Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes
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SHORT COMMUNICATION
Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes Marco Witkowski 1 & Julian Friebel 1 & Termeh Tabaraie 1 & Sinah Grabitz 1 & Andrea Dörner 1 & Lena Taghipour 1 & Kai Jakobs 1 & Bernd Stratmann 2 & Diethelm Tschoepe 2 & Ulf Landmesser 1 & Ursula Rauch 1 Accepted: 15 July 2020 # The Author(s) 2020
Abstract 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. Keywords Metformin . diabetes mellitus . coagulation . tissue factor . vascular inflammation . thrombosis . microRNA . vascular complications . cardiovascular disease
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10557-020-07040-7) contains supplementary material, which is available to authorized users. * Ursula Rauch [email protected] 1
Charité Centrum 11, Department of Cardiology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
2
Herz und Diabeteszentrum NRW, Ruhr Universität Bochum, Bad Oeynhausen, Germany
Being presc
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