Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Original Research

Urinary Markers of Nucleic Acid Oxidation and Long-Term Mortality of Newly Diagnosed Type 2 Diabetic Patients

  1. Kasper Broedbaek, MD1,2⇓,
  2. Volkert Siersma, PHD3,
  3. Trine Henriksen, PHD1,2,
  4. Allan Weimann, PHD1,2,
  5. Morten Petersen, MD1,2,
  6. Jon T. Andersen, MD1,2,
  7. Espen Jimenez-Solem, MD1,2,
  8. Elisabeth S. Stovgaard, MD1,2,
  9. Lars J. Hansen, PHD3,
  10. Jan Erik Henriksen, PHD4,
  11. Steen J. Bonnema, PHD4,
  12. Niels de Fine Olivarius, MD3 and
  13. Henrik E. Poulsen, DMSC1,2,5
  1. 1Laboratory of Clinical Pharmacology, Rigshospitalet, Copenhagen, Denmark
  2. 2Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark
  3. 3Research Unit for General Practice and Section of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
  4. 4Department of Endocrinology, Odense University Hospital, Odense, Denmark
  5. 5Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  1. Corresponding author: Kasper Broedbaek, kasper.broedbaek{at}rh.regionh.dk.
Diabetes Care 2011 Dec; 34(12): 2594-2596. https://doi.org/10.2337/dc11-1620
PreviousNext
  • Article
  • Figures & Tables
  • Suppl Material
  • Info & Metrics
  • PDF
Loading

Abstract

OBJECTIVE 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.

RESEARCH DESIGN AND METHODS 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.

RESULTS 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.

CONCLUSIONS 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.

Over the last decade, there has been an increased focus on the role of oxidative stress in the pathophysiology of diabetes-related complications. The diabetic state is associated with increased levels of markers of oxidative stress, and evidence derived from mechanistic studies suggests that oxidative stress has an important role in the pathogenesis of diabetes complications (1–7). Markers of intracellular oxidative stress that could be used as new biomarkers in diabetes are the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), which are widely used as markers of DNA and RNA oxidation, respectively. These markers can conveniently be assessed in the urine, which makes them well suited for use in risk stratification and therapy control.

The prognostic importance of urinary markers of oxidative stress in patients with type 2 diabetes is unknown. In the current study we used data from a population-based cohort of 1,381 patients newly diagnosed with diabetes to test the hypothesis that the urinary markers of oxidative stress 8-oxodG and 8-oxoGuo are independent predictors of mortality.

RESEARCH DESIGN AND METHODS

Study population

In the Diabetes Care in General Practice study (8), 474 general practitioners agreed to include all subjects on their practice list who fulfilled the following criteria: newly diagnosed diabetes based on hyperglycemic symptoms and/or raised blood glucose values, diagnosed between 1 March 1989 and 28 February 1992, and aged 40 years or over. Accordingly, a total of 1,543 newly diagnosed diabetic patients were eligible, but 162 were excluded because of protocol-based exclusion criteria: life-threatening somatic disease (50 patients), severe mental illness (50 patients), or unwillingness to participate (62 patients). This gave a final study population of 1,381 patients. Based on the onset of insulin treatment within 180 days of diagnosis, ∼97.5% of the patients were considered to have type 2 diabetes (8).

The protocol was approved by the ethics committee of Copenhagen and Frederiksberg, and informed consent was obtained from all patients.

Baseline assessments

The participants produced a freshly voided morning urine sample as soon as possible after the day of diagnosis (median time from diagnosis to urine sample was 11 days; interquartile range, 4–29 days). Urinary markers of nucleic acid oxidation were measured at the Laboratory of Clinical Pharmacology (Rigshospitalet, Copenhagen). The urine samples, stored at −80°C until analysis, were assayed between 2009 and 2010 for the oxidatively modified guanine nucleosides 8-oxodG and 8-oxoGuo using a validated method of ultraperformance liquid chromatography and tandem mass spectrometry (9). 8-oxodG and 8-oxoGuo were normalized against urinary creatinine concentration.

Outcome assessments

The vital status of all the diabetic patients was certified on 1 January 2009 through the Danish Civil Registration System (10).

Diabetes-related death was defined as at least one of the following entries in the Danish National Register of Causes of Death (11): sudden death or death from myocardial infarction, stroke, renal disease, hyperglycemia, hypoglycemia, or peripheral vascular disease.

Statistical analysis

The associations between oxidative stress and all-cause mortality and diabetes-related mortality, respectively, were analyzed in Cox proportional hazards regression models based on time from diagnosis to death or censoring. Oxidative stress is represented by the natural logarithm of 8-oxodG and 8-oxoGuo, and by a four-class ordinal variable corresponding to the quartiles of the distribution. Three models were estimated for each of the oxidative stress variables and each of the outcomes: a univariate (unadjusted) model, a model adjusted for age and sex, and a multivariate model. Covariates included in the multivariate model were age, sex, smoking status, cohabitation status, physical activity, education, BMI, presence or absence of hypertension and of microalbuminuria, glycated hemoglobin, total cholesterol, triglycerides, serum creatinine, presence or absence of retinopathy and of peripheral neuropathy, and history of acute myocardial infarction and stroke.

RESULTS

Baseline characteristics according to quartiles of 8-oxodG and 8-oxoGuo are provided in Supplementary Tables 1 and 2. After a median follow-up period of 18.7 years (interquartile range, 18.2–19.2 years), 966 (70.0%) patients had died, of whom 584 were regarded as having had a diabetes-related death. The results of the unadjusted and adjusted Cox regression analyses are shown in Table 1. In the adjusted analyses, only 8-oxoGuo was significantly associated with mortality. The multivariate adjusted 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 (95% CI 1.12–1.85; P = 0.004) and 1.54 (1.13–2.10; P = 0.006), respectively.

View this table:
  • View inline
  • View popup
Table 1

Relationship of 8-oxodG and 8-oxoGuo with all-cause and diabetes-related mortality

When log 8-oxodG and log 8-oxoGuo were considered as continuous covariates, the results were similar to those described above. The multivariate adjusted hazard ratios for all-cause and diabetes-related mortality per unit increase in log 8-oxoGuo were 1.33 (95% CI 1.07–1.64; P = 0.009) and 1.40 (1.08–1.81; P = 0.01), respectively.

CONCLUSIONS

This study is, to our knowledge, the first to explore the association between urinary excretion of markers of oxidative stress and mortality in diabetic patients. Urinary excretion of the RNA oxidation marker 8-oxoGuo in a freshly voided morning urine sample shortly after diagnosis of diabetes independently predicted all-cause and diabetes-related mortality, whereas the DNA oxidation marker 8-oxodG did not. The risk of death among those in the highest quartile of 8-oxoGuo excretion was nearly 50% higher than among those in the lowest quartile.

The prognostic information of 8-oxoGuo was independent of other characteristics of patients with type 2 diabetes that have been linked to mortality, most importantly age, sex, glycated hemoglobin, lipids, urinary albumin excretion, blood pressure, smoking, and pre-existing cardiovascular disease.

This observation suggests that measurement of urinary 8-oxoGuo provides additional information about risk and might be useful for identifying patients who would benefit the most from intensified treatment or specific treatment strategies, including nonpharmacological interventions. The combined use of 8-oxoGuo and other known risk factors in a multivariate risk factor approach could be useful for improving risk stratification of diabetic patients. 8-oxoGuo is a prime candidate for further investigation to establish the exact mechanisms responsible for its association with mortality in diabetic patients, and to evaluate its potential role as a clinical biomarker in diabetes.

Acknowledgments

This study was supported by research funding from the Research Committee at Copenhagen University Hospital, Rigshospitalet (Rigshospitalets Forskningsudvalg), the Danish Medical Research Council, the Aase and Ejnar Danielsen Foundation, the P. Carl Petersen Foundation, the Augustinus Foundation, the Lundbeck Foundation, the Danish Research Foundation for General Practice, the Health Insurance Foundation, the Danish Ministry of Health, Novo Nordisk Farmaka Denmark Ltd., the A.P. Møller Foundation for the Advancement of Medical Science, and the Pharmacy Foundation. No other potential conflicts of interest relevant to this article were reported.

H.E.P., N.d.F.O., and K.B. are the guarantors for this article. K.B. researched data, contributed to discussion, wrote the manuscript, and reviewed and edited the manuscript. V.S., T.H., A.W., M.P., J.T.A., E.J.-S., E.S.S., L.J.H., J.E.H., S.J.B., N.d.F.O., and H.E.P. researched data, contributed to discussion, and reviewed and edited the manuscript.

The authors gratefully acknowledge the technical assistance of laboratory technician Katja Luntang Christensen (Rigshospitalet).

Footnotes

  • This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc11-1620/-/DC1.

  • Received August 23, 2011.
  • Accepted September 20, 2011.
  • © 2011 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

References

  1. ↵
    1. Piconi L,
    2. Quagliaro L,
    3. Ceriello A
    . Oxidative stress in diabetes. Clin Chem Lab Med 2003;41:1144–1149pmid:14598863
    OpenUrlCrossRefPubMedWeb of Science
    1. Matheson A,
    2. Willcox MD,
    3. Flanagan J,
    4. Walsh BJ
    . Urinary biomarkers involved in type 2 diabetes: a review. Diabetes Metab Res Rev 2010;26:150–171pmid:20222150
    OpenUrlCrossRefPubMed
    1. Brownlee M
    . The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615–1625pmid:15919781
    OpenUrlFREE Full Text
    1. Calcutt NA,
    2. Cooper ME,
    3. Kern TS,
    4. Schmidt AM
    . Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat Rev Drug Discov 2009;8:417–429pmid:19404313
    OpenUrlCrossRefPubMedWeb of Science
    1. Ceriello A
    . New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 2003;26:1589–1596pmid:12716823
    OpenUrlAbstract/FREE Full Text
    1. Mazzone T,
    2. Chait A,
    3. Plutzky J
    . Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 2008;371:1800–1809pmid:18502305
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    Broedbaek K, Weimann A, Stovgaard ES, Poulsen HE. Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine as a biomarker in type 2 diabetes. Free Radic Biol Med 2011;51:1473–1479
  3. ↵
    1. Olivarius NF,
    2. Beck-Nielsen H,
    3. Andreasen AH,
    4. Hørder M,
    5. Pedersen PA
    . Randomised controlled trial of structured personal care of type 2 diabetes mellitus. BMJ 2001;323:970–975pmid:11679387
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Henriksen T,
    2. Hillestrøm PR,
    3. Poulsen HE,
    4. Weimann A
    . Automated method for the direct analysis of 8-oxo-guanosine and 8-oxo-2′-deoxyguanosine in human urine using ultraperformance liquid chromatography and tandem mass spectrometry. Free Radic Biol Med 2009;47:629–635pmid:19501155
    OpenUrlCrossRefPubMed
  5. ↵
    1. Pedersen CB,
    2. Gøtzsche H,
    3. Møller JO,
    4. Mortensen PB
    . The Danish Civil Registration System. A cohort of eight million persons. Dan Med Bull 2006;53:441–449pmid:17150149
    OpenUrlPubMed
  6. ↵
    1. Juel K,
    2. Helweg-Larsen K
    . The Danish registers of causes of death. Dan Med Bull 1999;46:354–357pmid:10514943
    OpenUrlPubMedWeb of Science
PreviousNext
Back to top
Diabetes Care: 34 (12)

In this Issue

December 2011, 34(12)
  • Table of Contents
  • About the Cover
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Urinary Markers of Nucleic Acid Oxidation and Long-Term Mortality of Newly Diagnosed Type 2 Diabetic Patients
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Urinary Markers of Nucleic Acid Oxidation and Long-Term Mortality of Newly Diagnosed Type 2 Diabetic Patients
Kasper Broedbaek, Volkert Siersma, Trine Henriksen, Allan Weimann, Morten Petersen, Jon T. Andersen, Espen Jimenez-Solem, Elisabeth S. Stovgaard, Lars J. Hansen, Jan Erik Henriksen, Steen J. Bonnema, Niels de Fine Olivarius, Henrik E. Poulsen
Diabetes Care Dec 2011, 34 (12) 2594-2596; DOI: 10.2337/dc11-1620

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Urinary Markers of Nucleic Acid Oxidation and Long-Term Mortality of Newly Diagnosed Type 2 Diabetic Patients
Kasper Broedbaek, Volkert Siersma, Trine Henriksen, Allan Weimann, Morten Petersen, Jon T. Andersen, Espen Jimenez-Solem, Elisabeth S. Stovgaard, Lars J. Hansen, Jan Erik Henriksen, Steen J. Bonnema, Niels de Fine Olivarius, Henrik E. Poulsen
Diabetes Care Dec 2011, 34 (12) 2594-2596; DOI: 10.2337/dc11-1620
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • RESEARCH DESIGN AND METHODS
    • RESULTS
    • CONCLUSIONS
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Tables
  • Suppl Material
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

Original Research

  • Alcohol Abstinence and the Risk of Atrial Fibrillation in Patients With Newly Diagnosed Type 2 Diabetes Mellitus: A Nationwide Population-Based Study
  • Glucagon-Like Peptide 1 Receptor Agonists and Chronic Lower Respiratory Disease Exacerbations Among Patients With Type 2 Diabetes
  • Autoantibodies Against Methylglyoxal-Modified Apolipoprotein B100 and ApoB100 Peptide Are Associated With Less Coronary Artery Atherosclerosis and Retinopathy in Long-Term Type 1 Diabetes
Show more Original Research

Pathophysiology/Complications

  • Impact of Type 1 Diabetes in the Developing Brain in Children: A Longitudinal Study
  • Obstructive Sleep Apnea, Glucose Tolerance, and β-Cell Function in Adults With Prediabetes or Untreated Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study
  • Importance of Intestinal Environment and Cellular Plasticity of Islets in the Development of Postpancreatectomy Diabetes
Show more Pathophysiology/Complications

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.