The Effect of Dimethylbiguanide on Thrombin Activity, FXIII Activation, Fibrin Polymerization, and Fibrin Clot Formation
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The antihyperglycemic drug dimethylbiguanide (DMB, also known as metformin) reduces the risk of cardiovascular complications in type 2 diabetes, although the mechanism(s) involved are unclear. DMB reduces glycosylation-related protein cross-linking, a process similar to fibrin cross-linking catalyzed by activated factor XIII (FXIII). To investigate whether the cardioprotective effect of DMB could be related to effects on clot stabilization, we studied the effects of DMB on FXIII, thrombin activity, and cleavage of fibrin(ogen). Activity of purified and plasma FXIII was inhibited by DMB. Analysis by mass spectrometry and FXIII-coupled magnetic particles excluded binding of DMB to FXIII. Thrombin-induced cleavage of the activation peptide from FXIII was inhibited in a dose-dependent manner, as was fibrinopeptide cleavage from fibrinogen. Ancrod-induced cleavage of fibrinopeptide A was not affected. DMB prolonged clotting time of normal plasma. Fiber thickness and pore size of fibrin clots, measured by permeation experiments and visualized by scanning electron microscopy, decreased significantly with DMB. No interactions between DMB and the active site of thrombin were found. Turbidity experiments demonstrated that DMB changed polymerization and lateral aggregation of protofibrils. These results suggest that DMB interferes with FXIII activation and fibrin polymerization, but not only by binding to thrombin on a different location than the active site. In patients on DMB therapy, FXIII antigen and activity levels in vivo were reduced over a 12-week period. These findings indicate that part of the cardioprotective effect of DMB in patients with type 2 diabetes may be attributed to alterations in fibrin structure/function.
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Many different mechanisms beyond glycemic control have been implicated in vascular protection induced by metformin, including improvements in the inflammatory pathway, coagulation, oxidative stress and glycation, endothelial dysfunction, haemostasis, insulin resistance, lipid profiles, and fat redistribution.
“Many different mechanisms, beyond glycemic control, have been implicated in vascular protection induced by metformin such as improvements in the inflammatory pathway [86], coagulation [87], oxidative stress and glycation [88-92], endothelial dysfunction [88-90], haemostasis [88,91-93], insulin resistance improvement [94], lipid profiles [95,96], and fat redistribution [97,98].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [92]
Metformin has direct effects on fibrin structure and function by decreasing factor XIII activity and changing fibrin structure.
“It has also direct effects on fibrin structure and function by decreasing factor XIII activity and changing fibrin structure [92].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [92]
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Metformin: An Old But Still the Best Treatment for Type 2 Diabetes
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- Authors
- Standeven, K. F., Ariëns, R. A. S., Whitaker, P., Ashcroft, A. E., Weisel, J. W., & Grant, P. J.
- Affiliations
- University of Leeds (GB)
- Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds, U.K.
- University of Pennsylvania (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-01-01
- Volume
- 51
- Issue
- 1
- Pages
- 189-197
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2140616436
- Cited by
- 106
- References
- 38
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 8 · 2022: 4 · 2021: 8 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 6 · 2012: 5
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- British Heart Foundation (PG/98104)
- National Institutes of Health
- Medical Research Council (G9900904)
- National Heart, Lung, and Blood Institute (R01HL030954, HL30954)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Trauma, Hemostasis, Coagulopathy, Resuscitation
- Keywords
- metformin, factor XIII activation, thrombin, fibrin polymerization, fibrin clot formation, fibrin cross-linking, glycosylation, type 2 diabetes, cardioprotection, anticoagulant activity, fibrin structure
- MeSH terms
- Blood Coagulation, Cardiotonic Agents, Diabetic Angiopathies, Enzyme Activation, Factor XIII, Fibrin, Fibrinogen, Humans, Hypoglycemic Agents, Kinetics, Metformin, Thrombin
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