Factors associated with high oxidative stress in patients with type 2 diabetes: a meta-analysis of two cohort studies.

OBJECTIVE: Our objective is to identify the potential factors associated with serum Diacron's reactive oxygen metabolites test (D-ROM) levels of patients with type 2 diabetes mellitus (T2DM) by conducting cross-sectional and longitudinal analyses in two large cohorts and further strengthening these results by performing a meta-analysis. METHODS: Serum D-ROM concentrations were measured in 1045 and 1101 patients with T2DM from two independent cohort studies from Germany at baseline and repeatedly 3-4 years later. The cross-sectional and longitudinal associations of various potential determinants with D-ROM levels were assessed with a backwards selection algorithm in multivariable adjusted models. RESULTS: In the meta-analysis of the cross-sectional analysis, female sex, low education, obesity, smoking, high total cholesterol, hemoglobin A1c ≥7%, no diabetes medication, a history of myocardial infarction, heart failure, a history of cancer and C reactive protein levels (CRP) >3 mg/L were statistically significantly associated with increased D-ROM levels in patients with T2DM. The meta-analysis of the longitudinal analysis revealed that old age, female sex, obesity, smoking, physical inactivity, high alcohol consumption, ≥5 years since diabetes diagnosis and CRP levels between 3 mg/L and 10 mg/L were statistically significantly associated with D-ROM levels measured 3-4 years later. CONCLUSIONS VALIDITY, LIMITATIONS AND CLINICAL APPLICABILITY: This comprehensive analysis confirmed that several modifiable risk factors are being associated with oxidative stress in patients with T2DM within an observational study design. We discuss potential prevention measures against these risk factors that might help to reduce oxidative stress and to prevent some cases of premature mortality in patients with T2DM.

Longitudinal Associations of Body Mass Index, Waist Circumference, and Waist-to-Hip Ratio with Biomarkers of Oxidative Stress in Older Adults: Results of a Large Cohort Study.

BACKGROUND: In the literature, obesity is discussed as a determinant of high oxidative stress (OS). Hence, prevention or reduction of obesity could prevent high OS and subsequently serve as a target for "healthy aging." METHODS: Diacron's reactive oxygen metabolites test (D-ROM) and total thiol levels (TTL), a marker of antioxidant defense capacity, were measured in 1,734 participants of a population-based cohort study of older adults (age range: 57-83 years) at 2 time points 3 years apart. The longitudinal associations of body mass index, waist-to-hip ratio, and waist circumference with D-ROM and TTL were assessed with multivariable adjusted generalized linear models. Dose-response analyses were conducted with restricted cubic splines. RESULTS: D-ROM was not significantly associated with any of the weight measures. On the contrary, TTL showed statistically significant, inverse linear associations with all weight measures. CONCLUSION: A healthy body weight seems to be highly relevant for the antioxidative defense capacity of human beings. In contrast, D-ROM levels were independent of the study participant's weight. Clinical trials are needed to corroborate if loss of weight by obese individuals can effectively increase TTL and subsequently also life expectancy.

Serum total thiol levels and the risk of lung, colorectal, breast and prostate cancer: A prospective case-cohort study.

Free thiol groups of intra and extracellular molecules are considered to be antioxidative and to protect cells from damage caused by free radicals. However, the associations of serum total thiol levels (TTL) with the incidences of the four most frequent cancer sites have not yet been investigated in a large population-based, prospective study. TTL was measured in case-cohort design in a sample from the population-based, Norwegian Tromsø 3 study (cancer cases: n = 941; random subcohort: n = 1,000) and was repeatedly measured at Tromsø 5. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by weighted multivariable-adjusted Cox regression with time-dependent modeling of TTL for incident lung, colorectal, breast and prostate cancer. High serum TTL were associated with a reduced risk of all four major cancers. The associations with lung (top vs. bottom tertile: HR, 0.64; 95% CI, 0.41, 0.99) and breast cancer (top vs. bottom tertile: HR, 0.64; 95% CI, 0.42, 0.96) were statistically significant, whereas associations with colorectal (top vs. bottom tertile: HR, 0.79; 95% CI, 0.54, 1.16) and prostate cancer (top vs. bottom tertile: HR, 0.79; 95% CI, 0.53, 1.17) were not statistically significant but pointed in the same protective direction. These findings from a large, prospective Norwegian cohort study suggest a preventive role of thiols against the development of the four most frequent cancers. Whereas associations with breast and lung cancer could be shown with statistical significance, larger studies are needed to corroborate potential associations of TTL with colorectal and prostate cancer.

Oxidatively Damaged DNA/RNA and 8-Isoprostane Levels Are Associated With the Development of Type 2 Diabetes at Older Age: Results From a Large Cohort Study.

OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Nitric Oxide Metabolites and Lung Cancer Incidence: A Matched Case-Control Study Nested in the ESTHER Cohort.

Studies suggest that nitric oxide (NO) may have a possible role in lung carcinogenesis. This study is aimed to evaluate the association of the NO metabolites, namely, nitrite and nitrate, with lung cancer incidence. We conducted a matched case-control study (n = 245 incident lung cancer cases and n = 735 controls) based on the German ESTHER cohort (n = 9,940). Controls were matched to cases on age, sex, smoking status (never/former/current smoking), and pack-years of smoking. The sum of nitrite and nitrate was measured in urine samples using a colorimetric assay and was standardized for renal function by urinary creatinine. Conditional logistic regression models, adjusted for lifestyle factors, asthma prevalence, and family history of lung cancer, were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). Among incident lung cancer cases, high nitrite/nitrate levels were statistically significantly associated with current smoking, a low BMI, and the oxidative stress biomarker 8-isoprostane levels. Nitrite/nitrate levels in the top quintile were statistically significantly associated with lung cancer incidence: the OR (95% CI) was 1.37 (1.04-1.82) for comparison with the bottom quintile. This association was unaltered after additional adjustment for 8-isoprostane levels and C-reactive protein (CRP). In conclusion, this large cohort study suggested that subjects with high urinary nitrite/nitrate concentrations had an increased risk of lung cancer and this association was independent of smoking, CRP, 8-isoprostane levels, and other established lung cancer risk factors. Further studies are needed to validate these findings and to confirm the hypothesis that pathologically high levels of NO are involved in lung cancer development.

Association of Serum Markers of Oxidative Stress With Incident Major Cardiovascular Events, Cancer Incidence, and All-Cause Mortality in Type 2 Diabetes Patients: Pooled Results From Two Cohort Studies.

OBJECTIVE: Oxidative stress plays an important role in the pathophysiology of type 2 diabetes mellitus (T2DM). However, associations of biomarkers of oxidative stress with diabetes complications have not yet been addressed in large cohort studies. RESEARCH DESIGN AND METHODS: Derivatives of reactive oxygen metabolites (d-ROMs) levels, a proxy for the reactive oxygen species burden, and total thiol levels (TTLs), a proxy for the reductive capacity, were measured in 2,125 patients with T2DM from two German cohort studies of almost equal size at baseline and 3-4 years later. Multivariable adjusted Cox proportional hazards models with time-dependent modeled d-ROMs levels and TTLs were used to assess the associations with incident major cardiovascular events (MCE), cancer incidence, and all-cause mortality. RESULTS: In total, 205, 179, and 394 MCE, cancer, and all-cause mortality cases were observed during 6-7 years of follow-up, respectively. Both oxidative stress biomarkers and the d-ROMs-to-TTL ratio were statistically significantly associated with all-cause mortality in both cohorts, and the pooled hazard ratios (HRs) and 95% CIs for top versus bottom tertiles were 2.10 (95% CI 1.43, 3.09) for d-ROMs levels, 0.59 (0.40, 0.87) for TTLs, and 2.50 (1.86, 3.36) for d-ROMs-to-TTL ratio. The d-ROMs-to-TTL ratio was also statistically significantly associated with incident MCE for top versus bottom tertile (1.65 [1.07, 2.54]), but this association did not persist after additional adjustment for chronic diseases. No associations with cancer were detected. CONCLUSIONS: The observed strong associations of both biomarkers with mortality suggest an important contribution of an imbalanced redox system to the premature mortality of patients with diabetes.

Investigation on potential associations of oxidatively generated DNA/RNA damage with lung, colorectal, breast, prostate and total cancer incidence.

Oxidative stress has been linked to cancer development in previous studies. However, the association between pre-diagnostic oxidatively generated DNA/RNA damage levels and incident cancer has rarely been investigated. Urinary oxidized guanine/guanosine (OxGua) concentrations, including 8-hydroxy-2'-deoxyguanosine, were assessed in 8,793 older adults in a population-based German cohort. 1,540 incident cancer cases, including 207 lung, 196 colorectal, 218 breast and 245 prostate cancer cases were diagnosed during over 14 years of follow-up. Associations of OxGua levels with cancer outcomes were not observed in the total population in multi-variable adjusted Cox regression models. However, in subgroup analyses, colorectal cancer incidence increased by 8%, 9% and 8% with one standard deviation increase in OxGua levels among current non-smokers, female and non-obese participants, respectively. Additionally, among non-smokers, overall and prostate cancer incidences statistically significantly increased by 5% and 13% per 1 standard deviation increase in OxGua levels, respectively. In contrast, OxGua levels were inversely associated with the risk of prostate cancer among current smokers. However, none of the subgroup analyses had p-values below a threshold for statistical significance after correction for multiple testing. Thus, results need to be validated in further studies. There might be a pattern that oxidatively generated DNA/RNA damage is a weak cancer risk factor in the absence of other strong risk factors, such as smoking, obesity and male sex.

Association of serum markers of oxidative stress with myocardial infarction and stroke: pooled results from four large European cohort studies.

Oxidative stress contributes to endothelial dysfunction and is involved in the pathogenesis of myocardial infarction (MI) and stroke. However, associations of biomarkers of oxidative stress with MI and stroke have not yet been addressed in large cohort studies. A nested case-control design was applied in four population-based cohort studies from Germany, Czech Republic, Poland and Lithuania. Derivatives of reactive oxygen metabolites (d-ROMs) levels, as a proxy for the reactive oxygen species burden, and total thiol levels (TTL), as a proxy for the reductive capacity, were measured in baseline serum samples of 476 incident MI cases and 454 incident stroke cases as well as five controls per case individually matched by study center, age and sex. Statistical analyses were conducted with multi-variable adjusted conditional logistic regression models. d-ROMs levels were associated with both MI (odds ratio (OR), 1.21 [95% confidence interval (CI) 1.05-1.40] for 100 Carr units increase) and stroke (OR, 1.17 [95% CI 1.01-1.35] for 100 Carr units increase). TTL were only associated with stroke incidence (OR, 0.79 [95% CI 0.63-0.99] for quartiles 2-4 vs. quartile 1). The observed relationships were stronger with fatal than with non-fatal endpoints; association of TTL with fatal MI was statistically significant (OR, 0.69 [95% CI 0.51-0.93] for 100 µmol/L-increase). This pooled analysis of four large population-based cohorts suggests an important contribution of an imbalanced redox system to the etiology of mainly fatal MI and stroke events.

Pre-diagnostic derivatives of reactive oxygen metabolites and the occurrence of lung, colorectal, breast and prostate cancer: An individual participant data meta-analysis of two large population-based studies.

Oxidative stress may be involved in carcinogenesis and biomarkers of oxidative stress like derivatives of reactive oxygen metabolites (d-ROM) may be useful for cancer prediction. However, no previous study assessed the association of pre-diagnostic d-ROM measurements with cancer incidence. We measured serum d-ROM levels in a cohort sample of n = 4,345 participants of the German ESTHER study and in a case-cohort sample of the Norwegian Tromsø study (cancer cases: n = 941; subcohort: n = 1,000). Moreover, d-ROM was repeatedly measured at follow-ups of both studies. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were derived by (weighted) multivariable-adjusted Cox regression with time-dependent modeling of d-ROM levels for incident lung, colorectal, breast and prostate cancer. Individual study results were pooled by random effects meta-analysis. The HRs (95% CI) for comparison of top and bottom d-ROM tertile were statistically significant for lung (1.90 [1.25-2.89]), colorectal (1.70 [1.15-2.51]) and breast cancer incidence (1.45 [1.01-2.09]) but not for prostate cancer incidence (1.20 [0.84-1.72]). In conclusion, this individual participant data meta-analysis of two large population-based cohort studies with repeated d-ROM measurements yielded evidence for an involvement of high oxidative stress in carcinogenesis. Given the observed associations of pre-diagnostic d-ROM measurements with lung, colorectal and breast cancer incidence, subjects with increased serum d-ROM levels should be recommended to reduce these levels by lifestyle changes including smoking cessation, a healthy diet and an increase in physical activity.

Urinary 8-isoprostane levels and occurrence of lung, colorectal, prostate, breast and overall cancer: Results from a large, population-based cohort study with 14 years of follow-up.

BACKGROUND: Urinary 8-isoprostane is an established biomarker for lipid peroxidation. However, the association between its pre-diagnostic levels and cancer incidence has rarely been evaluated. METHODS: 8793 older adults from the German ESTHER cohort were followed up for cancer incidence by cancer registry data. A directed acyclic graph was utilized to identify potential confounders. Multivariate Cox regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI). RESULTS: During 14-year follow-up, 1540 incident cancer cases, including 207 lung, 196 colorectal, 218 breast and 245 prostate cancer cases were detected. 8-isoprostane concentrations were positively associated with lung cancer, but not with cancer at the other sites. The HR (95% CI) for the association with lung cancer was 1.61 (1.10, 2.34) for comparison of the top with bottom tertile in total population. The association of 8-isoprostane levels with lung cancer persisted after the adjustment for smoking and other potential confounders and was multiplicative to the effect of smoking. However, 8-isoprostane levels did not improve lung cancer prediction when added to a model containing age, sex and smoking. A protective association of increasing 8-isoprostane levels was observed for prostate cancer incidence but this association was only statistically significant among current smokers. DISCUSSION: Our findings suggest that lipid peroxidation is involved in the development of lung cancer. However, high oxidative stress may be a protective factor for prostate cancer, especially among current smokers.