemia. However insulin at elevated doses can promote oxidative stress which is thought to be an important mediator of some of the deleterious effects of insulin. Our study shows that the link between insulin action and oxidative stress in type 2 diabetes is complex and warrants further study.

Topics: Aged; Body Mass Index; Caloric Restriction; Diabetes Mellitus, Type 2; Dinoprost; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Oxidative Stress; Reproducibility of Results; Thiazolidinediones

Patients with diabetes experience increased cardiovascular complications after cardiac surgery. Hyperglycaemia predicts increased mortality after myocardial infarction and may influence cardiovascular risk in humans. Impaired prosurvival phosphatase and tensin homologue on chromosome 10 (PTEN)-Akt signalling could be an important feature of the diabetic heart rendering it resistant to preconditioning. This study was designed to evaluate for differences and relationships of myocardial PTEN-Akt-related signalling and baseline glycaemic control marker in type 2 diabetic and nondiabetic patients undergoing coronary artery bypass surgery.. Right atrial biopsies and coronary sinus blood were obtained from 18 type 2 diabetic and 18 nondiabetic patients intraoperatively. Expression and phosphorylation of Akt, endothelial nitric oxide synthase (eNOS), Bcl-2 and PTEN were evaluated by Western blot. Plasma 15-F(2t) -isoprostane concentrations were evaluated by liquid chromatography-mass spectrometry.. PTEN expression and 15-F(2t) -isoprostane concentrations were significantly higher in diabetic patients. Increased fasting blood glucose levels correlated with increased coronary sinus plasma 15-F(2t) -isoprostane concentrations. Increased cardiac 15-F(2t) -isoprostane generation was highly correlated with myocardial PTEN expression. Bcl-2 expression and eNOS phosphorylation were significantly lower in diabetic compared with nondiabetic patients. Akt phosphorylation tended to be lower in diabetic patients; however, this tendency failed to reach statistical significance.. The current results suggest that prosurvival PTEN-Akt signalling is impaired in the diseased diabetic myocardium. Hyperglycaemia and increased oxidative stress may contribute to this phenomenon. These findings strengthen the understanding of the underlying biologic mechanisms of cardiac injury in diabetic patients, which could facilitate development of new treatments to prevent cardiovascular complications in this high-risk population.

Topics: Aged; Blotting, Western; Cardiovascular Diseases; Chromatography, Liquid; Coronary Artery Bypass; Coronary Sinus; Diabetes Mellitus, Type 2; Dinoprost; Female; Humans; Male; Mass Spectrometry; Middle Aged; Myocardium; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; PTEN Phosphohydrolase; Signal Transduction

The effect of glycemic variability (GV) on cardiovascular risk has not been fully clarified in type 2 diabetes. We evaluated the effect of GV, blood pressure (BP), and oxidative stress on intima-media thickness (IMT), left ventricular mass index (LVMI), flow-mediated dilation (FMD), and sympathovagal balance (low frequency [LF]/high frequency [HF] ratio) in 26 type 2 diabetic patients (diabetes duration 4.41±4.81 years; HbA1c 6.70±1.25%) receiving diet and/or metformin treatment, with no hypotensive treatment or complications.. Continuous glucose monitoring (CGM) data were used to calculate mean amplitude of glycemic excursion (MAGE), continuous overall net glycemic action (CONGA)-2, mean blood glucose (MBG), mean postprandial glucose excursion (MPPGE), and incremental area under the curve (IAUC). Blood pressure (BP), circadian rhythm, and urinary 15-F2t-isoprostane (8-iso-prostaglandin F2α [PGF2α]) were also evaluated. Subjects were divided into dipper (D) and nondipper (ND) groups according to ΔBP.. IMT and LVMI were increased in ND versus D (0.77±0.08 vs. 0.68±0.13 [P=0.04] and 67±14 vs. 55±11 [P=0.03], respectively). MBG, MAGE, and IAUC were significantly associated with LF/HF ratio at night (r=0.50, P=0.01; r=0.40, P=0.04; r=0.41, P=0.04, respectively), MPPGE was negatively associated with FMD (r=-0.45, P=0.02), and CONGA-2 was positively associated with LVMI (r=0.55, P=0.006). The Δsystolic BP was negatively associated with IMT (r=-0.43, P=0.03) and with LVMI (r=-0.52, P=0.01). Urinary 8-iso-PGF2α was positively associated with LVMI (r=0.68 P<0.001).. An impaired GV and BP variability is associated with endothelial and cardiovascular damage in short-term diabetic patients with optimal metabolic control. Oxidative stress is the only independent predictor of increased LV mass and correlates with glucose and BP variability.

Topics: Aged; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Circadian Rhythm; Diabetes Mellitus, Type 2; Dinoprost; Heart Ventricles; Humans; Middle Aged; Treatment Outcome; Tunica Intima

Oxidative stress plays a leading role in the progression of diabetic secondary complications, e.g., of cardio-vascular illnesses. Physical activity has been shown to delay and even prevent the progression of type 2 diabetes by improving the antioxidative capacity and thereby decreasing systemic oxidative stress. Peroxiredoxins (PRDX) are important antioxidative components that are highly abundant in erythrocytes. The present study examines the influence of glycemic control and physical fitness on oxidative stress and the peroxiredoxin system in the erythrocytes of non-insulin-dependent type 2 diabetic men ( N=22, years=61 ± 10) at rest. Oxidative stress was measured by immunohistochemical stainings for 8-iso-prostaglandin-F2α (8-Iso-PGF) and the overoxidized form of peroxiredoxins (PRDX-SO (2-3)). Peroxiredoxin isoforms PRDX1 and PRDX2 were also quantified immunohistochemically. Physical fitness was determined during the WHO-step test. Regression analyses showed a positive relationship between 8-Iso-PGF plotted against HbA (1c) (hyperbolic curve (y=a+b/x), R (2)=0.346, P=0.013), a positive relationship between 8-Iso-PGF plotted against fasting glucose (hyperbolic curve (y=a+b/x), R (2)=0.440, P=0.003), as well as positive relationships between PRDX2 plotted against VO (2 peak) (S-curve (y=e(a+b/x)), R(2)=0.259, P=0.018) and between PRDX2 plotted against the workload corresponding to the 4 mmol/l blood lactate concentration (hyperbolic curve (y=a+b/x), R(2)=0.203, P=0.041). Further significant relationships were not found.. Poor glycemic control may increase oxidative stress in the erythrocytes of type 2 diabetic men. Good physical fitness seems to be associated with increased peroxiredoxin contents. Therefore, it can be speculated that physical training can contribute to the improvement of the erythrocyte peroxiredoxin system to counteract free radicals in type 2 diabetic patients.

Topics: Aged; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dinoprost; Erythrocytes; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Lipid Peroxidation; Male; Middle Aged; Overweight; Oxidation-Reduction; Oxidative Stress; Peroxiredoxins; Physical Fitness

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

Little is known about the vascular contractile responsiveness to, and signaling pathways for, extracellular nucleotides in the chronic stage of type 2 diabetes or whether the ANG II type 1 receptor blocker losartan might alter such responses. We hypothesized that nucleotide-induced arterial contractions are augmented in diabetic Goto-Kakizaki (GK) rats and that treatment with losartan would normalize the contractions. Here, we investigated the vasoconstrictor effects of ATP/UTP in superior mesenteric arteries isolated from GK rats (37-42 wk old) that had or had not received 2 wk of losartan (25 mg·kg(-1)·day(-1)). In arteries from GK rats (vs. those from Wistar rats), 1) ATP- and UTP-induced contractions, which were blocked by the nonselective P2 antagonist suramin, were enhanced, and these enhancements were suppressed by endothelial denudation, by cyclooxygenase (COX) inhibitors, or by a cytosolic phospholipase A(2) (cPLA(2)) inhibitor; 2) both nucleotides induced increased release of PGE(2) and PGF(2α); 3) nucleotide-stimulated cPLA(2) phosphorylations were increased; 4) COX-1 and COX-2 expressions were increased; and 5) neither P2Y2 nor P2Y6 receptor expression differed, but P2Y4 receptor expression was decreased. Mesenteric arteries from GK rats treated with losartan exhibited (vs. untreated GK) 1) reduced nucleotide-induced contractions, 2) suppressed UTP-induced release of PGE(2) and PGF(2α), 3) suppressed UTP-stimulated cPLA(2) phosphorylation, 4) normalized expressions of COX-2 and P2Y4 receptors, and 5) reduced superoxide generation. Our data suggest that the diabetes-related enhancement of ATP-mediated vasoconstriction was due to P2Y receptor-mediated activation of the cPLA(2)/COX pathway and, moreover, that losartan normalizes such contractions by a suppressing action within this pathway.

Topics: Adenosine Triphosphate; Angiotensin II Type 1 Receptor Blockers; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Dinoprostone; Disease Models, Animal; Group IV Phospholipases A2; Losartan; Male; Membrane Proteins; Mesenteric Artery, Superior; Phosphorylation; Purinergic P2 Receptor Antagonists; Rats; Rats, Wistar; Receptors, Purinergic P2; Receptors, Purinergic P2Y2; Signal Transduction; Superoxides; Uridine Triphosphate; Vasoconstriction

The main purpose of this study was to investigate whether treatment with long-acting insulin once a day or short-acting insulin three times before each meal daily has a stronger antioxidative effect in patients with type 2 diabetes. These patients had not been treated previously with insulin and were hospitalized for initiation of glycemic control by insulin injection. The patients (n=43) were assigned consecutively and alternately to a group treated with insulin aspart injection three times daily just before each meal and a group treated with insulin detemir injection once daily before bedtime. The results showed that insulin aspart three times a day produced a greater improvement in plasma glucose, and particularly in mean postprandial plasma glucose, compared with insulin detemir once a day (p = 0.0006 for comparison of changes between the two insulin treatments). The amount of insulin needed to approach the target levels of plasma glucose was larger in the insulin aspart group (26.0 ± 10.7 U/day vs. 13.7 ± 4.9 U/day; p < 0.0001). However, only insulin detemir significantly decreased oxidative stress evaluated based on the level of urinary 8-iso-prostaglandin F2α (p = 0.0079), although the mechanisms are not fully evident.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dinoprost; Drug Administration Schedule; Female; Humans; Insulin Aspart; Insulin Detemir; Insulin, Long-Acting; Male; Middle Aged; Oxidative Stress

Chromium is an essential element for carbohydrate, fat, and protein metabolism. The therapeutic potential of chromium histidinate (CrHis) in the treatment of diabetes has been elucidated. The present study investigated the effects of CrHis on serum parameters of renal function, on oxidative stress markers (malondialdehyde [MDA] and 8-isoprostane), and on the expression of heat-shock proteins (HSPs) in rats.. Male Wistar rats (n=60, 8 weeks old) were divided into four groups. Group 1 received a standard diet (12% of calories as fat). Group 2 received a standard diet, plus CrHis. Group 3 received a high-fat diet (40% of calories as fat) for 2 weeks, and was then injected with streptozotocin (STZ) on day 14 (STZ, 40 mg/kg intraperitoneally). Group 4 was treated in the same way as group 3 (HFD/STZ), but was supplemented with 110 microg CrHis/kg/body weight/day. Oxidative stress in the kidneys of diabetic rats was evidenced by an elevation in levels of MDA and 8-isoprostane. Protein concentrations of HSP60 and HSP70 in renal tissue were determined by Western blot analyses.. Chromium histidinate supplementation lowered kidney concentrations of MDA, 8-isoprostane levels, serum urea-N, and creatinine, and reduced the severity of renal damage in the STZ-treated group (i.e., the diabetes-induced group). The expression of HSP60 and HSP70 was lower in the STZ group that received CrHis than in the group that did not. No significant effect of CrHis supplementation was detected in regard to the overall measured parameters in the control group.. Chromium histidinate significantly decreased lipid peroxidation levels and HSP expression in the kidneys of experimentally induced diabetic rats. This study supported the efficacy of CrHis in reducing renal risk factors and impairment because of diabetes.

Topics: Animals; Chaperonin 60; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dietary Fats; Dinoprost; Heat-Shock Proteins; Histidine; HSP70 Heat-Shock Proteins; Kidney; Lipid Peroxidation; Male; Malondialdehyde; Organometallic Compounds; Oxidative Stress; Rats; Rats, Wistar

We examined whether type of diabetes and/or insulin treatment can modulate the impact of sustained hyperglycaemia and glycaemic variability as activators of oxidative stress.. This was an observational study in 139 patients with diabetes, 48 with type 1, 60 with type 2 treated by oral hypoglycaemic agents (OHAs) alone and 31 with type 2 treated with insulin plus OHAs. In addition, two groups of ten patients with type 2 diabetes were investigated either before and after introducing insulin treatment (add-on insulin group) or before and after add-on OHA therapy to metformin (add-on OHA group). Oxidative stress was estimated from 24 h urinary excretion rates of 8-isoprostaglandin F2alpha (8-iso-PGF2alpha). HbA(1c) was assessed and mean amplitude of glycaemic excursions (MAGE) was estimated by continuous monitoring.. The 24 h excretion rate of 8-iso-PGF2alpha (median [range] picomoles per millimole of creatinine) was much higher (p < 0.0001) in type 2 diabetes patients treated with OHAs alone (112 [26-329]) than in the type 1 diabetes group (65 [29-193]) and the type 2 diabetes group treated with insulin (69 [30-198]). It was associated with HbA(1c) (F = 12.9, p = 0.0008) and MAGE (F = 7.7, p = 0.008) in non-insulin-treated, but not in insulin-treated patients. A significant reduction in 24 h excretion rate of 8-iso-PGF2alpha from 126 (47-248) to 62 (35-111] pmol/mmol of creatinine was observed in the add-on insulin group (p = 0.005) but not in the add-on OHA group.. In type 1 and type 2 diabetes, insulin exerts an inhibitory effect on oxidative stress, a metabolic disorder that is significantly activated by sustained hyperglycaemia and glucose variability in non-insulin-treated type 2 diabetes.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Oxidative Stress

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

The association of dietary advanced glycation endproducts (AGEs) intake with the oxidative and inflammatory status in type 2 diabetic patients was examined.. Seventy-four healthy controls, 50 low AGEs intake and 68 high AGEs intake type 2 diabetic patients were requested to complete a 7-day dietary record. Blood levels of several oxidative and inflammatory biomarkers were determined.. Diabetic patients with high AGEs intake had significantly elevated plasma levels of AGEs, HbA1c, low-density lipoprotein (LDL), LDL-cholesterol and glycated LDL than low AGEs intake patients and controls (P < 0.05). These high AGEs intake patients also had significantly increased plasma levels of 8-isoprostane, interleukin (IL)-1α, tumor necrosis factor-α, monocyte chemoattractant protein (MCP)-1 and lower superoxide dismutase (SOD) activity than low AGEs intake patients (P < 0.05). Correlation coefficients of dietary AGEs versus plasma AGEs, HbA1c, 8-isoprostane, IL-1α and MCP-1 were >0.6; but the correlation coefficient of dietary AGEs versus plasma SOD activity was <-0.6.. Increasing dietary AGEs intake might enrich circulating AGE level and contribute to oxidative and inflammatory progression under diabetic condition. The circulating 8-isoprostane, IL-1α and MCP-1 levels and SOD activity might be appropriate biomarkers used to evaluate dietary AGEs-associated oxidative and inflammatory stress.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Chemokine CCL2; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycation End Products, Advanced; Humans; Inflammation; Interleukin-1alpha; Lipoproteins, LDL; Male; Middle Aged; Oxidative Stress; Superoxide Dismutase; Tumor Necrosis Factor-alpha

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

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

Regulation of coronary function in diabetic hearts is an important component in preventing ischemic cardiac events but remains poorly studied. Exercise is recommended in the management of diabetes, but its effects on diabetic coronary function are relatively unknown. We investigated coronary artery myogenic tone and endothelial function, essential elements in maintaining vascular fluid dynamics in the myocardium. We hypothesized that exercise reduces pressure-induced myogenic constriction of coronary arteries while improving endothelial function in db/db mice, a model of type 2 diabetes. We used pressurized mouse coronary arteries isolated from hearts of control and db/db mice that were sedentary or exercised for 1 h/day on a motorized exercise-wheel system (set at 5.2 m/day, 5 days/wk). Exercise caused a approximately 10% weight loss in db/db mice and decreased whole body oxidative stress, as measured by plasma 8-isoprostane levels, but failed to improve hyperglycemia or plasma insulin levels. Exercise did not alter myogenic regulation of arterial diameter stimulated by increased transmural pressure, nor did it alter smooth muscle responses to U-46619 (a thromboxane agonist) or sodium nitroprusside (an endothelium-independent dilator). Moderate levels of exercise restored ACh-simulated, endothelium-dependent coronary artery vasodilation in db/db mice and increased expression of Mn SOD and decreased nitrotyrosine levels in hearts of db/db mice. We conclude that the vascular benefits of moderate levels of exercise were independent of changes in myogenic tone or hyperglycemic status and primarily involved increased nitric oxide bioavailability in the coronary microcirculation.

Topics: Animals; Blood Glucose; Body Weight; Coronary Circulation; Coronary Vessels; Diabetes Mellitus, Type 2; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Exercise Therapy; Hyperglycemia; Insulin; Mice; Microcirculation; Nitric Oxide; Oxidative Stress; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Endothelial dysfunction often precedes Type 2 diabetes-associated cardiovascular complications. One important cause of endothelial dysfunction is oxidative stress, which can lead to reduced nitric oxide (NO) bioavailability. In this study, we examined the effects of ramipril (an angiotensin-converting enzyme inhibitor, ACEI) on reactive oxygen species (ROS) production and endothelium-dependent vasodilation using a Type 2 diabetic (db/db) murine model. Plasma concentration of 8-isoprostane ([8-isoP]) was measured and used as an indication of the amount of ROS production. Six weeks of ramipril (10 mg/kg/day) treatment significantly reduced [8-isoP] and improved acetylcholine(ACh)-induced vasodilation in db/db mice without altering responses in wild-type (WT) mice. Responsiveness of smooth muscle cells to NO, assessed by sodium nitroprusside-induced vasodilation, was not different between db/db and WT mice regardless of ramipril or vehicle treatment. Our results suggest that ramipril specifically improved endothelium-dependent vasodilation in Type 2 diabetic mice, possibly by reducing ROS levels.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Male; Mice; Mice, Inbred Strains; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Oxidative Stress; Ramipril; Reactive Oxygen Species; Time Factors; Vasodilation; Vasodilator Agents

Although it has been reported that angiotensin II receptor blockers inhibited the formation and accumulation of advanced glycation endproducts (AGEs) in vitro and in vivo, whether they can do so clinically is not clear. We investigated the effects of 12-month valsartan therapy on various markers of inflammation, glycation, and oxidation in type 2 diabetic subjects with hypertension. We started 40 mg/day valsartan treatment in 15 type 2 diabetic patients with hypertension. In 6 patients, the dose of valsartan was increased to 80 mg/day after 6 months and maintained until 12 months. Metabolic parameters including BMI and serum high molecular weight (HMW)-adiponectin, high-sensitivity C-reactive protein (hs-CRP) as an inflammation marker, AGEs, paraoxonase activity, platelet-activating factor (PAF)- acetylhydrolase activity, and urine 8-isoprostane levels were measured at baseline and after 6 and 12 months of treatment. Urine microalbumin level and carotid artery intima-media thickness (IMT) were also measured. Even after valsartan therapy, the blood pressure levels of the patients were not decreased significantly. Serum AGEs and urine 8-isoprostane levels decreased at both 6 and 12 months (P < 0.05 for both), although other metabolic and oxidative markers were unchanged. Though urine microalbumin levels tended to be decreased after 6 and 12 months of valsartan treatment, the changes were not significant. Mean IMT at 12 months was not changed from the baseline value. In conclusion, the findings suggest that treatment with valsartan, even at a low dose, may ameliorate some glycation and oxidative stress markers independently of an effect on blood pressure in hypertensive type 2 diabetic subjects.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adiponectin; Aged; Albuminuria; Antihypertensive Agents; Aryldialkylphosphatase; Biomarkers; C-Reactive Protein; Carotid Arteries; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycation End Products, Advanced; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Tetrazoles; Valine; Valsartan

Exposure to hyperbaric oxygen leads to increased amount of reactive oxygen species (ROS) that are derived from various sources. After the discovery that ROS can function as signaling molecules, the idea of ROS being hazardous to biological tissues has been challenged. The aim of this study was to examine the changes in oxidative stress parameters in diabetics undergoing hyperbaric oxygen therapy (HBOT) due to foot ulcers. Twenty patients, who received HBOT for diabetic foot ulcers, were included in the study. Blood samples were taken before HBOT and 30 min after exit from the chamber, on the day of the first and the fifteenth HBOT sessions. They were used for the determinations of malondialdehyde (MDA), 8-isoprostane and advanced oxidation protein products (AOPPs). 8-Isoprostane and AOPP levels were not altered significantly after the first HBOT session, while both were increased on the fifteenth day (p<0.05). MDA was significantly increased only after the first HBOT session, and remained unchanged on the fifteenth day (within-day variations). Plasma AOPP levels were lowered significantly after fifteen consecutive HBOT sessions (between-day variations). Decreased AOPP levels suggest that increased oxygenation of tissues due to HBO therapy may activate some endogenous factors that prevent hazardous effects of the disease itself.

Topics: Adult; Aged; Antioxidants; Biomarkers; Blood Proteins; Diabetes Mellitus, Type 2; Diabetic Foot; Dinoprost; Female; Humans; Hyperbaric Oxygenation; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Treatment Outcome

Vascular dysfunction is linked with increased free radical generation and is a major contributor to the high mortality rates observed in diabetes. Several probable sources of free radical generation have been suggested in diabetes, including cytochrome P450 (CYP) monooxygenase-dependent pathways. CYP-mediated superoxide production reduces nitric oxide (NO) bioavailability. In this study, we focus on the contribution of monooxygenase enzyme-generated reactive oxygen species in vascular dysfunction in an experimental model of diabetes mellitus type II. Diabetic male mice (db/db strain) and their age-matched controls received daily intraperitoneal injections of either the CYP 2C inhibitor sulfaphenazole (5.13 mg/kg) or saline (vehicle control) for 8 weeks. Although sulfaphenazole did not change endothelium-dependent vasodilation in control mice, it restored endothelium-mediated relaxation in db/db mice. We report for the first time that CYP 2C inhibition reduces oxidative stress (measured as plasma levels of 8-isoprostane), increases NO bioavailability (measured as NO(2)(-)) and restores endothelial function in db/db mice without affecting plasma glucose levels. Based on our findings, we speculate that inhibition of free radical generating CYP 450 monooxygenase enzymes restores endothelium-dependent vasodilation to acetylcholine. In addition, it reduces oxidative stress and increases NO bioavailability.

Topics: Acetylcholine; Animals; Antioxidants; Aorta, Thoracic; Biomarkers; Blood Glucose; Cyclic N-Oxides; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Type 2; Dinoprost; Dose-Response Relationship, Drug; Endothelium, Vascular; Fasting; In Vitro Techniques; Injections, Intraperitoneal; Male; Mice; Mice, Mutant Strains; Nitrites; Nitroprusside; Spectrophotometry; Spin Labels; Sulfaphenazole; Vasodilation; Vitamin E

Fructose consumption is increasing worldwide and is likely to play a role in metabolic disorders. Dietary fructose is often recommended for diabetic patients, as this form of carbohydrate leads to a lower postprandial rise in plasma glucose and insulin. However, fructose contributes to the generation of free radicals. The aim of this work was to investigate the acute effects of a fructose load in patients with type 2 diabetes mellitus (T2DM), compared with healthy controls, on several metabolic oxidative biomarkers, particularly plasma 15-F2t isoprostanes (15-F2t isoPs).. Six T2DM patients and six healthy subjects were recruited. All patients underwent a single fructose tolerance test (75 g of anhydrous fructose). Plasma 15-F2t isoPs concentrations, plasma total antioxidant capacity (TAS) and thiobarbituric acid reactive substances (TBARS) were measured at baseline, and at 60, 120, 180 and 240 min after fructose absorption.. Baseline plasma 15-F2t isoPs concentrations were significantly increased in T2DM patients compared with controls (310+/-47 versus 237+/-20 pg/mL, respectively; P<0.01) and rose significantly (P<0.01) to 414+/-45 pg/mL in diabetic patients. No change in TAS or TBARS was observed in either group.. Plasma 15-F2t isoPs are increased during acute fructose loading in T2DM. Knowing the potentially deleterious effect of plasma 15-F2t isoPs-in particular, vascular lesions-and in light of our results, it is necessary to reconsider fructose consumption in T2DM patients, as we can now show, for the first time, a possible association between acute fructose loading and deleterious effects in such patients.

Topics: Adult; Blood Glucose; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 2; Dinoprost; Fasting; Female; Fructose; Humans; Lactates; Lipoproteins; Male; Middle Aged; Reference Values; Triglycerides

1. The present study was performed to test the hypothesis that the reactive oxygen species (ROS)-angiotensinogen (AGT)-renin angiotensin system (RAS) axis is sequentially activated in the development of diabetic nephropathy in Zucker diabetic fatty (ZDF) obese rats. 2. Genetic pairs of male ZDF obese and control ZDF lean rats (n = 12 of each species) were killed every 3 weeks from 12 to 21 weeks of age (n = 6 at each time point). 3. The ZDF obese rats developed diabetes mellitus at 12 weeks. At that time, urinary excretion rates of 8-isoprostane were similar between the groups; however, urinary 8-isoprostane levels were significantly increased at 15 weeks in ZDF obese rats compared with controls (36 +/- 6 vs 15 +/- 2 ng/day, respectively). At 15 weeks, protein levels of cortical angiotensinogen were similar between groups; however, cortical angiotensinogen levels were significantly increased at 18 weeks in ZDF obese rats compared with controls (relative ratio of 2.32 +/- 0.21 vs 1.00 +/- 0.20, respectively). At 12 weeks, angiotensin (Ang) II-like immunoreactivity was similar between groups in both the glomeruli and tubules; however, AngII-like immunoreactivity was increased significantly at 21 weeks in ZDF obese rats compared with controls (relative ratios of 1.98 +/- 0.55 vs 1.00 +/- 0.03, respectively, for glomeruli and 1.58 +/- 0.16 vs 1.00 +/- 0.13, respectively, for tubules). Moreover, at 21 weeks, the desmin-positive area in the glomeruli (0.63 +/- 0.08 vs 0.22 +/- 0.05%) and Masson's trichrome stain-positive area in the interstitium (4.97 +/- 0.05 vs 3.18 +/- 0.41%) were significantly increased in ZDF obese rats compared with controls, even though these differences had not been observed earlier. 4. These data suggest that the sequential activation of the ROS-AGT-RAS axis plays an important role in the development of diabetic nephropathy in ZDF obese rats.

Topics: Angiotensinogen; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Male; Obesity; Rats; Rats, Zucker; Reactive Oxygen Species; Renin-Angiotensin System; Time Factors

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

Advanced glycation end products (AGEs) contribute to diabetic vascular complications by engaging the AGE receptor (RAGE). A soluble RAGE form (sRAGE) acts as a decoy domain receptor, thus decreasing AGE cellular binding. A cross-sectional comparison of sRAGE, asymmetric dimethylarginine (ADMA) plasma levels (index of endothelial dysfunction), and urinary 8-iso-prostaglandin (PG)F(2alpha) (marker of oxidative stress) was performed between 86 diabetic patients and 43 controls. Plasma sRAGE levels were significantly lower and ADMA levels were significantly higher in diabetic patients as compared to controls (P<0.0001). HbA1c and urinary 8-iso-PGF(2alpha) were correlated inversely with sRAGE and directly with ADMA. On multivariate analysis HbA1c was independently related to sRAGE levels in diabetic patients. Twenty-four of 86 patients with newly diagnosed diabetes and 12 patients in poor metabolic control were reevaluated after treatment with a hypoglycemic agent or insulin, respectively. Improvement in metabolic control by oral agents or insulin resulted in a significant increase in sRAGE and decrease in ADMA levels (P<0.0001). Thus, poor glycemic control reduces sRAGE levels, in association with enhanced oxidative stress and endothelial dysfunction in diabetes. These abnormalities are susceptible to modulation by improvement in metabolic control.

Topics: Arginine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Oxidative Stress; Receptor for Advanced Glycation End Products; Receptors, Immunologic

Glycemic disorders, one of the main risk factors for cardiovascular disease, are associated with activation of oxidative stress.. To assess the respective contributions of sustained chronic hyperglycemia and of acute glucose fluctuations to oxidative stress in type 2 diabetes.. Case-control study of 21 patients with type 2 diabetes (studied 2003-2005) compared with 21 age- and sex-matched controls (studied in 2001) in Montpellier, France.. Oxidative stress, estimated from 24-hour urinary excretion rates of free 8-iso prostaglandin F2alpha (8-iso PGF2alpha). Assessment of glucose fluctuations was obtained from continuous glucose monitoring system data by calculating the mean amplitude of glycemic excursions (MAGE). Postprandial contribution to glycemic instability was assessed by determining the postprandial increment of glucose level above preprandial values (mean postprandial incremental area under the curve [AUCpp]). Long-term exposure to glucose was estimated from hemoglobin A1c, from fasting glucose levels, and from mean glucose concentrations over a 24-hour period.. Mean (SD) urinary 8-iso PGF2alpha excretion rates were higher in the 21 patients with diabetes (482 [206] pg/mg of creatinine) compared with controls (275 [85] pg/mg of creatinine). In univariate analysis, only MAGE (r = 0.86; P<.001) and AUCpp (r = 0.55; P = .009) showed significant correlations with urinary 8-iso PGF2alpha excretion rates. Relationships between 8-iso PGF2alpha excretion rates and either MAGE or AUCpp remained significant after adjustment for the other markers of diabetic control in multiple linear regression analysis (multiple R2 = 0.72 for the model including MAGE and multiple R2 = 0.41 for the model including AUCpp). Standardized regression coefficients were 0.830 (P<.001) for MAGE and 0.700 (P = .003) for AUCpp.. Glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia. The present data suggest that interventional trials in type 2 diabetes should target not only hemoglobin A1c and mean glucose concentrations but also acute glucose swings.

Topics: Aged; Blood Glucose; Case-Control Studies; Chronic Disease; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Linear Models; Male; Middle Aged; Oxidative Stress

The objective of this study was to establish if diabetes in the presence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN) is associated with alterations in the amounts of 8-epi-PGF2alpha (IP) and its metabolites including 2, 3-dinor-8-epi-PGF2alpha (dinor-IP) and 2, 3-dinor-5, 6 dihydro-8-epi-PGF2alpha (dinor-dihydro-IP) in urine. Mass spectrometric separation showed that excretion of IP was similar in the PN + /CAN- and PN+/CAN+ groups but higher than in the PN-/CAN- group (n = 103, 22 and 60, respectively; P < 0.05). By contrast, excretion of dinor-IP or dinor-dihydro-IP were similar in the PN-/CAN- and PN+/CAN- groups but higher than in PN+/CAN+ group. Correlations were obtained between IP and dinor-IP or dinor-dihydro-IP (r = 0.30; P < 0.001 and r = 0.31; P < 0.001, respectively). A significant association was also observed between dinor-IP and dinor-dihydro-IP (r = 0.48; P < 0.001). In conclusion, these biomarkers should prove useful in studies evaluating the impact of therapeutic drugs or antioxidant interventions aimed at delaying the onset of diabetic complications.

Topics: Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dinoprost; F2-Isoprostanes; Female; Humans; Male; Middle Aged; Oxidation-Reduction; Polyneuropathies

Oxidative stress plays a role in cardiovascular dysfunction. This is of interest in diabetes, a clinical condition characterized by oxidative stress and increased prevalence of cardiovascular disease. The role of p66(shc) in oxidative stress-related response has been demonstrated by resistance to and reduction of oxidative stress and prolonged lifespan in p66(shc-/-) mice. In this study we assess p66(shc) gene expression in peripheral blood mononuclear cells (PBM) from type 2 diabetic patients and healthy subjects. The p66(shc) mRNA level was assessed using RT-PCR with two sets of primers mapping for different p66(shc) regions. p66(shc) is expressed in both monocytes and lymphocytes. The level of p66(shc) mRNA was significantly higher in type 2 diabetic patients compared with controls (0.38 +/- 0.07 densitometric units vs. 0.13 +/- 0.08; P < 0.0001). In addition, total plasma 8-isoprostane levels, a marker of oxidative stress, were higher in type 2 diabetics (0.72 +/- 0.04 ng/ml) than in normal subjects (0.43 +/- 0.04, P < 0.001) and were significantly correlated to the p66(shc) mRNA level in PBM from type 2 diabetics (r(2) = 0.47; P = 0.0284). In conclusion, diabetes induces p66(shc) gene expression in circulating PBM; this up-regulation in expression is significantly associated with markers of oxidative stress. p66(shc) gene expression in PBM may represent a useful tool to investigate the oxidative stress involved in the pathogenesis of long-term diabetic complications.

Topics: Adaptor Proteins, Signal Transducing; Animals; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dinoprost; Gene Expression Regulation; Humans; Leukocytes, Mononuclear; Mice; Mice, Knockout; Middle Aged; Oxidative Stress; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1

Oxidative stress and the gene expression at the transcriptional level of antioxidant enzymes were investigated in two models of diabetes in mice. We used KKAy mice as a model of obese insulin-resistant diabetes, and streptozotocin-induced diabetic mice (STZ mice) as a model of insulin-deficient diabetes. C57BL mice and saline-injected ICR mice were used as the respective non-diabetic controls. To assess oxidative damage, plasma malonedialdehyde (MDA), urine 8-isoprostane and 8-hydroxy deoxyguanosine (8-OHdG) were measured. The mRNA expression of antioxidant enzymes, superoxide dismutase 1 (SOD-1) and glutathione peroxidase 1 (GPx-1) in the kidney and heart were quantified using a real-time polymerase chain reaction. The KKAy mice demonstrated moderate hyperglycemia and hyperlipidemia, and the STZ mice showed severe hyperglycemia and hypolipidemia. The KKAy mice, but not the STZ mice, showed elevated plasma MDA relative to the non-diabetic controls. Urine 8-isoprostane and 8-OHdG in both diabetic mouse groups increased significantly. The urine oxidative stress markers in the severely hyperglycemic STZ mice were higher than those in the moderately hyperglycemic KKAy mice. Although GPx-1 and SOD-1 showed elevated mRNA expression in the KKAy mice in the kidney and heart, in the STZ mice they did not increase compared to the controls. The compensatory up-regulation of the mRNA expression of antioxidant enzymes may be impaired in the insulin-deficient severely hyperglycemic state.

Topics: Animals; Base Sequence; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Disease Models, Animal; DNA Primers; Gene Expression Regulation, Enzymologic; Glutathione Peroxidase; Insulin Resistance; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Mutant Strains; Myocardium; Obesity; Superoxide Dismutase

Dietary advanced glycosylation end products (AGEs) have been linked to insulin resistance in db/db(++) mice. To test whether dietary AGEs play a role in the progression of insulin resistance in normal mice fed high-fat diets, normal C57/BL6 mice were randomly assigned to high-fat diets (35% g fat), either high (HAGE-HF group; 995.4 units/mg AGE) or low (by 2.4-fold LAGE-HF group; 329.6 units/mg AGE) in AGE content for 6 months. Age-matched C57/BL6 and db/db(++) mice fed regular diet (5% g fat, 117.4 units/mg AGE) served as controls. After 6 months, 75% of HAGE-HF mice were diabetic and exhibited higher body weight (P < 0.001), fasting glucose (P < 0.001), insulin (P < 0.001), and serum AGEs (P < 0.01) than control mice, while none of the LAGE-HF mice were diabetic despite a similar rise in body weight and plasma lipids. The HAGE-HF group displayed markedly impaired glucose and insulin responses during glucose tolerance tests and euglycemic and hyperglycemic clamps and altered pancreatic islet structure and function compared with those of LAGE-HF mice, in which findings resembled those of control mice. The HAGE-HF group had more visceral fat (by two- and fourfold) and more AGE-modified fat (by two- and fivefold) than LAGE-HF and control mice, respectively. In the HAGE-HF group, plasma 8-isoprostane was higher (P < 0.01) and adiponectin lower (P < 0.001) than control mice, while in the LAGE-HF group, these were more modestly affected (P < 0.05). These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dietary Fats; Dinoprost; Fasting; Female; Glucose Clamp Technique; Glucose Tolerance Test; Glycation End Products, Advanced; Hyperplasia; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Lipids; Mice; Mice, Inbred C57BL

The renin angiotensin system has been shown to be involved in the pathogenesis of vascular and renal sequelae of diabetes mellitus. In type 2 diabetes mellitus, angiotensin receptor blockers have been shown to exert clinical benefit by reducing the progression of diabetic nephropathy. They also improve endothelium-mediated vascular function. The latter effect is partly due to the reduction of angiotensin II-associated oxidative stress. Moreover, small clinical studies have shown that treatment with angiotensin receptor blockers also reduces the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. In the VIVALDI trial, the ability of the angiotensin receptor blocker telmisartan to reduce the progression of diabetic nephropathy (associated with proteinuria) in comparison with valsartan in more than 800 patients with type 2 diabetes during 1 year of treatment is being studied. In order to gain more detailed insight into the potential pathomechanisms associated with this effect, further end-points have been defined. Among these are the circulating levels of ADMA and the urinary excretion rate of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). The former is an endogenous inhibitor of NO-mediated vascular function(s) and a prospectively determined marker of major cardiovascular events and mortality; the latter is a lipid peroxidation product resulting from the nonenzymatic peroxidation of arachidonic acid, which exerts detrimental vascular effects similar to those of thromboxane A2. Urinary 8-iso-PGF2alpha has been shown in clinical studies to be an independent marker of cardiovascular disease. Highlighting the effects of telmisartan on ADMA and 8-iso-PGF levels in such a large cohort of diabetic patients will enhance our understanding of the roles of dysfunctional NO metabolism and redox mechanisms in the pathogenesis of end-organ damage and its prevention by pharmacotherapy with angiotensin receptor blockers.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Arginine; Benzimidazoles; Benzoates; Clinical Protocols; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Endothelium, Vascular; Humans; Hypertension; Middle Aged; Multicenter Studies as Topic; Oxidative Stress; Randomized Controlled Trials as Topic; Renal Insufficiency; Telmisartan; Tetrazoles; Valine; Valsartan

Involvement of cyclooxygenase (COX)-mediated inflammation in type 2 diabetes has not been studied, and the association between cytokine-mediated inflammation and diabetes is not fully clarified.. 15-Keto-dihydro-prostaglandin F2alpha (a metabolite of prostaglandin F2alpha and an indicator of COX-mediated inflammation), high-sensitivity C-reactive protein (CRP), serum amyloid protein A (SAA), 8-iso-PGF2alpha (a nonenzymatic, free radical product of arachidonic acid and an indicator of oxidative stress), and alpha-tocopherol were measured in a population-based sample of 77-year-old men (n=765), in which 112 men had type 2 diabetes. The inflammatory indicators were increased in men with diabetes (urinary 15-keto-dihydro-PGF2alpha, P<0.001, CRP and SAA, P<0.05). However, when adjusted for body mass index, waist circumference, or fasting insulin, no association was found between diabetes and CRP or SAA. The oxidative stress indicator 8-iso-PGF2alpha in urine was increased (P<0.01) in men with diabetes. Patients who were newly diagnosed with diabetes (<7 years since diagnosis) had increased urinary 15-keto-dihydro-PGF2alpha and decreased alpha-tocopherol, but 8-iso-PGF2alpha was unaltered.. This is the first study to show that type 2 diabetes in elderly men is related to COX-mediated inflammation, reflected by enhanced prostaglandin formation. The high levels of cytokine-mediated acute-phase proteins observed in men with diabetes appear to be related to obesity and increased fasting insulin. The results further suggest that the appearance of chronic inflammation is an early process in the pathogenesis of diabetes, whereas oxidative injury may be a later process, possibly related to inflammation.

Topics: Aged; alpha-Tocopherol; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biomarkers; Blood Glucose; Body Mass Index; C-Reactive Protein; Cohort Studies; Comorbidity; Diabetes Mellitus, Type 2; Dinoprost; Follow-Up Studies; Humans; Inflammation; Insulin; Lipids; Male; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Serum Amyloid A Protein; Sweden

Diabetes mellitus (DM) is associated with enhanced lipid oxidation and persistent platelet activation. We investigated whether oxidant stress (OS) also affects circulating proteins and is associated with an abnormal coagulative pattern. In 72 type 2 DM (T2DM) patients, urinary 8-iso-prostaglandin (PG) F2alpha and 11-dehydro-thromboxane B2 (TXM) were measured as markers of lipid peroxidation and platelet activation, respectively. The carbonyl content of plasma proteins (PCARB) was measured as global index of protein oxidation. 8-Iso-PGF2alpha and PCARB levels were higher in DM patients than in controls (P < 0.05). Likewise, both TXM and prothrombin F1+2 levels were higher in diabetics (P < 0.05). By contrast, anticoagulant markers, such as activated protein C, protein C activation peptide, and soluble thrombomodulin (TM) were depressed in T2DM (P < 0.05). In conclusion, OS in T2DM involves circulating proteins and is associated with an unbalanced promotion of procoagulant reactions. These effects in concert with platelet activation may contribute to atherothrombotic complications in T2DM.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Proteins; Case-Control Studies; Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Female; Hemostasis; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Platelet Activation; Thrombosis; Thromboxane B2

Acute hyperglycemia in type 2 diabetes increases the generation of plasma 8-epi-prostaglandin F2 (8-epi-PGF2alpha) isoprostane, a sensitive direct marker of in vivo free radical oxidative damage to membrane phospholipids.. A total of 21 patients with type 2 diabetes underwent an oral 75-g glucose tolerance test. Plasma 8-epi-PGF2alpha isoprostane concentrations (by gas chromatography [GC]/mass spectrometry [MS]), intralymphocyte reduced-to-oxidized glutathione ratios, and plasma total antioxidant capacity were measured at baseline and 90 min after glucose loading.. Plasma 8-epi-PGF2alpha isoprostane concentrations rose significantly (P=0. 010) from 0.241 +/- 0.1 to 0.326 +/- 0.17 ng/l after 90 min. Intracellular oxidative balance and plasma antioxidant capacity did not change in either group.. Plasma concentrations of 8-epi-PGF2alpha isoprostane increase during acute hyperglycemia in type 2 diabetes, providing direct evidence of free radical-mediated oxidative damage and demonstrating a pathway for an association between acute rather than fasting hyperglycemia and macrovascular risk in type 2 diabetes.

Topics: Adult; Aged; Antioxidants; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Female; Free Radicals; Gas Chromatography-Mass Spectrometry; Glucose Tolerance Test; Glutathione; Glutathione Disulfide; Humans; Hyperglycemia; Lymphocytes; Male; Middle Aged

Diabetes mellitus (DM) is a well-established risk factor of cardiovascular diseases. We investigated the mechanism of the progression of arteriosclerosis in DM, focusing on the role of oxidative stress and insulin resistance in vivo. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an experimental model of type 2 DM, were assigned to 3 groups, based on supplementation with vitamin E (VE) or troglitazone (TR), a VE-derived agent which improves insulin-resistance. At 36 weeks, plasma and aortic tissue 8-iso-PGF2alpha contents, a vascular proliferating eicosanoid produced in vivo by oxidative stress, were measured by EIA. TGF-beta1 and TGF-beta1 receptor II were immunohistochemically analyzed. Histopathologically, medial area and the nuclear number of smooth muscle cells of the aorta were measured. The tissue 8-iso-PGF2alpha content (pg/g tissue) was significantly decreased by either VE or TR in the aorta (untreated-OLETF, 15,332+/-3,254 vs. TR-treated-OLETF, 7,092+/-1,992 or VE-treated-OLETF, 5,394+/-836, both p<0.01), but that in plasma decreased by only VE. VE and TR improved the increased the level of the actual medial area and the number of smooth muscle cells. The expression of TGF-beta1 was reduced, but TGF-beta1 receptor II was not. 8-iso-PGF2alpha may play an important role in the progression of arteriosclerosis. Antioxidant treatment may promise significant clinical benefits in the early diabetic stage.

Topics: Animals; Aorta; Arteriosclerosis; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Disease Progression; Eicosanoids; F2-Isoprostanes; Lipids; Male; Oxidative Stress; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Transforming Growth Factor beta1

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

Human serum paraoxonase (PON) is an antioxidative enzyme, which circulates on high-density lipoproteins and appears to use oxidized phospholipids as physiological substrates. PON M/L55 substitution changes the ability of PON to prevent lipid oxidation. Urinary 8-iso-PGF(2alpha) (one of F2 -isoprostanes) may represent a non-invasive in vivo index of free radical generation and we propose that PON might influence the biosynthesis of 8-iso-PGF(2alpha) in the vasculature. We studied the urinary excretion of 8-iso-PGF(2alpha) and related it to PON M/L55 genotypes in patients with type 2 diabetes mellitus (n = 55) and non-diabetic control subjects (n = 55). Urinary 8-iso-PGF(2alpha) was determined by competitive ELISA and the PON genotype by a PCR based restriction enzyme digestion method. LL homozygotes were compared to M-allele carriers (ML heterozygotes and MM homozygotes). The urinary excretion of 8-iso-PGF(2alpha) among non-diabetic non-smoking LL homozygotes was 3995.5 +/- 3352.8 ng/24-hour and among M-allele carriers 1689.8 +/- 1051.3 ng/24-hour (p = 0.017, ANCOVA; gender, hypertension, total cholesterol, triglycerides and LDL cholesterol as covariates). The excretion of 8-iso-PGF(2alpha), was increased in type 2 diabetes mellitus compared to non-diabetic control subjects. PON may thus protect against oxidative stress by destroying some biologically active lipids. Excretion of 8-iso-PGF(2alpha) is increased in type 2 diabetes, which may reflect oxidant injury.

Topics: Aryldialkylphosphatase; Ascorbic Acid; Case-Control Studies; Diabetes Mellitus, Type 2; Dinoprost; Esterases; F2-Isoprostanes; Female; Glomerular Filtration Rate; Homozygote; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Polymorphism, Genetic; Random Allocation; Reference Values; Smoking

To measure oxidative stress, endothelial dysfunction and insulin resistance in Indian Mauritians at different stages of development of Type II (non-insulin-dependent) diabetes mellitus.. Plasma total 8-epi-PGF2alpha, an indicator of oxidative stress, was determined in age-matched subjects with normal glucose metabolism (n = 39), impaired glucose tolerance (n = 14), newly diagnosed diabetes (n = 8) and established diabetes (n = 14). Plasma glucose and insulin were measured at baseline and 2 h following an oral glucose tolerance test. Endothelial function was assessed by non-invasive digital pulse wave photoplethysmography.. Plasma 8-epi-PGF2alpha increased in subjects with impaired glucose tolerance (p < 0.05) compared with control subjects, and was even higher in newly diagnosed diabetic patients (p < 0.01) and established (p < 0.01) diabetic patients. A tendency towards reduced endothelial function in subjects with impaired glucose tolerance became significant in patients with newly diagnosed and established diabetes (p < 0.01), and was correlated with 8-epi-PGF2alpha (r = 0.36, p < 0.01). Insulin resistance (homeostasis model assessment) did not change in subjects with impaired glucose tolerance compared with control subjects, but increased in newly diagnosed (p < 0.01) and established (p < 0.001) diabetic subjects. The 8-epi-PGF2alpha was correlated with fasting glucose (r = 0.50, p < 0.001), triglycerides (r = 0.40, p < 0.001) and insulin resistance (r = 0.35, p < 0.001).. Oxidant stress is an early event in the evolution of Type II diabetes and could precede the development of endothelial dysfunction and insulin resistance.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dinoprost; Endothelium, Vascular; F2-Isoprostanes; Fasting; Female; Glucose; Glucose Intolerance; Humans; India; Insulin Resistance; Male; Mauritius; Middle Aged; Oxidative Stress; Reference Values; Triglycerides

Oxidative stress is pivotal in atherogenesis. Although the most widely used indirect assay to quantify oxidative stress is LDL oxidative susceptibility, direct assays such as urinary F(2)-isoprostanes have shown great promise.. We evaluated the utility of both a direct measure of oxidative stress (urinary F(2)-isoprostanes) and an indirect measure of copper-catalyzed, LDL oxidation in a model of increased oxidative stress (diabetes). We also evaluated an enzyme immunoassay (EIA) method for urinary F(2)-isoprostanes with a gas chromatography-mass spectrometry method.. Excellent intraassay and interassay CVs of <4% were obtained with our EIA method. A good correlation was obtained between the two methods (r = 0.80; n = 68) of F(2)-isoprostane measurement. An excellent correlation for F(2)-isoprostane concentrations was obtained between a timed collection vs 24-h urine (r = 0.96; n = 46). Baseline F(2)-isoprostane concentrations by EIA were significantly higher in both type 2 diabetics with and without macrovascular complications compared with controls (P <0.001). Supplementation with alpha-tocopherol led to a significant reduction in F(2)-isoprostane concentrations in all diabetic patients compared with baseline values (2.51 +/- 1.76 compared with 1.69 +/- 1.32 ng/mg creatinine; P <0.001). There were no significant differences in LDL oxidation in both diabetic groups compared with controls. alpha-Tocopherol supplementation led to significant increases in the lag phase of oxidation as measured by 3 indices in all groups.. The measurement of urinary F(2)-isoprostanes provides a direct measure of in vivo lipid peroxidation and oxidative stress and appears to be superior to an indirect measure, e.g., LDL oxidative susceptibility, in type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Female; Gas Chromatography-Mass Spectrometry; Humans; Immunoenzyme Techniques; Lipoproteins, LDL; Male; Oxidation-Reduction; Oxidative Stress; Reproducibility of Results

Liquid chromatography-tandem mass spectrometry (LC/MS-MS) was applied to the quantitative analysis of urinary 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)) level. 8-Epi-PGF(2alpha) and its internal standard, [(2)H(4)]-8-epi-PGF(2alpha), were extracted from urine by using a solid phase extraction cartridge and loaded to LC/MS-MS in selected reaction monitoring (SRM) mode. The standard curve showed good linearity in the range of 40 pg to 10 ng (r = 0. 997). The accuracy of the added 8-epi-PGF(2alpha) ranged from 96.8 to 104.9% with a mean +/- SD of 99.5+/-2.5%. The average level +/- SD of urinary 8-epi-PGF(2alpha) in 13 healthy volunteers (five women and eight men, 31+/-7.4 years old) was 429.4+/-149.6 pg/mg creatinine. The level of seven patients with noninsulin dependent diabetes mellitus (two women and five men, 40+/-13.6 years old), 630.9+/-275.6 pg/mg creatinine, was statistically higher than that of healthy volunteers (P<0.05). This finding suggested that diabetics are in a highly oxidative condition. This simple and rapid LC/MS-MS method can be used to elucidate the pathophysiological feature of diabetes or for monitoring the curative effect.

Topics: Adult; Chromatography, Liquid; Creatinine; Diabetes Mellitus, Type 2; Dinoprost; Evaluation Studies as Topic; Female; Humans; Male; Mass Spectrometry; Middle Aged; Reference Standards; Smoking

Diabetes mellitus (DM) is associated with enhanced lipid peroxidation and persistent platelet activation. We tested the hypothesis that the in vivo formation of the F2-isoprostane 8-iso-prostaglandin (PG)F2alpha, a bioactive product of arachidonic acid peroxidation, is enhanced in DM and contributes to platelet activation.. Urine samples were obtained from 85 diabetic patients and 85 age- and sex-matched healthy subjects for measurement of immunoreactive 8-iso-PGF2alpha and 11-dehydro-thromboxane B2 (TXM), an in vivo index of platelet activation. Sixty-two had non-insulin-dependent (NID)DM, and 23 had insulin-dependent (ID) DM. Vitamin E supplementation, metabolic control, and cyclooxygenase inhibitors were used to investigate the mechanisms of formation of 8-iso-PGF2alpha in this setting. Urinary 8-iso-PGF2alpha excretion was significantly higher (P=0.0001) in NIDDM patients (419+/-208 pg/mg creatinine; range 160 to 1014) than in age-matched control subjects (208+/-92; 41 to 433). Urinary 8-iso-PGF2alpha was linearly correlated with blood glucose and urinary TXM. 8-iso-PGF2alpha excretion was also significantly (P=0. 0001) higher in IDDM patients (400+/-146; 183 to 702) than in control subjects (197+/-69; 95 to 353). Vitamin E supplementation (600 mg/d for 14 days) was associated with a statistically significant reduction in both urinary 8-iso-PGF2alpha (by 37%) and TXM (by 43%) in 10 NIDDM patients. Improved metabolic control was associated with a significant (P=0.0001) reduction in 8-iso-PGF2alpha and TXM excretion by 32% and 41%, respectively, in 21 NIDDM patients. 8-iso-PGF2alpha was unchanged after 2-week dosing with aspirin and indobufen despite profound suppression of TXM excretion.. We conclude that DM is associated with increased formation of F2-isoprostanes, as a correlate of impaired glycemic control and enhanced lipid peroxidation. This may provide an important biochemical link between impaired glycemic control and persistent platelet activation. These results provide a rationale for dose-finding studies of antioxidant treatment in diabetes.

Topics: Adult; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Platelet Activation; Thromboxane B2; Vitamin E

Severe reproductive dysfunction has been described in non-insulin-dependent diabetes mellitus (NIDDM), correlated with high glucose levels in the plasma. We have characterized an abnormal prostanoid profile in tissues from NIDDM rats, and a tight correlation between nitric oxide (NO) levels and prostaglandin production. Likewise, we have determined that parturition is delayed in NIDDM rats compared to control animals. In order to characterize the events which precede delayed parturition in NIDDM rats, we evaluate (a) the arachidonic acid (AA) conversion in placental tissue obtained from control (day 21 and 22) and NIDDM (day 21, 22 and 23) late pregnant rats into prostaglandin E2 (PGE2) and F2alpha (PGF2alpha), thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), and (b) NO synthase (NOS) activity in control and NIDDM late pregnant animals. Placental arachidonate conversion from control rats into different prostanoids, namely PGE2, PGF2alpha, and TXB2, is higher in day 22 than in day 21, and radioconversion from diabetic rats into PGE2, PGF22, TXB2 and 6-keto-PGF1alpha on day 23 is higher than in day 21 and 22. 6-keto-PGF1alpha is lower and TXB2 is higher in diabetic tissues than in control. Placental AA conversion of control diabetic tissues on the day of delivery is decreased by N(G) monomethyl-L-arginine (LNMMA) (600 mM), a well known NOS inhibitor, while prostanoid production remains unaltered on previous days. NOS activity is higher in control on day 22 when compared to day 21, and in diabetic on day 23 when compared to day 22 of pregnancy. We conclude that elevated NO placental levels are observed in control (day 22) and NIDDM (day 23) rats, and may increase placental prostaglandin production on the day of delivery.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Diabetes Mellitus, Type 2; Dinoprost; Dinoprostone; Enzyme Inhibitors; Female; Gestational Age; Male; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Placenta; Pregnancy; Pregnancy in Diabetics; Prostaglandins; Rats; Rats, Wistar; Reference Values; Thromboxane B2

Severe uterine and placental disturbances have been described in diabetes pathology. The relative severity of these changes appears to correlate with high glucose levels in the plasma and incubating environment. In order to characterize changes in eicosanoid production we compared uterine and placental arachidonic acid conversion from control and non-insulin-dependent diabetes mellitus (NIDDM) rats on day 21 of pregnancy, into different prostanoids, namely PGE2, PGF22alpha, TXB2 (indicating the production of TXA2) and 6-keto-PGF1 (indicating the generation of PGI2). PGE2, PGF2alpha and TXB2 production was higher and 6-keto-PGF1alpha was similar in diabetic compared to control uteri. PLA2 activity was found diminished in the NIDDM uteri in comparison to control. A role for PLA2 diminution as a protective mechanism to avoid prostaglandin overproduction in uterine tissue from NIDDM rats is discussed. Placental tissues showed an increment in TXB2 generation and a decrease in 6-keto PGF1alpha level in diabetic rats when compared to control animals. Moreover, when control uterine tissue was incubated in the presence of elevated glucose concentrations (22 mM), similar generation of 6-keto PGF1alpha and elevated production of PGE2, PGF2alpha and TXB2 were found when compared to those incubated with glucose 11 mM. Placental TXB2 production was higher and 6-keto PGF1alpha was lower when control tissues were incubated in the presence of high glucose concentrations. However, high glucose was unable to modify uterine or placental prostanoid production in diabetic rats. We conclude that elevated glucose levels induced an abnormal prostanoid profile in control uteri and placenta, similar to those observed in non-insulin-dependent diabetic tissues.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Dinoprostone; Eicosanoids; Female; Maternal-Fetal Exchange; Placenta; Pregnancy; Pregnancy in Diabetics; Pregnancy, Animal; Prostaglandins A; Rats; Rats, Wistar; Thromboxane A2; Thromboxane B2; Uterus

Eicosanoid production by intrauterine tissues from control and neonatal-streptozotocin induced diabetic rats during late pregnancy was evaluated. In diabetic placenta the release of 6-keto-PGF1alpha was found diminished when compared to controls. In addition, LTB4 generation was increased in diabetic placenta. No alterations in the production of TXA2, PGE2, PGE1 and PGF2alpha was found when diabetic and control placenta were compared. In amnion tissue a decreased generation of 6-keto-PGF1alpha was observed in the diabetic group, but no alteration in any other eicosanoid evaluated was found. Oxytocin (5 mU/ml, in vitro), which increases prostaglandin synthesis in rabbit and human amnion tissues, did not modify eicosanoid generation in control rat amnion. In contrast, in diabetic amnion the presence of oxytocin further decreased the release of 6-keto-PGF1alpha and diminished PGE1 generation. The present results suggest that this mildly diabetic state induces alterations in eicosanoid production in intrauterine tissues, abnormalities probably enhanced during parturition, when endogenous concentrations of oxytocin are elevated.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Amnion; Animals; Culture Media; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Dinoprostone; Eicosanoids; Female; Humans; In Vitro Techniques; Oxytocin; Placenta; Pregnancy; Pregnancy in Diabetics; Rabbits; Rats; Rats, Wistar; Thromboxane A2

Topics: Biomarkers; Diabetes Mellitus, Type 2; Dinoprost; Gas Chromatography-Mass Spectrometry; Humans; Hyperlipidemias; Kidney Failure, Chronic; Reference Values

Eicosanoid production, glucose (Glu), glycogen (Gly) and triglyceride (TG) metabolism, spontaneous contractile activity, PGF2 alpha and oxytocin-induced contractions have been studied in uterine tissue obtained from control (C) and non-insulin-dependent diabetic (D) rats prior to parturition. Parturition occurs on day 22 of gestation in control animals, whereas a 24 hr delay was observed in diabetic rats. Production of PGE2, PGE1, 6-keto-PGF1 alpha, PGF2 alpha, TXB2 and LTB4 was similar in uterine tissue obtained from control and diabetic rats on day 21 of pregnancy. Uterine metabolism, on day 21 of pregnancy, based on the production of 14CO2 from U14C-glucose was lower in tissues obtained from diabetic rats than in controls. Levels of TG were similar at 0 hr and after 60 min incubation in Glu or Glu-free medium in both experimental groups. Initially Gly levels in diabetic and control uteri were similar. After 60 minutes of incubation, levels of Gly in control tissue decreased only in the absence of Glu in the incubation medium. In contrast, in diabetic uterine strips, levels of Gly decreased after 60 minutes of incubation either in Glu or Glu-free medium. "In vitro" isometric-developed tension (IDT) evaluated on day 21 (C and D) and 22 (D) of pregnancy was similar at 0 hr in control and diabetic uterine preparations, but IDT in both diabetic groups was decreased after a 40 minute incubation when compared to controls. Alterations in PGF2 alpha-induced uterine responses were not seen in 21 or 22 days pregnant diabetic uterine tissue when compared to controls. In contrast, impaired oxytocin responses were observed in diabetic uteri on day 21 of gestation, but they were similar to control responses of uterine tissue from day 22 diabetic rats. We conclude that in the non-insulin-dependent late pregnant rat, there are no alterations in uterine tissue eicosanoid production, but metabolic and contractile abnormalities are present. Involvement of these alterations in the delayed initiation of parturition is discussed.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Dose-Response Relationship, Drug; Eicosanoids; Female; Glucose; Glycogen; In Vitro Techniques; Isometric Contraction; Oxytocin; Pregnancy; Rats; Rats, Wistar; Streptozocin; Time Factors; Triglycerides; Uterine Contraction; Uterus

Ovulation, oocyte maturation and PGE and PGF2 alpha production by oocyte-cumulus complexes were evaluated in rats with non-insulin-dependent diabetes induced by neonatal streptozotocin. Diabetic rats had normal estrous cycles, but ovulated a lower number of oocytes at estrus. When oocytes from control and diabetic rats obtained at proestrus were matured "in vitro" during 1, 2 or 4 hours (hr) of culture, differences were not found in the percent of germinal vesicle breakdown between both experimental groups. PGE and PGF2 alpha accumulation was higher in ovulated oocyte-cumulus complexes when compared to immature or "in vitro"-matured oocyte-cumulus complexes in both normal and diabetic rats. When control and diabetic rats are compared, more PGE and PGF2 alpha accumulation was observed in immature, "in vitro"-matured and in ovulated oocyte-cumulus complexes. A lower number of oocytes ovulated and increased oocyte-cumulus complexes prostaglandin production has been observed in this mildly diabetic experimental model. These abnormalities are similar to those previously found when 10 day embryos were evaluated in non-insulin-dependent diabetic rats.

Topics: Animals; Diabetes Mellitus, Type 2; Dinoprost; Disease Models, Animal; Estrus; Female; Meiosis; Oocytes; Prostaglandins E; Rats; Rats, Wistar

This study reports plasma levels of a specific nonenzymatic peroxidation product of arachidonic acid, esterified 8-epi-PGF2 alpha, from healthy- and NIDDM individuals as an index of oxidative stress in vivo. Plasma 8-epi-PGF2 alpha was isolated by solid-phase extraction on a C18 followed by an NH2 cartridge and analyzed by GC-MS/NICI as PFB-ester/TMS-ether derivative. We found that the average concentration of esterified 8-epi-PGF2 alpha among NIDDM subjects (0.93 +/- 0.07 nM, n = 39) was higher (P < 0.0001, Mann-Whitney test) than in healthy individuals (0.28 +/- 0.04 nM, n = 15). These data indicate that NIDDM is associated with increased plasma lipid peroxidation.

Topics: Adult; Aspirin; Chromatography, Gas; Diabetes Mellitus, Type 2; Dinoprost; Esterification; Humans; Indomethacin; Mass Spectrometry; Models, Chemical; Oxidative Stress

In uterine tissue obtained from castrated control and non-insulin dependent diabetic (NIDDM) rats, eicosanoid production and its regulation by glucose levels and by the activity of phospholipase A2 (PLA2) was assessed. Basal outputs of prostaglandins (PGs) PGE2, PGE1, PGF2 alpha, 6-keto-PGF1 alpha (indicating the production of prostacyclin), thromboxane B2 (TXB2) (indicating the generation of TXA2) and leukotriene B4 (LTB4) were similar in control and NIDDM uterine preparations as assessed by RIA. When uterine conversion of labelled arachidonate into different prostanoids was evaluated, generation of 6-keto-PGF1 alpha, PGE2 and PGF2 alpha was similar in control and NIDDM uterine tissue, while TXB2 production was higher in the diabetic group. Moreover, when control tissue was incubated in the presence of elevated concentrations of glucose (22 mM) and compared to control tissue incubated in concentrations of glucose 11 mM, similar generation of 6-keto-PGF1 alpha, PGE2 and PGF2 alpha was observed, and higher concentrations of TXB2 were found, similar to those observed in diabetic uterine tissue. When NIDDM uterine tissue was incubated in the presence of glucose 22 mM, no difference in any prostanoid evaluated was observed when compared to values obtained in the presence of glucose 11 mM. In this work we have observed in NIDDM uterine tissue a normal TXA2 production when evaluated by RIA from endogenous arachidonic acid (AA) and a higher TXA2 generation from exogenous labelled AA. In addition PLA2 activity was found diminished in the NIDDM uteri in comparison to control uteri. A role of the diminished PLA2 as a protective mechanism that avoids TXA2 overproduction in uterine tissue from NIDDM rats is discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Arachidonic Acid; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Dinoprostone; Eicosanoids; Female; Leukotriene B4; Ovariectomy; Phospholipases A; Phospholipases A2; Rats; Rats, Wistar; Thromboxane B2; Uterus

Platelet prostaglandin (PG) E and plasma PGF2 alpha concentrations were measured by radioimmunoassay methods and compared in non-pregnant and pregnant, normal and diabetic subjects. The blood samples were obtained in the follicular phase in the non-pregnant women and in the third trimester and after delivery in the pregnant women. The immunoreactive platelet PGE (IRPGE) levels were significantly higher in the pregnant diabetic women than in the normal non-pregnant and pregnant women and diabetic non-pregnant women. The immunoreactive plasma PGF2 alpha (IRPGF2 alpha) concentrations were significantly higher in the non-pregnant diabetic women than in the normal non-pregnant and pregnant women. During pregnancy, the plasma IRPGF2 alpha were further increased significantly in the diabetic subjects compared to the non-pregnant diabetics. Both the platelet IRPGE and plasma IRPGF2 alpha concentrations were higher in the pregnant diabetic subjects with retinopathy than in those without retinopathy. These findings suggest that pregnancy and diabetes influence the synthesis of PGE and PGF2 alpha in the platelets and plasma, respectively. The increased production of these prostaglandins are possible exacerbating factors of diabetic retinopathy during pregnancy.

Topics: Adult; Blood Platelets; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dinoprost; Female; Humans; Postpartum Period; Pregnancy; Pregnancy in Diabetics; Pregnancy Trimester, Third; Prostaglandins E; Puerperal Disorders; Reference Values