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Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes

PURPOSE: Metformin is the first-line antidiabetic drug and shown to reduce cardiovascular risk independent from its glucose lowering action. Particularly in poorly controlled diabetes, tissue factor (TF) is expressed in the vasculature and accounts for thromboembolic complications. Here, we aimed to...

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Autores principales: Witkowski, Marco, Friebel, Julian, Tabaraie, Termeh, Grabitz, Sinah, Dörner, Andrea, Taghipour, Lena, Jakobs, Kai, Stratmann, Bernd, Tschoepe, Diethelm, Landmesser, Ulf, Rauch, Ursula
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266708/
https://www.ncbi.nlm.nih.gov/pubmed/32940892
http://dx.doi.org/10.1007/s10557-020-07040-7
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author Witkowski, Marco
Friebel, Julian
Tabaraie, Termeh
Grabitz, Sinah
Dörner, Andrea
Taghipour, Lena
Jakobs, Kai
Stratmann, Bernd
Tschoepe, Diethelm
Landmesser, Ulf
Rauch, Ursula
author_facet Witkowski, Marco
Friebel, Julian
Tabaraie, Termeh
Grabitz, Sinah
Dörner, Andrea
Taghipour, Lena
Jakobs, Kai
Stratmann, Bernd
Tschoepe, Diethelm
Landmesser, Ulf
Rauch, Ursula
author_sort Witkowski, Marco
collection PubMed
description PURPOSE: Metformin is the first-line antidiabetic drug and shown to reduce cardiovascular risk independent from its glucose lowering action. Particularly in poorly controlled diabetes, tissue factor (TF) is expressed in the vasculature and accounts for thromboembolic complications. Here, we aimed to assess the effect of metformin on TF activity and markers of vascular inflammation in poorly controlled type 2 diabetes. METHODS: In a cohort of patients with uncontrolled type 2 diabetes (glycosylated hemoglobin 8.39 ± 0.24%, 68.1 ± 2.6 mmol/mol, n = 46) of whom half of the individuals were treated with metformin and the other half did not receive metformin as part of an anti-diabetic combination therapy, we assessed TF activity and markers of vascular inflammation. In vitro, human monocytic cells (THP-1) were exposed to metformin and TF expression measured in the presence and absence of the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide riboside (AICAR) or the AMPK inhibitor compound C. RESULTS: In the patients, metformin treatment was associated with lower levels of TF protein (241.5 ± 19 vs. 315.4 ± 25 pg/mL, p = 0.03) and reduced TF activity (408.9 ± 49 vs. 643.8 ± 47 U/mL, p = 0.001) compared with controls. Moreover, the patients on metformin showed lower levels of vascular cell adhesion molecule (VCAM)1 (26.6 ± 1.4 vs. 35.03 ± 3.1 ng/mL, p = 0.014) and higher expression of miR-126-3p/U6sno (11.39 ± 2.8 vs. 4.26 ± 0.9, p = 0.006), a known post-transcriptional down regulator of TF and VCAM1. In vitro, metformin dose-dependently reduced lipopolysaccharide (LPS)-induced TF expression in THP-1 cells. The AMPK activator AICAR alone lowered TF expression in THP-1, while the AMPK inhibitor compound C abrogated the metformin-dependent reduction in TF expression. CONCLUSIONS: Our data are the first to report that metformin is associated with reduced plasma TF procoagulant activity possibly explaining—at least in part—the vasculoprotective properties of metformin. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10557-020-07040-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-82667082021-07-20 Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes Witkowski, Marco Friebel, Julian Tabaraie, Termeh Grabitz, Sinah Dörner, Andrea Taghipour, Lena Jakobs, Kai Stratmann, Bernd Tschoepe, Diethelm Landmesser, Ulf Rauch, Ursula Cardiovasc Drugs Ther Short Communication PURPOSE: Metformin is the first-line antidiabetic drug and shown to reduce cardiovascular risk independent from its glucose lowering action. Particularly in poorly controlled diabetes, tissue factor (TF) is expressed in the vasculature and accounts for thromboembolic complications. Here, we aimed to assess the effect of metformin on TF activity and markers of vascular inflammation in poorly controlled type 2 diabetes. METHODS: In a cohort of patients with uncontrolled type 2 diabetes (glycosylated hemoglobin 8.39 ± 0.24%, 68.1 ± 2.6 mmol/mol, n = 46) of whom half of the individuals were treated with metformin and the other half did not receive metformin as part of an anti-diabetic combination therapy, we assessed TF activity and markers of vascular inflammation. In vitro, human monocytic cells (THP-1) were exposed to metformin and TF expression measured in the presence and absence of the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide riboside (AICAR) or the AMPK inhibitor compound C. RESULTS: In the patients, metformin treatment was associated with lower levels of TF protein (241.5 ± 19 vs. 315.4 ± 25 pg/mL, p = 0.03) and reduced TF activity (408.9 ± 49 vs. 643.8 ± 47 U/mL, p = 0.001) compared with controls. Moreover, the patients on metformin showed lower levels of vascular cell adhesion molecule (VCAM)1 (26.6 ± 1.4 vs. 35.03 ± 3.1 ng/mL, p = 0.014) and higher expression of miR-126-3p/U6sno (11.39 ± 2.8 vs. 4.26 ± 0.9, p = 0.006), a known post-transcriptional down regulator of TF and VCAM1. In vitro, metformin dose-dependently reduced lipopolysaccharide (LPS)-induced TF expression in THP-1 cells. The AMPK activator AICAR alone lowered TF expression in THP-1, while the AMPK inhibitor compound C abrogated the metformin-dependent reduction in TF expression. CONCLUSIONS: Our data are the first to report that metformin is associated with reduced plasma TF procoagulant activity possibly explaining—at least in part—the vasculoprotective properties of metformin. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10557-020-07040-7) contains supplementary material, which is available to authorized users. Springer US 2020-09-17 2021 /pmc/articles/PMC8266708/ /pubmed/32940892 http://dx.doi.org/10.1007/s10557-020-07040-7 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Short Communication
Witkowski, Marco
Friebel, Julian
Tabaraie, Termeh
Grabitz, Sinah
Dörner, Andrea
Taghipour, Lena
Jakobs, Kai
Stratmann, Bernd
Tschoepe, Diethelm
Landmesser, Ulf
Rauch, Ursula
Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes
title Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes
title_full Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes
title_fullStr Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes
title_full_unstemmed Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes
title_short Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes
title_sort metformin is associated with reduced tissue factor procoagulant activity in patients with poorly controlled diabetes
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266708/
https://www.ncbi.nlm.nih.gov/pubmed/32940892
http://dx.doi.org/10.1007/s10557-020-07040-7
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