8-hydroxyguanosine and Diabetes-Mellitus--Type-2

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

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

The urinary marker of RNA oxidation, 8‑oxo‑7,8‑dihydroguanosine (8-oxoGuo), but not the corresponding marker of DNA oxidation, 8‑oxo‑7,8‑dihydro‑2'‑deoxyguanosine (8-oxodG), is a prognostic biomarker in patients with type 2 diabetes (T2D). The aim of the present study was to investigate the effect of structured personal care (individualized multifactorial treatment) versus standard care on RNA oxidation level in patients with T2D and to assess if the effect of structured personal care on all-cause and diabetes-related mortality was modified by RNA oxidation level.. Urine samples were analyzed for 8-oxoGuo/8-oxodG from 1381 newly diagnosed T2D patients from the cluster randomized trial Diabetes Care in General Practice cohort, and 970 patients were reexamined after six years of intervention.. The yearly variation in RNA oxidation levels were not significantly different between the structured personal care group and standard care group. The effect of treatment on all-cause and diabetes-related mortality was not modified by the level of RNA oxidation. No changes in DNA oxidation were seen.. Structured personal care does not influence RNA oxidation level nor is it better for patients with high RNA oxidation level. Thus, structured personal care may not impact the disease-related aspects identified by RNA oxidation level in T2D patients.

Topics: Aged; Biomarkers; Diabetes Mellitus, Type 2; DNA; Female; Follow-Up Studies; General Practice; Guanosine; Humans; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Precision Medicine; Prognosis; RNA

The RNA oxidation product, 8-oxo-7,8-dihydroguanosine (8-oxoGuo), has been associated with mortality in patients with type 2 diabetes (T2D). However, the identification and the potential effect of approved treatments decreasing urine 8-oxoGuo level remain unraveled. In the Steno-2 study intensified multifactorial treatment compared with conventional multifactorial treatment reduced mortality in T2D patients with microalbuminuria by 45%. We assessed association between 8-oxoGuo at advanced baseline and total mortality with up to 19.9 years follow-up and from end of intervention to end of follow-up up to (up to 13.9 years).. In 1993, 160 T2D patients with microalbuminuria were included in the Steno-2 trial. Urine samples from baseline were not available, but samples were available from 155 patients (97%) in 1995 (advanced baseline) and from 125 patients (96%) in 2001 (end of intervention). Hazard ratios (HR) for log2-transformed 8-oxoGuo and dichotomized (cut-off at median; low vs. high RNA oxidation) were estimated using Cox regressions.. During follow-up of 19.9 years after advanced baseline, 89 died and no association between 8-oxoGuo and mortality was found (p = 0.40). From the end of 7.8 years of intervention and during remaining 13.9 years of observation, 61 died and doubling the urine 8-oxoGuo level was associated with mortality with a HR 3.08 (95% CI [1.86 -5.12]; p < 0.001) after multiple adjustments. Patients with low 8-oxoGuo in the intensified-treatment had the lowest risk of dying compared with high 8-oxoGuo in the conventional-treatment both from advanced baseline onwards, adjusted HR 0.40 (95% CI [0.21 -0.75]; p = 0.004), and from end of intervention onwards, adjusted HR 0.28 (95% CI [0.13 -0.61]; p = 0.001).. In T2D patients with microalbuminuria, high levels of urine 8-oxoGuo after 7.8 years of multifactorial intervention was associated with higher mortality during 13.9 years of post-trial follow-up. Patients with low 8-oxoGuo in the intensified treatment group had the lowest risk of dying.

Topics: Aged; Albuminuria; Biomarkers; Combined Modality Therapy; Diabetes Mellitus, Type 2; Female; Guanosine; Humans; Longitudinal Studies; Male; Middle Aged; Oxidation-Reduction; Prognosis; RNA; Survival Analysis

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

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

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

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

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

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

The urinary biomarker for oxidative stress to RNA, 8-oxo-7,8-dihydro-guanosine (8-oxoGuo) is associated with mortality in patients with type 2 diabetes. Iron has also been linked to diabetes. In individuals with untreated hereditary iron overload it has been observed that 8-oxoGuo was higher compared to controls. In the current study, we hypothesized that 8-oxoGuo was associated with diagnosis of diabetes, and that iron confounded this association.. Participants from a general Danish population were included in the study (n = 3567). UPLC-MS/MS method was used for 8-oxoGuo (nmol/mmol creatinine) measurement in spot urine. Iron biomarkers included total plasma iron, ferritin, transferrin saturation (TS) and transferrin.. 8-oxoGuo was 17% higher in diabetes patients (n = 208) compared to non-diabetes controls. Unadjusted logistic regression model showed an odds ratio of diabetes of 1.38 (95%CI:1.21-1.57, P < 0.0001) per unit increase of 8-oxoGuo. When the model was adjusted for possible confounders the odds ratio was 1.09 (95%CI:0.94-1.26, P = 0.24). When additional adjustment was performed including ferritin, TS, or transferrin, respectively, the OR were 1.14 (95%CI:0.97-1.33, P = 0.09), 1.10 (95%CI: 0.95-1.28, P = 0.18), and 1.17 (95%CI:1.01-1.38, P = 0.04).. Our study indicates that 8-oxoGuo is higher in diabetes patients. The lack of association between 8-oxoGuo and diabetes in the adjusted model may be due to the cross-sectional design including post-treatment bias. Our data did not show consistent effect of all iron biomarkers in relation to diabetes. Most likely, the iron biomarkers were affected by inflammation thus not reflecting true iron levels.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Creatinine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Ferritins; Guanosine; Humans; Iron; Iron Overload; Logistic Models; Male; Middle Aged; Odds Ratio; Oxidation-Reduction; Oxidative Stress; RNA; Transferrin

Urinary albumin is an important biomarker used to identify high risk patients with diabetes, but there is a need for new biomarkers that alone or in combination with urinary albumin could give an even better prediction of clinical patient outcomes. One promising biomarker is 8-oxo-7,8-dihydroguanosine (8-oxoGuo) that represents intracellular oxidative stress. We investigated the ability of microalbuminuria (MA) and urinary 8-oxoGuo, alone and in combination, to predict mortality and cardiovascular disease (CVD) in patients with type 2 diabetes. We used data from 1381 newly diagnosed diabetes patients, and urinary albumin and 8-oxoGuo were assessed in morning urine collected at the time of diabetes diagnosis and at a follow-up visit 6 years later. Associations between the urinary markers and mortality and CVD were assessed in Cox proportional hazards regression models. Test performance was assessed using sensitivity, specificity, positive predictive value and negative predictive value for 10-year mortality and 10-year incidence of CVD. Both 8-oxoGuo and urinary albumin were statistically significantly associated with all-cause mortality at diagnosis as well as at 6-year follow-up. At diagnosis only urinary albumin was associated with CVD. In contrast, only 8-oxoGuo was associated with CVD at 6-year follow-up. When investigating test performance, we found that by combining information from MA and 8-oxoGuo the ability to correctly identify patients at risk could be improved. The findings suggest that measurement of urinary 8-oxoGuo provides additional information about risk to that obtained from urinary albumin, and that the combined use of 8-oxoGuo and urinary albumin could be useful for a better identification of patients at risk of CVD and death.

Topics: Aged; Albuminuria; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Guanosine; Humans; Male; Middle Aged

Cardiovascular mortality risk remains high among patients with type 2 diabetes. Oxidative stress indicated by high urinary excretion of the biomarker for RNA oxidation, 8-oxo-7,8-dihydroguanosine (8-oxoGuo), is associated with an increased risk of death in newly diagnosed and treated patients. We assessed whether 8-oxoGuo is associated with specific cardiovascular and all-cause mortality risk.. Urinary biomarkers for nucleic acid oxidation were measured in a cohort of patients with type 2 diabetes aged ≥60 years (. During the 5-year follow-up, 173 of 1,863 patients had died (9.3%), including 73 patients who died of cardiovascular disease (42.2%). Doubling of RNA oxidation was associated with an HR of all-cause mortality of 2.10 (95% CI 1.63-2.71;. We conclude that high RNA oxidation is associated with all-cause and cardiovascular mortality risk in patients with type 2 diabetes. Targeting oxidative stress via interventions with long-term follow-up may reveal the predictive potential of the biomarker 8-oxoGuo.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Guanosine; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Proportional Hazards Models; Prospective Studies; Risk; RNA

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

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

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

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

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

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

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

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

Consumption of a high-fructose diet (HFrD) can induce the development of a metabolic syndrome, manifesting as nonalcoholic steatohepatitis (NASH) and/or type 2 diabetes mellitus (T2DM), via a process in which oxidative stress plays a critical role. Peroxiredoxin 4 (PRDX4) is a unique and only known secretory member of the PRDX antioxidant family. However, its putative roles in the development of NASH and/or T2DM have not been investigated.. To elucidate the functions of PRDX4 in a metabolic syndrome, we established a nongenetic mouse model of T2DM by feeding mice a HFrD after injecting a relatively low dose of streptozotocin. Compared with wild-type (WT), human PRDX4 transgenic (Tg) mice exhibited significant improvements in insulin resistance, characterized by a lower glucose and insulin concentration and faster responses in glucose tolerance tests. The liver of Tg also showed less severe vesicular steatosis, inflammation, and fibrosis, along with lower lipid concentrations, lower levels of oxidative stress markers, more decreased expression of hepatic aminotransferase, and more reduced stellate cell activation than those in the WT liver, reminiscent of human early NASH. Hepatocyte apoptosis was also significantly repressed in Tg mice. By contrast, serum adiponectin levels and hepatic adiponectin receptor expression were significantly lower in WT mice, consistent with greater insulin resistance in the peripheral liver tissue compared with Tg mice.. Our data for the first time show that PRDX4 may protect against NASH, T2DM, and the metabolic syndrome by ameliorating oxidative stress-induced injury.

Topics: Adiponectin; Aldehydes; Animals; Apoptosis; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Fatty Liver; Guanosine; Hepatocytes; Humans; Inflammation Mediators; Liver; Male; Mice; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Peroxiredoxins; Receptors, Adiponectin; T-Lymphocytes; Thiobarbituric Acid Reactive Substances

Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress. Pioglitazone, an anti-diabetic agent that improves insulin resistance, was also reported to decrease inflammation and protect against atherosclerosis. This study aimed to evaluate the utility of combination therapy with both medicines from the viewpoint of anti-inflammatory effects.. We administered candesartan (12 mg daily) and pioglitazone (15 mg daily) simultaneously for 6 months to hypertensive patients with type 2 diabetes mellitus (T2DM) and evaluated whether there were improvements in the serum inflammatory parameters of high-molecular-weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1), and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of reductions in blood pressure and HbA1c values and improvements in inflammatory factors. Furthermore, we analyzed the relationship between pulse pressure and the degree of lowering of HbA1c and improvements in inflammatory factors. Finally, we examined predictive factors in patients who received benefits from the co-administration of candesartan with pioglitazone from the viewpoint of inflammatory factors.. After 6 months of treatment, in all patients significant improvements from baseline values were observed in HMW-ADN and PAI-1 but not in VCAM-1, Hs-CRP, and U-8-OHdG. Changes in HbA1c were significantly correlated with changes in HMW-ADN and PAI-1 in all patients, but changes in blood pressure were not correlated with any of the parameters examined. Correlation and multilinear regression analyses were performed to determine which factors could best predict changes in HbA1c. Interestingly, we found a significant positive correlation of pulse pressure values at baseline with changes in HbA1c.. Our data suggest that the pulse pressure value at baseline is a key predictive factor of changes in HbA1c. Co-administration of candesartan with pioglitazone, which have anti-inflammatory (changes in HMW-ADN and PAI-1) effects and protective effects on organs, could be an effective therapeutic strategy for treating hypertensive patients with type 2 diabetes mellitus.. UMIN-CTR: UMIN000010142.

Topics: Adiponectin; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Blood Pressure; C-Reactive Protein; Cohort Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Guanosine; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Pioglitazone; Plasminogen Activator Inhibitor 1; Prospective Studies; Tetrazoles; Thiazolidinediones; Treatment Outcome; Vascular Cell Adhesion Molecule-1

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

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