The effect of structured personal care on RNA oxidation: A 19-year follow-up of the randomized trial Diabetes Care in General Practice (DCGP)

doi:10.1016/j.jdiacomp.2018.12.004

Journal of Diabetes and its Complications

Volume 33, Issue 3, March 2019, Pages 202-207

https://doi.org/10.1016/j.jdiacomp.2018.12.004 Get rights and content

Abstract

Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Introduction

Diabetes is an increasing global burden affecting 425 million people in 2017, and of which 90% are patients with type 2 diabetes.¹ Despite improved survival of diabetes patients in recent years,² the increasing number of patients calls for continuous optimization of diabetes care to prevent related complications.

Evidence shows that oxidative stress is involved in the pathogenesis of type 2 diabetes complications and can damage nucleic acids.³^,⁴ Nucleic acid oxidation markers are believed to reflect intracellular mechanisms not achieved by traditional extracellular markers.⁵ In two large, independent prospective cohort studies we have recently documented that the urinary nucleic acid oxidation marker for RNA, 8‑oxo‑7,8‑dihydroguanosine (8-oxoGuo), but not for DNA, 8‑oxo‑7,8‑dihydro‑2′‑deoxyguanosine (8-oxodG), is prognostic for all-cause and cardiovascular mortality in patients with type 2 diabetes irrespective of disease duration.6., 7., 8., 9. However, to our knowledge, recommended treatment with the potential of lowering nucleic acid oxidation markers has not been studied in large prospective cohorts.

In the randomized controlled trial Diabetes Care in General Practice (DCGP), patients with type 2 diabetes were allocated to six years of either intervention to support structured personal care (individualized multifactorial treatment) for type 2 diabetes or standard care.¹⁰^,¹¹ After 19 years of follow-up the intervention group experienced almost 20% reduction in incidence of the aggregate outcome “any diabetes-related outcome” and myocardial infarction.¹¹ This effect was to a major degree confined to women.¹²

The aim of this study was to assess the effect of an intervention of structured personal care in patients with type 2 diabetes compared with standard care on urinary nucleic acid oxidation markers. The second aim was to investigate if the effect of the intervention on hard clinical outcomes could be explained by high or low nucleic acid oxidation level at baseline. For both aims, sex differences were explored.

Section snippets

Study population

In this study, 1381 patients with newly diagnosed type 2 diabetes aged ≥40 years from the DCGP study were included. Of these, 97.5% were considered to have type 2 diabetes.¹⁰ Patients were enrolled between 1 March 1989 and 28 February 1992. During the last year of inclusion, only the 71 general practitioners (GPs) in the structured care group recruited patients for the intervention.¹¹ The eligibility criteria were raised blood glucose and/or symptoms of hyperglycemia. Subsequently, diagnosis

Patient characteristics

Baseline characteristics are presented in Table 1. All socio-demographic, clinical, biochemical and behavioral characteristics were similar across treatment groups (Table 1).

Primary outcomes

The yearly change in nucleic acid oxidation markers from baseline to the end of intervention did not differ between the structured personal care and the standard care group (Table 2). 50% of those in the structured personal care group that was still alive when the intervention ended had a yearly change in RNA oxidation

Discussion

This study did not show any differences in yearly change in urinary nucleic acid oxidation markers between structured personal care versus standard care during six years of intervention. Moreover, our study did not find any difference in the treatment effect on survival among those with high versus low urinary nucleic acid oxidation. There were no sex differences found between treatment groups, except for the low RNA oxidation group on diabetes-related mortality.

The original DCGP study did not

Conclusions

We conclude that six years of structured personal care did not affect the urinary markers of nucleic acid oxidation. Furthermore, the effects of structured personal care on all-cause and diabetes-related mortality were not expressed differently for different levels of the markers of nucleic acid oxidation; in fact, no such treatment effects were found.

Future randomized controlled trials with up-to-date anti-diabetic treatment and long-term follow-up should be performed to assess the potential

Acknowledgements

We thank chemist Trine Henriksen and laboratory technician Katja Luntang Christensen for the excellent technical assistance with the analyses of the urinary nucleic acid oxidation markers.

Contribution statement

HEP and NdFO are guarantors. NdFO is responsible for the original DCGP study. LKK researched data, contributed to interpretation, wrote the draft of the manuscript and reviewed and edited the manuscript. MKG and VS did the statistical analyses. All authors made substantial contribution to the research question, design, analyses and interpretation of data. All authors have approved the final version of the manuscript for submission.

Funding

This study was funded by the Toyota Foundation Denmark. The DCGP study received its major funding from the Danish Medical Research Council, the Danish Ministry of Health, the Danish Research Foundation for General Practice, the Health Insurance Foundation, the Pharmacy Foundation, the Novo Nordisk Farmaka Denmark, and the Novo Nordisk Foundation.

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Cited by (2)

Biomarkers of nucleic acid oxidation – A summary state-of-the-art
2021, Redox Biology
Citation Excerpt :
Supportive this proposal there is an increasing number of medical conditions in which 8-oxoGuo in extracellular matrices (mainly urine) has been measured in humans, as a biomarker of RNA oxidation. These include: aging, and related disorders (summarised in Ref. [102]), hemochromatosis [103], diabetes [104–110], and a number of psychiatric disorders, such as schizophrenia [111], depression [112], bipolar disorder [113], psychosis [114], liver injury associated with Hepatitis B virus infection [115], sepsis [116], cerebral infarction [117], traumatic brain injury [118], and spontaneous intra-cerebral haemorrhage [119]. Unfortunately, to date, the mechanistic studies to explain the potential role of RNA oxidation in the above conditions, is less well advanced compared to these observational studies.
Oxidatively generated damage to DNA has been implicated in the pathogenesis of a wide variety of diseases. Increasingly, interest is also focusing upon the effects of damage to the other nucleic acids, RNA and the (2′-deoxy-)ribonucleotide pools, and evidence is growing that these too may have an important role in disease. LC-MS/MS has the ability to provide absolute quantification of specific biomarkers, such as 8-oxo-7,8-dihydro-2′-deoxyGuo (8-oxodG), in both nuclear and mitochondrial DNA, and 8-oxoGuo in RNA. However, significant quantities of tissue are needed, limiting its use in human biomonitoring studies. In contrast, the comet assay requires much less material, and as little as 5 μL of blood may be used, offering a minimally invasive means of assessing oxidative stress in vivo, but this is restricted to nuclear DNA damage only. Urine is an ideal matrix in which to non-invasively study nucleic acid-derived biomarkers of oxidative stress, and considerable progress has been made towards robustly validating these measurements, not least through the efforts of the European Standards Committee on Urinary (DNA) Lesion Analysis. For urine, LC-MS/MS is considered the gold standard approach, and although there have been improvements to the ELISA methodology, this is largely limited to 8-oxodG. Emerging DNA adductomics approaches, which either comprehensively assess the totality of adducts in DNA, or map DNA damage across the nuclear and mitochondrial genomes, offer the potential to considerably advance our understanding of the mechanistic role of oxidatively damaged nucleic acids in disease.
Interventions targeted at oxidatively generated modifications of nucleic acids focused on urine and plasma markers
2019, Free Radical Biology and Medicine
Citation Excerpt :
From the title and abstract of the 6613 identified studies, a total of 232 were selected for full reading. Thirty-five studies [94–128] were identified as having measured 8-oxodG in plasma and 78 studies [11,104,129–204] were identified as having measured 8-oxodG/creatinine in urine; these were selected for comparing the concentrations between analysis procedures. None of the studies used LC-ECD and LC-MS/MS methods for determining 8-oxodG in plasma; thus, we used non-intervention studies as references for the LC-ECD [82,205] and LC-MS/MS methods [206–210].
Oxidative stress is associated with the development and progression of numerous diseases. However, targeting oxidative stress has not been established in the clinical management of any disease. Several methods and markers are available to measure oxidative stress, including direct measurement of free radicals, antioxidants, redox balance, and oxidative modifications of cellular macromolecules. Oxidatively generated nucleic acid modifications have attracted much interest due to the pre-mutagenic oxidative modification of DNA into 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), associated with cancer development. During the last decade, the perception of RNA has changed from that of a ‘silent messenger’ to an ‘active contributor’, and, parallelly oxidatively generated RNA modifications measured as 8-oxo-7,8-dihydro-guanosine (8-oxoGuo), has been demonstrated as a prognostic factor for all-caused and cardiovascular related mortality in patients with type 2 diabetes. Several attempts have been made to modify the amount of oxidative nucleic acid modifications. Thus, this review aims to introduce researchers to the measurement of oxidatively generated nucleic acid modifications as well as critically review previous attempts and provide future directions for targeting oxidatively generated nucleic acid modifications.

: Declaration of interest: The authors declare no conflict of interest.

View full text

The effect of structured personal care on RNA oxidation: A 19-year follow-up of the randomized trial Diabetes Care in General Practice (DCGP)

Abstract

Aims

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Patient characteristics

Primary outcomes

Discussion

Conclusions

Acknowledgements

Contribution statement

Funding

Int J Biochem Cell Biol

Free Radic Biol Med

Redox Biol

Free Radic Biol Med

Free Radic Biol Med

Mutat Res

Free Radic Biol Med

Free Radic Biol Med

IDF Diabetes atlas - 2017 Atlas

Mortality and cardiovascular disease in type 1 and type 2 diabetes

N Engl J Med

The pathobiology of diabetic complications: a unifying mechanism

Diabetes

Cardiovascular and all-cause mortality risk associated with urinary excretion of 8-oxoGuo, a biomarker for RNA oxidation, in patients with type 2 diabetes: a prospective cohort study

Diabetes Care

Urinary markers of nucleic acid oxidation and long-term mortality of newly diagnosed type 2 diabetic patients

Diabetes Care

Association between urinary markers of nucleic acid oxidation and mortality in type 2 diabetes: a population-based cohort study

Diabetes Care

Randomised controlled trial of structured personal care of type 2 diabetes mellitus

BMJ

Structured personal care of type 2 diabetes: a 19 year follow-up of the study diabetes Care in General Practice (DCGP)

Diabetologia

The impact of gender on the long-term morbidity and mortality of patients with type 2 diabetes receiving structured personal care: a 13 year follow-up study

Diabetologia