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

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • New and Noteworthy
    • Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Special Collections
    • Recent ADA Position Statements
  • Info
    • About the Journal
    • Meet the Editors
    • Reprints & Permissions
    • Journal Policies
    • For Authors
    • For Reviewers
    • For Advertisers
  • Subscriptions
    • Manage Online Access
    • Individual Subscriptions
    • Institutional Subscriptions
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Diabetes Discovery
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • Standards of Medical Care
    • Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • New and Noteworthy
    • Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Special Collections
    • Recent ADA Position Statements
  • Info
    • About the Journal
    • Meet the Editors
    • Reprints & Permissions
    • Journal Policies
    • For Authors
    • For Reviewers
    • For Advertisers
  • Subscriptions
    • Manage Online Access
    • Individual Subscriptions
    • Institutional Subscriptions
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Diabetes Discovery
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • Peer Review
Letters: Observations

Plasma Total Homocysteine Levels Are Associated With von Willebrand Factor, Soluble Intercellular Adhesion Molecule-1, and Soluble Tumor Necrosis Factor-α Receptors in Young Type 1 Diabetic Patients Without Clinical Evidence of Macrovascular Complications

  1. Giovanni Targher, MD12,
  2. Luciano Zenari, MD1,
  3. Lorenzo Bertolini, MD1,
  4. Giancarlo Falezza, MD1,
  5. Michele Muggeo, MD2 and
  6. Giacomo Zoppini, MD2
  1. 1Diabetes Unit, Sacro Cuore Hospital of Negrar, Negrar
  2. 2Division of Endocrinology and Metabolic Diseases, University of Verona Medical School, Verona, Italy
    Diabetes Care 2001 Aug; 24(8): 1496-1497. https://doi.org/10.2337/diacare.24.8.1496-a
    PreviousNext
    • Article
    • Info & Metrics
    • PDF
    Loading

    Elevated plasma total homocysteine (tHcy) levels are a powerful risk factor for atherosclerotic vascular disease (1), but it is still unclear by which pathophysiological mechanisms tHcy may promote atherothrombosis. In both experimental animal and cell culture studies (2,3), acute hyperhomocysteinemia induces endothelial dysfunction, leading to a low-grade inflammatory state that results in increased leukocyte adherence by upregulation of cell adhesion molecules. Accordingly, an impaired endothelium-dependent flow-mediated dilation was found in nondiabetic subjects with high tHcy when compared with subjects with low tHcy levels (4). In a recent cross-sectional study (5) of both nondiabetic individuals and type 2 diabetic subjects, tHcy was significantly associated with endothelial dysfunction, as estimated from plasma von Willebrand factor (vWF), and with leukocyte adhesion, as estimated from plasma vascular cell adhesion molecule-1. To our knowledge, there is a lack of available data regarding the relationships of tHcy levels with plasma markers of endothelial dysfunction and inflammation in young type 1 diabetic adults. It has been reported in only one previous study (6) that type 1 diabetic patients with higher tHcy levels compared with patients with lower tHcy levels had significantly elevated soluble thrombomodulin, a marker of endothelial function. However, because the group of patients with higher tHcy also had a significantly increased prevalence of microvascular and macrovascular complications, these results should be interpreted with some degree of caution. We have previously demonstrated that young type 1 diabetic patients have significantly higher tHcy levels than healthy control subjects and that smoking itself may be one of the major lifestyle determinants of tHcy (7). In this study, we endeavored to evaluate a selected group of 36 (16 men and 20 women) lean (BMI 23.6 ± 0.5 kg/m2), nonsmoking, normotensive (systolic/diastolic blood pressure 125 ± 2/80 ± 1 mmHg), normolipidemic (total cholesterol and triglycerides 4.6 ± 0.1 and 0.92 ± 0.1 mmol/l, respectively), young (age 31 ± 1 year) type 1 diabetic adults who were without any clinical evidence of macrovascular complications. Their average glycometabolic control was good (HbA1c 6.6 ± 0.2%), and their average duration of diabetes was 15 ± 1 years. To exclude the presence of clinical macroangiopathy, a 12-lead resting electrocardiogram, a measurement of the ankle brachial pressure index, and carotid ultrasonography were performed in all of the diabetic patients. We measured plasma levels of tHcy (by an automated high-performance liquid chromatography analyzer with fluorescence detection) (7) and fibrinogen (IL-test-PT-fibrinogen HS; Instrumentation Laboratory, Lexington, KY). By using commercially available enzyme-linked immunosorbent assay kits, we measured interleukin-6 (IL-6), vWF, soluble intercellular adhesion molecule-1 (sICAM-1), P-selectin, and soluble tumor necrosis factor (TNF)-α receptors (i.e., sTNF-R1 and sTNF-R2), which reflect the degree of TNF-α activation more accurately than the measurement of TNF-α itself. The tHcy levels were significantly associated with sICAM-1 (r = 0.34, P < 0.05), vWF (r = 0.45, P < 0.01), and sTNF-R1 (r = 0.56, P < 0.001). The adjustment for potential confounders did not modify these results. The tHcy levels did not significantly correlate with fibrinogen, IL-6, P-selectin, or sTNF-R2 levels. Similarly, when diabetic patients were subdivided into groups according to the median value of the distribution of tHcy, the two groups were comparable for age, sex, BMI, lipids, creatinine, blood pressure, glycometabolic control, diabetes duration, and microvascular complications (i.e., retinopathy and/or microalbuminuria). Nevertheless, plasma levels of sICAM-1 (273 ± 11 vs. 241 ± 7 ng/ml), vWF (122 ± 8 vs. 91 ± 8%), and sTNF-R1 (2.0 ± 0.2 vs. 1.5 ± 0.1 ng/ml) were markedly elevated (P < 0.05 or less) in patients with higher tHcy (n = 18, 12.7 ± 0.8 μmol/l) versus lower tHcy levels (n = 18, 8.8 ± 0.2 μmol/l). Fibrinogen concentration tended to be higher in patients with higher tHcy (3.53 ± 0.3 vs. 3.06 ± 0.1 g/l, P = 0.08) but did not achieve statistical significance. No significant differences were found in IL-6, P-selectin, and sTNF-R2 levels between the two groups.

    Overall, therefore, these results indicate that in nonsmoking, normotensive, normolipidemic young type 1 diabetic adults with good glycometabolic control and without any clinical evidence of macrovascular complications, there is a significant relationship between tHcy and plasma markers of endothelial dysfunction and inflammation. Although this study is cross-sectional and therefore cannot prove a direct cause-and-effect relationship, our results extend previous observations in nondiabetic and type 2 diabetic individuals, supporting the hypothesis that the pathophysiological link between tHcy and atherothrombosis can, at least in part, be explained by endothelial dysfunction, which leads to an increased endothelial adherence of leukocytes and a low-level chronic inflammatory state.

    Footnotes

    • Address correspondence to Giovanni Targher, MD, Servizio di Diabetologia, Ospedale Sacro Cuore, Via Sempreboni, 5, 37024 Negrar (VR), Italy. E-mail: targher{at}sacrocuore.it.

    References

    1. ↵
      Hankey GJ, Eikelboom JW: Homocysteine and vascular disease. Lancet 354:407–413, 1999
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      Pruefer D, Scalia R, Lefer AM: Homocysteine provokes leukocyte-endothelium interaction by down-regulation of nitric oxide. Gen Pharmacol 33:487–498, 1999
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf MR, Tanji N, Ferran LJ, Kohl B, Rao V, Kisiel W, Stern DM, Schmidt AM: Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 107:675–683, 2001
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      Woo KS, Chook P, Lolin YI, Cheung ASP, Chan LT, Sun YY, Sanderson JE, Metreweli C, Celermajer DS: Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation 96:2542–2544, 1997
      OpenUrlAbstract/FREE Full Text
    5. ↵
      Becker A, Van Hinsbergh VW, Kostense PJ, Jager A, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD: Serum homocysteine is weakly associated with von Willebrand factor and soluble vascular cell adhesion molecule 1, but not with C-reactive protein in type 2 diabetic and non-diabetic subjects: the Hoorn Study. Eur J Clin Invest 30:763–770, 2000
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      Hofmann MA, Kohl B, Zumbach MS, Borcea V, Bierhaus A, Henkels M, Amiral J, Fiehn W, Ziegler R, Wahl P, Nawroth PP: Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM. Diabetes Care 20:1880–1886, 1997
      OpenUrlAbstract/FREE Full Text
    7. ↵
      Targher G, Bertolini L, Zenari L, Cacciatori V, Muggeo M, Faccini G, Zoppini G: Cigarette smoking and plasma total homocysteine levels in young adults with type 1 diabetes. Diabetes Care 23:524–528, 2000
      OpenUrlAbstract
    View Abstract
    PreviousNext
    Back to top
    Diabetes Care: 24 (8)

    In this Issue

    August 2001, 24(8)
    • 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.
    Plasma Total Homocysteine Levels Are Associated With von Willebrand Factor, Soluble Intercellular Adhesion Molecule-1, and Soluble Tumor Necrosis Factor-α Receptors in Young Type 1 Diabetic Patients Without Clinical Evidence of Macrovascular Complications
    (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.
    Citation Tools
    Plasma Total Homocysteine Levels Are Associated With von Willebrand Factor, Soluble Intercellular Adhesion Molecule-1, and Soluble Tumor Necrosis Factor-α Receptors in Young Type 1 Diabetic Patients Without Clinical Evidence of Macrovascular Complications
    Giovanni Targher, Luciano Zenari, Lorenzo Bertolini, Giancarlo Falezza, Michele Muggeo, Giacomo Zoppini
    Diabetes Care Aug 2001, 24 (8) 1496-1497; DOI: 10.2337/diacare.24.8.1496-a

    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

    Plasma Total Homocysteine Levels Are Associated With von Willebrand Factor, Soluble Intercellular Adhesion Molecule-1, and Soluble Tumor Necrosis Factor-α Receptors in Young Type 1 Diabetic Patients Without Clinical Evidence of Macrovascular Complications
    Giovanni Targher, Luciano Zenari, Lorenzo Bertolini, Giancarlo Falezza, Michele Muggeo, Giacomo Zoppini
    Diabetes Care Aug 2001, 24 (8) 1496-1497; DOI: 10.2337/diacare.24.8.1496-a
    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

    • Weight Gain and Gestational Diabetes Mellitus Is a Sensitive Issue
    • Beneficial Effects of a 4-Week Exercise Program on Plasma Concentrations of Adhesion Molecules
    • Malignant Melanoma Misdiagnosed as a Diabetic Foot Ulcer
    Show more Letters: Observations

    Similar Articles

    Navigate

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

     

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

    © 2018 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.