Urinary albumin and 8-oxo-7,8-dihydroguanosine as markers of mortality and cardiovascular disease during 19 years after diagnosis of type 2 diabetes:A comparative study of two markers to identify high risk patients

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

Clinical relevance of biomarkers of oxidative stress

SIGNIFICANCE Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 00, 000-000

Association between Urinary Excretion of Cortisol and Markers of Oxidatively Damaged DNA and RNA in Humans

Chronic psychological stress is associated with accelerated aging, but the underlying biological mechanisms are not known. Prolonged elevations of the stress hormone cortisol is suspected to play a critical role. Through its actions, cortisol may potentially induce oxidatively generated damage to cellular constituents such as DNA and RNA, a phenomenon which has been implicated in aging processes. We investigated the relationship between 24 h excretion of urinary cortisol and markers of oxidatively generated DNA and RNA damage, 8-oxo-7,8-dihydro-2′-deoxyguanosine and 8-oxo-7,8-dihydroguanosine, in a sample of 220 elderly men and women (age 65 – 83 years). We found a robust association between the excretion of cortisol and the oxidation markers (R2 = 0.15, P<0.001 for both markers). Individuals in the highest quartile of cortisol excretion had a 57% and 61% higher median excretion of the DNA and RNA oxidation marker, respectively, than individuals in the lowest quartile. The finding adds support to the hypothesis that cortisol-induced damage to DNA/RNA is an explanatory factor in the complex relation between stress, aging and disease

Telomere length, antioxidant status and incidence of ischaemic heart disease in type 2 diabetes

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of ischaemic heart disease (IHD). An accelerated process of vascular ageing induced by an increased oxidative stress exposure is suggested as potential pathway accounting for this association. However, no studies have explored the relationship between markers of vascular ageing, measures of oxidative stress and risk of IHD in T2D. OBJECTIVES: To explore the association between plasma antioxidant status, marker of cellular ageing (leukocyte telomere length, LTL) and 10years risk of IHD in patients with T2D. METHODS: Between 2001 and 2002, 489 Caucasians subjects with T2D were enrolled at the diabetic clinic, University College London Hospital. Plasma total anti-oxidant status (TAOS) and LTL were measured by photometric microassay and RT-PCR, respectively. The incidence of IHD over 10years was determined through linkage with the national clinical audit of acute coronary syndrome in UK. RESULTS: At baseline, TAOS was associated with LTL (age adjusted: r=0.106, p=0.024). After 10years, 61 patients developed IHD. Lower TAOS and shorter LTL at baseline predicted an increased IHD risk at follow-up (age adjusted: p=0.033 and p=0.040, respectively). These associations were independent of age, gender, cardiovascular risk factors, circulating levels of CRP and medication differences. CONCLUSIONS: Reduced TAOS and short LTL are interrelated pathways which predict risk of IHD in patients with T2D. Our findings suggest that antioxidant defences are important to maintain telomere integrity, potentially reducing the progression of vascular ageing in patients with T2D

Reactive species and DNA damage in chronic inflammation: Reconciling chemical mechanisms and biological fates

Chronic inflammation has long been recognized as a risk factor for many human cancers. One mechanistic link between inflammation and cancer involves the generation of nitric oxide, superoxide and other reactive oxygen and nitrogen species by macrophages and neutrophils that infiltrate sites of inflammation. Although pathologically high levels of these reactive species cause damage to biological molecules, including DNA, nitric oxide at lower levels plays important physiological roles in cell signaling and apoptosis. This raises the question of inflammation-induced imbalances in physiological and pathological pathways mediated by chemical mediators of inflammation. At pathological levels, the damage sustained by nucleic acids represents the full spectrum of chemistries and likely plays an important role in carcinogenesis. This suggests that DNA damage products could serve as biomarkers of inflammation and oxidative stress in clinically accessible compartments such as blood and urine. However, recent studies of the biotransformation of DNA damage products before excretion point to a weakness in our understanding of the biological fates of the DNA lesions and thus to a limitation in the use of DNA lesions as biomarkers. This review will address these and other issues surrounding inflammation-mediated DNA damage on the road to cancer.National Institute of Environmental Health Sciences (CA116318)National Institute of Environmental Health Sciences (CA103146)National Institute of Environmental Health Sciences (CA026731)National Institute of Environmental Health Sciences (ES016450)National Institute of Environmental Health Sciences (ES002109)National Institute of Environmental Health Sciences (ES017010)National Cancer Institute (U.S.)National Science Foundation (U.S.) (grant no. CHE-1019990)Singapore-MIT Alliance for Research and TechnologyMassachusetts Institute of Technology (Westaway Fund