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
Editorials

Pathogenetic Loop Between Diabetes and Cell Senescence

  1. Roberto Testa, MD1 and
  2. Antonio Ceriello, MD2
  1. 1Gerontological Research, Italian National Research Centre on Aging, Ancona, Italy
  2. 2Centre of Excellence in Diabetes and Endocrinology, University Hospital of Coventry and Warwickshire, University of Warwick, Coventry, U.K
  1. Address correspondence and reprint requests to Prof. Antonio Ceriello, Warwick Medical School, Clinical Science Research Institute, Clinical Science Building, University Hospital–Walsgrave Campus, Clifford Bridge Road, Coventry CV2 2DX, U.K. E-mail: antonio.ceriello{at}warwick.ac.uk
Diabetes Care 2007 Nov; 30(11): 2974-2975. https://doi.org/10.2337/dc07-1534
PreviousNext
  • Article
  • Info & Metrics
  • PDF
Loading

Cell senescence has recently been postulated as an important cause/consequence of type 2 diabetes and its complications. Cellular senescence is defined as a limited ability of human cells to divide, and it becomes evident through phenotypic changes in morphology, gene expression, and function (1). It has long been known that genomic instability, a hallmark of premature aging disorders such as in the Werner syndrome, is associated with type 2 diabetes (2), and, recently, great attention has been paid to the potential impact of vascular cellular senescence on diabetes by means of the study on endothelial progenitor cells (EPCs). EPCs were discovered in 1997. They are derived from bone marrow and are mobilized to the peripheral circulation in response to different stimuli. Defined as circulating immature cells that contribute to vascular homeostasis and compensatory angiogenesis (3), EPCs are able to regenerate injured endothelium, accelerate re-endothelization, and limit the formation of atherosclerotic lesions. Their identification has prompted an explosion of interest regarding their role in the pathogenesis of micro- and macrovascular diseases. Different studies have demonstrated that EPCs are impaired in diabetic subjects and that high glucose levels appear to be the most important cause of enhanced EPCs senescence (4). Senescence leads to the impairment of proliferative activity and may have an important causative role in the development and progression of diabetes complications. The telomere hypothesis is a widely accepted explanation of the occurrence of senescence. In particular, telomeres are repetitive G-rich tandem DNA sequences and specialized proteins at the ends of eukaryotic chromosomes, and their length shortens as a function of cellular division. Short telomere length has been hypothesized to trigger the onset of senescence (5). Telomeres contribute to the maintenance of genome stability and integrity. They are necessary for successful DNA replication and extended proliferative life span both in cultured cells and in the whole organism (6). Telomere dysfunction has also been considered an important factor in the pathogenesis of atherosclerosis, hypertension, diabetes (7,8), and vascular aging (9). There is an ongoing debate whether oxidative DNA damage is one of the main causes leading to telomeric DNA damage and accelerated telomere shortening at cell division, as well as to senescent phenotypes in multiple cell types, such as endothelial and monocyte-macrophage cells, in type 2 diabetes (10,11). In support of this hypothesis, it has been found that nitric oxide (NO) can prevent endothelial senescence. In particular, the ingestion of NO-boosting substances (i.e., l-arginine, l-citrulline, and antioxidants) has been demonstrated to delay endothelial senescence under high glucose conditions (12). In this issue of Diabetes Care, Tentolouris et al. (13) report that in patients with microalbuminuria, telomere length was shorter than in those without microalbuminuria. The novelty of this study is the demonstration, for the first time, that type 2 diabetic patients with microalbuminuria have shorter telomere length than diabetic individuals without this complication, with a large difference of 590 bp between microalbuminuria-positive and microalbuminuria-negative subjects, implying a profound gap between biological and chronological age of the two groups. Previous publications have hypothesized that increased renal oxidative DNA damage in type 2 diabetes is associated with telomere damage and attrition. In particular, it has been suggested that DNA oxidation favors early expression of a renal phenotype of progressive glomerular cell senescence and proteinuria associated with accelerated endothelial and vascular cell senescence and atherogenesis (10). This hypothesis is supported by evidences that a biomarker of oxidative DNA damage, the 8-hydroxydeoxyguanosine, is more excreted in albuminuric than in normoalbuminuric diabetic patients (14) and that plasma 8-hydroxydeoxyguanosine is related to enhanced diabetic nephropathy (15). The findings of Tentolouris et al. also lead the authors to hypothesize that arterial stiffness, found in patients with microalbuminuria, may be due to the more pronounced “aging” of these patients.

Interesting findings are also emerging about the possible pathogenetic role of telomere shortening in inducing diabetes. It has recently been published that telomere shortening is present even at the stage of impaired glucose tolerance and may represent a nontraditional risk factor of diabetes (16). Progressive pancreatic β-cell senescence and failure have been highlighted as early features of type 2 diabetes (17). β-Cell telomere shortening has been demonstrated to predict the risk of β-cell growth arrest and senescence in human adult islet cell cultures (18).

The study of Tentolouris et al. does not explain the inner mechanisms responsible for the short telomere length in microalbuminuric patients, and further studies may be useful to clarify the causes of this relationship. However, it surely arouses scientific interest to verify, as stated by Tenolouris et al., “the links between WBC telomere length and diseases of aging”. In fact, as mentioned above, cell senescence could be both a cause and a consequence of diabetes and its complications.

To date, solutions or therapies that may reverse this process can only be hypothesized. Even if cell-based models need to be translated into valid therapeutic strategies, potential therapeutic areas in this field are emerging. For instance, chemopreventive compounds that can decrease cell aldehyde load may counter some of the consequences of carbonyl stress (19), while a “causal” antioxidant therapy also deserves attention (20).

In conclusion, breaking the loop between diabetes and cell senescence by new defense methods against DNA oxidative damage seems to be an interesting path to explore for prevention of diabetes complications.

Footnotes

  • DIABETES CARE

References

  1. ↵
    Goldstein S: Replicative senescence: the human fibroblast comes of age. Science 249: 1129–1133, 1990
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Davis T, Wyllie FS, Rokicki MJ, Bagley MC, Kipling D: The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging. Ann N Y Acad Sci 1100: 455–469, 2007
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    Fadini GP, Sartore S, Agostini C, Avogaro A: Significance of endothelial progenitor cells in subjects with diabetes. Diabetes Care 30: 1305–1313, 2007
    OpenUrlFREE Full Text
  4. ↵
    Chen YH, Lin SJ, Lin FY, Wu TC, Tsao CR, Huang PH, Liu PL, Chen YL, Chen JW: High glucose impairs early and late endothelial progenitor cells by modifying nitric oxide–related but not oxidative stress–mediated mechanisms. Diabetes 56: 1559–1568, 2007
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    Liu JP: Studies of the molecular mechanisms in the regulation of telomerase activity. FASEB J 13: 2091–2104, 1999
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Saretzki G, Von Zglinicki T: Replicative aging, telomeres, and oxidative stress. Ann N Y Acad Sci 959: 24–29, 2002
    OpenUrlPubMedWeb of Science
  7. ↵
    Serrano AL, Andrés V: Telomeres and cardiovascular disease: does size matter? Circ Res 94: 575–584, 2004
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Fitzpatrick AL, Kronmal RA, Gardner JP, Psaty BM, Jenny NS, Tracy RP, Walston J, Kimura M, Aviv A: Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol 165: 14–21, 2007
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Aviv A: Telomeres and human aging: facts and fibs. Sci Aging Knowledge Environ 22: pe43, 2004
    OpenUrl
  10. ↵
    Sampson MJ, Hughes DA: Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes. Diabetologia 49: 1726–1731, 2006
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    Sampson MJ, Winterbone MS, Hughes JC, Dozio N, Hughes DA: Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care 29: 283–289, 2006
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Hayashi T, Matsui-Hirai H, Miyazaki-Akita A, Fukatsu A, Funami J, Ding QF, Kamalanathan S, Hattori Y, Ignarro LJ, Iguchi A: Endothelial cellular senescence is inhibited by nitric oxide: implications in atherosclerosis associated with menopause and diabetes. Proc Natl Acad Sci U S A 103: 17018–17023, 2006
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Tentolouris N, Nzietchueng R, Cattan V, Poitevin G, Lacolley P, Papazafiropoulou A, Perrea D, Katsilambros N, Benetos A: White blood cells telomere length is shorter in males with type 2 diabetes and microalbuminuria. Diabetes Care 30: 2909–2915, 2007
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Xu GW, Yao QH, Weng QF, Su BL, Zhang X, Xiong JH: Study of urinary 8-hydroxydeoxyguanosine as a biomarker of oxidative DNA damage in diabetic nephropathy patients. J Pharm Biomed Anal 36: 101–104, 2004
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    Pan HZ, Chang D, Feng LG, Xu FJ, Kuang HY, Lu MJ: Oxidative damage to DNA and its relationship with diabetic complications. Biomed Environ Sci 20: 160–163, 2007
    OpenUrlPubMed
  16. ↵
    Adaikalakoteswari A, Balasubramanyam M, Ravikumar R, Deepa R, Mohan V: Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy. Atherosclerosis 11 January 2007 [Epub ahead of print]
  17. ↵
    Masiello P: Animal models of type 2 diabetes with reduced pancreatic beta-cell mass. Int J Biochem Cell Biol 38: 873–893, 2006
    OpenUrlCrossRefPubMedWeb of Science
  18. ↵
    Halvorsen TL, Beattie GM, Lopez AD, Hayek A, Levine F: Accelerated telomere shortening and senescence in human pancreatic cells stimulated to divide in vitro. J Endocrinol 166: 103–109, 2000
    OpenUrlAbstract
  19. ↵
    Ellis EM: Reactive carbonyls and oxidative stress: potential for therapeutic intervention. Pharmacol Ther 115: 13–24, 2007
    OpenUrlCrossRefPubMed
  20. ↵
    Ceriello A: New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 26: 1589–1596, 2003
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top
Diabetes Care: 30 (11)

In this Issue

November 2007, 30(11)
  • 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.
Pathogenetic Loop Between Diabetes and Cell Senescence
(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
Pathogenetic Loop Between Diabetes and Cell Senescence
Roberto Testa, Antonio Ceriello
Diabetes Care Nov 2007, 30 (11) 2974-2975; DOI: 10.2337/dc07-1534

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

Pathogenetic Loop Between Diabetes and Cell Senescence
Roberto Testa, Antonio Ceriello
Diabetes Care Nov 2007, 30 (11) 2974-2975; DOI: 10.2337/dc07-1534
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
    • Footnotes
    • References
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Strategies to Reduce the Cost of Renal Complications in Patients With Type 2 Diabetes
  • Aiming at New Targets to Achieve Normoglycemia During Pregnancy
  • Metformin Therapy During Pregnancy
Show more Editorials

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.