Charité Centrum 11, Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.
Herz und Diabeteszentrum NRW, Ruhr Universität Bochum, Bad Oeynhausen, Germany.
Cardiovasc Drugs Ther. 2021 Aug;35(4):809-813. doi: 10.1007/s10557-020-07040-7. Epub 2020 Sep 17.
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.
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.
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.
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.
二甲双胍是一线抗糖尿病药物，已被证明可独立于其降血糖作用降低心血管风险。特别是在控制不佳的糖尿病中，组织因子 (TF) 在血管中表达，并导致血栓栓塞并发症。在这里，我们旨在评估二甲双胍对控制不佳的 2 型糖尿病患者 TF 活性和血管炎症标志物的影响。
在一组未控制的 2 型糖尿病患者（糖化血红蛋白 8.39±0.24%，68.1±2.6mmol/mol，n=46）中，其中一半患者接受二甲双胍治疗，另一半患者未接受作为联合抗糖尿病治疗的一部分的二甲双胍治疗，我们评估了 TF 活性和血管炎症标志物。在体外，将人单核细胞 (THP-1) 暴露于二甲双胍中，并在存在和不存在 AMP 激活蛋白激酶 (AMPK) 激活剂 5-氨基咪唑-4-甲酰胺核苷 (AICAR) 或 AMPK 抑制剂化合物 C 的情况下测量 TF 表达。
与对照组相比，接受二甲双胍治疗的患者 TF 蛋白水平（241.5±19 与 315.4±25pg/mL，p=0.03）和 TF 活性（408.9±49 与 643.8±47U/mL，p=0.001）均较低。此外，接受二甲双胍治疗的患者血管细胞黏附分子 (VCAM)1 水平较低（26.6±1.4 与 35.03±3.1ng/mL，p=0.014），miR-126-3p/U6sno 表达较高（11.39±2.8 与 4.26±0.9，p=0.006），miR-126-3p/U6sno 是 TF 和 VCAM1 的已知转录后下调因子。在体外，二甲双胍剂量依赖性地降低了脂多糖 (LPS) 诱导的 THP-1 细胞中 TF 的表达。AMPK 激活剂 AICAR 单独降低了 THP-1 中的 TF 表达，而 AMPK 抑制剂化合物 C 阻断了二甲双胍依赖性 TF 表达的降低。
我们的数据首次报道，二甲双胍与降低血浆 TF 促凝活性有关，这可能至少部分解释了二甲双胍的血管保护特性。
