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

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • 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
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • 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
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Commentaries

Nonesterified Fatty Acids, Albumin, and Platelet Aggregation

  1. Sandeep Dhindsa1⇑,
  2. Husam Ghanim2 and
  3. Paresh Dandona2
  1. 1Division of Endocrinology and Metabolism, Texas Tech University Health Sciences Center, Permian Basin Campus, Odessa, TX
  2. 2Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo and Kaleida Health, Diabetes and Endocrinology Center of Western New York, Buffalo, NY
  1. Corresponding author: Sandeep Dhindsa, sandeep.dhindsa{at}ttuhsc.edu.
Diabetes 2015 Mar; 64(3): 703-705. https://doi.org/10.2337/db14-1481
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

It has been known for five decades that nonesterified fatty acids (NEFAs) have a role in the activation of platelets and thrombosis. Thus, the infusion of NEFAs leads to massive thrombosis and platelet activation (1–4). It has also been shown that their binding to albumin protects the platelets from activation (5). Thus, it follows that a fall in the concentrations of albumin, as in the nephrotic syndrome, would potentially lead to platelet activation. This has been demonstrated in several studies (6). Similarly, any condition that leads to an increase in NEFAs or a decrease in plasma albumin concentrations or a combination of the two would contribute to platelet hyperactivity. Insulin is a potent antilipolytic hormone and thus insulin-resistant states are characterized by accelerated lipolysis and increased NEFA concentrations. This promotes platelet aggregation. In addition, elevated NEFA concentrations interfere with insulin signal transduction and induce insulin resistance (7). NEFAs also induce oxidative and inflammatory stress (8) and thus activate monocytes, which express the prothrombotic tissue factor (TF) on their cell membranes (9). TF activates the extrinsic pathway of thrombin generation and hence may precipitate thrombosis. Activated platelets in patients with diabetes and peripheral vascular disease also release 5-hydroxytryptamine (5-HT), which leads to an increase in plasma 5-HT concentrations, which in turn promotes further vasoconstriction causing further platelet hyperaggregability (10).

It is also important to emphasize the fact that as increased NEFAs induce insulin resistance, the action of insulin at the cellular and molecular level would also be reduced. Insulin exerts a potent antiplatelet effect (11), and the presence of insulin resistance would potentially enhance platelet aggregation. The antiplatelet effect of insulin is mediated by nitric oxide (NO) generated by intraplatelet NO synthase (12). Reactive oxygen species generated by the action of NEFAs would oxidize NO to its metabolites, peroxynitrite, NO2, and NO3. These actions of NEFA have already been shown to impair flow-mediated vascular dilation within 2 h of their infusion (8). In addition, it has been shown that an increase in NEFA concentrations and a decrease in albumin concentrations reduce the stability of prostacyclin generated by the endothelium (13), which is a potent inhibitor of platelet aggregation and modulates platelet activity in the circulation. In addition, vascular ADPase activity, which inhibits ADP-induced platelet aggregation, is also inhibited by NEFAs (14). Thus, two potent antiplatelet modulators from vascular tissue are inhibited by NEFAs. NEFAs also inhibit prostacyclin production by aortic segments in vitro (15). In these three aspects, unsaturated fatty acids exert a significantly greater effect than saturated fatty acids.

Following the demonstration that NEFAs induce oxidative and inflammatory stress, it was also shown that an infusion of NEFA results in a hypertensive effect (16). Such an effect would promote atherogenesis. Thus, NEFAs induce several effects detrimental to platelet function and cardiovascular health.

It is in the context of these previous observations that Blache et al. (17) have now investigated the paradigm that the glycation or glycoxidation of albumin is relevant to NEFA-related pathophysiology as such modifications of albumin would potentially result in an impaired binding to NEFAs and an increase in unbound NEFAs and thus to platelet hyperactivity. The authors have shown that glycation of albumin induced in vitro with glucose or methylglyoxal, an advanced glycation end product, leads to a reduction in the binding of NEFA to albumin; these changes were similar to those observed in albumin prepared from patients with diabetes. The NEFA binding capacity of albumin isolated from patients with diabetes was lower by 32%. In addition, there were similarities in structural changes induced in vitro to those observed in albumin obtained from patients with diabetes, as analyzed with sophisticated fluorescence techniques.

An increase in NEFA concentrations promotes the oxidation of the Cys34 in the albumin molecule and consequent reduction of albumin’s antioxidant capacity, which leads to a further decrease in NEFA binding sites and the activation of platelets. Such activated platelets lead to a greater release of arachidonic acid (AA) and its metabolites, cyclooxygenase and lipoxygenase products, after stimulation and thus result in a greater magnitude of aggregatory response to AA. Blache et al. studied the ability of albumin isolated from patients with type 2 diabetes or that of modified albumin (by glucose or methylglyoxal) to inhibit thrombin-induced platelet aggregation. In both the cases, the ability of albumin to block platelet aggregation was reduced by ∼50% as compared with normal albumin. It is likely that the ability of modified albumin to sequester platelet-derived NEFAs, such as AA, is diminished, thus accounting for its decreased ability to inhibit platelet aggregation.

It is important to note that the mean HbA1c of patients in the study by Blache et al. was 9.3 ± 1.4%. For the in vitro experiments, albumin was modified after incubation with very high glucose concentrations (25 mmol/L). It is not clear if the study results will be applicable to patients with diabetes with a lesser degree of hyperglycemia or in patients with prediabetes. Studies in those populations will be needed to ascertain if albumin is modified to a significant degree and has lower NEFA binding capacity.

Thus, there are multiple mechanisms that may predispose patients with diabetes to a prothrombotic state (Fig. 1). Clearly, an increase in NEFA concentrations promotes platelet aggregation and thus contributes to the prothrombotic state in diabetes. Albumin concentrations also play a cardinal role in the regulation of unbound NEFAs, including platelet-derived AA, and thus a concomitant fall in albumin concentrations enhances the proaggregatory and prothrombotic milieu characterizing diabetes. In addition, the effect of NEFAs on oxidative and inflammatory stress is also proatherogenic.

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Role of NEFAs in prothrombotic state in insulin resistance and diabetes. eNOS, endothelial nitric oxide synthase.

Article Information

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Footnotes

  • See accompanying article, p. 960.

  • © 2015 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.

References

  1. ↵
    1. Connor WE,
    2. Hoak JC,
    3. Warner ED
    . Massive thrombosis produced by fatty acid infusion. J Clin Invest 1963;42:860–866pmid:14022629
    OpenUrlCrossRefPubMedWeb of Science
    1. Hoak JC,
    2. Warner ED,
    3. Connor WE
    . Platelets, fatty acids and thrombosis. Circ Res 1967;20:11–17pmid:4959657
    OpenUrlAbstract/FREE Full Text
    1. Hoak JC,
    2. Spector AA,
    3. Fry GL,
    4. Warner ED
    . Effect of free fatty acids on ADP-induced platelet aggregation. Nature 1970;228:1330–1332pmid:5488112
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. Burstein Y,
    2. Berns L,
    3. Heldenberg D,
    4. Kahn Y,
    5. Werbin BZ,
    6. Tamir I
    . Increase in platelet aggregation following a rise in plasma free fatty acids. Am J Hematol 1978;4:17–22pmid:655154
    OpenUrlCrossRefPubMed
  3. ↵
    1. Nordøy A
    . Albumin-bound fatty acids, platelets and endothelial cells in thrombogenesis. Haemostasis 1979;8:193–202pmid:511009
    OpenUrlPubMed
  4. ↵
    1. Barbano B,
    2. Gigante A,
    3. Amoroso A,
    4. Cianci R
    . Thrombosis in nephrotic syndrome. Semin Thromb Hemost 2013;39:469–476pmid:23625754
    OpenUrlCrossRefPubMed
  5. ↵
    1. Boden G,
    2. Lebed B,
    3. Schatz M,
    4. Homko C,
    5. Lemieux S
    . Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 2001;50:1612–1617pmid:11423483
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Tripathy D,
    2. Mohanty P,
    3. Dhindsa S, et al
    . Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003;52:2882–2887pmid:14633847
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Mach F,
    2. Schönbeck U,
    3. Bonnefoy JY,
    4. Pober JS,
    5. Libby P
    . Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation 1997;96:396–399pmid:9244201
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Barradas MA,
    2. Gill DS,
    3. Fonseca VA,
    4. Mikhailidis DP,
    5. Dandona P
    . Intraplatelet serotonin in patients with diabetes mellitus and peripheral vascular disease. Eur J Clin Invest 1988;18:399–404pmid:3139426
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    1. Trovati M,
    2. Anfossi G,
    3. Cavalot F,
    4. Massucco P,
    5. Mularoni E,
    6. Emanuelli G
    . Insulin directly reduces platelet sensitivity to aggregating agents. Studies in vitro and in vivo. Diabetes 1988;37:780–786pmid:2838353
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Trovati M,
    2. Anfossi G,
    3. Massucco P, et al
    . Insulin stimulates nitric oxide synthesis in human platelets and, through nitric oxide, increases platelet concentrations of both guanosine-3′, 5′-cyclic monophosphate and adenosine-3′, 5′-cyclic monophosphate. Diabetes 1997;46:742–749pmid:9133539
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Mikhailidis DP,
    2. Mikhailidis AM,
    3. Barradas MA,
    4. Dandona P
    . Effect of nonesterified fatty acids on the stability of prostacyclin activity. Metabolism 1983;32:717–721pmid:6345992
    OpenUrlCrossRefPubMedWeb of Science
  12. ↵
    1. Barradas MA,
    2. Mikhailidis DP,
    3. Dandona P
    . The effect of non-esterified fatty acids on vascular ADP-degrading enzyme activity. Diabetes Res Clin Pract 1987;3:9–19pmid:3028742
    OpenUrlCrossRefPubMed
  13. ↵
    1. Jeremy JY,
    2. Mikhailidis DP,
    3. Dandona P
    . Simulating the diabetic environment modifies in vitro prostacyclin synthesis. Diabetes 1983;32:217–221pmid:6337900
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Umpierrez GE,
    2. Smiley D,
    3. Robalino G, et al
    . Intravenous intralipid-induced blood pressure elevation and endothelial dysfunction in obese African-Americans with type 2 diabetes. J Clin Endocrinol Metab 2009;94:609–614pmid:19001516
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    1. Blache D,
    2. Bourdon E,
    3. Salloignon P, et al
    . Glycated albumin with loss of fatty acid binding capacity contributes to enhanced arachidonate oxygenation and platelet hyperactivity: relevance in patients with type 2 diabetes. Diabetes 2015;64:960–972pmid:25157094
    OpenUrlAbstract/FREE Full Text
View Abstract
PreviousNext
Back to top
Diabetes: 64 (3)

In this Issue

March 2015, 64(3)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
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.

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.
Nonesterified Fatty Acids, Albumin, and Platelet Aggregation
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Nonesterified Fatty Acids, Albumin, and Platelet Aggregation
Sandeep Dhindsa, Husam Ghanim, Paresh Dandona
Diabetes Mar 2015, 64 (3) 703-705; DOI: 10.2337/db14-1481

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

Nonesterified Fatty Acids, Albumin, and Platelet Aggregation
Sandeep Dhindsa, Husam Ghanim, Paresh Dandona
Diabetes Mar 2015, 64 (3) 703-705; DOI: 10.2337/db14-1481
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
    • Article Information
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Adipose Tissue Malfunction Drives Metabolic Dysfunction in Alström Syndrome
  • Staying Connected: Transcriptomics in the Search for Novel Diabetic Kidney Disease Treatments
  • Going in Early: Hypoxia as a Target for Kidney Disease Prevention in Diabetes?
Show more Commentaries

Similar Articles

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • 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 Care
  • 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 Print ISSN: 0012-1797, Online ISSN: 1939-327X.