OBJECTIVE In patients with diabetes mellitus, increased platelet reactivity predicts cardiac events. Limited evidence suggests that DPP-4 (dipeptidyl peptidase 4) influences platelets via GLP-1 (glucagon-like peptide 1)-dependent effects. Because DPP-4 inhibitors are frequently used in diabetes mellitus to improve the GLP-1-regulated glucose metabolism, we characterized the role of DPP-4 inhibition and of native intact versus DPP-4-cleaved GLP-1 on flow-dependent thrombus formation in mouse and human blood. Approach and Results: An ex vivo whole blood microfluidics model was applied to approach in vivo thrombosis and study collagen-dependent platelet adhesion, activation, and thrombus formation under shear-flow conditions by multiparameter analyses. In mice, in vivo inhibition or genetic deficiency of DPP-4 (Dpp4-/-), but not of GLP-1-receptors (Glp1r-/-), suppressed flow-dependent platelet aggregation. In human blood, GLP-1(7-36), but not DPP-4-cleaved GLP-1(9-36), reduced thrombus volume by 32% and impaired whole blood thrombus formation at both low/venous and high/arterial wall-shear rates. These effects were enforced upon ADP costimulation and occurred independently of plasma factors and leukocytes. Human platelets did not contain detectable levels of GLP-1-receptor transcripts. Also, GLP-1(7-36) did not inhibit collagen-induced aggregation under conditions of stirring or stasis of platelets, pointing to a marked flow-dependent role. CONCLUSIONS Native, intact GLP-1 is a natural suppressor of thrombus growth under physiological flow conditions, with DPP-4 inhibition and increased intact GLP-1 suppressing platelet aggregation under flow without a main relevance of GLP-1-receptor on platelets.

中文翻译：

---

天然，完整的胰高血糖素样肽1是生理流条件下血栓生长的天然抑制剂。

目的在糖尿病患者中，血小板反应性增加预示心脏事件。有限的证据表明DPP-4（二肽基肽酶4）通过GLP-1（胰高血糖素样肽1）依赖性作用影响血小板。由于DPP-4抑制剂经常用于糖尿病中以改善GLP-1调节的葡萄糖代谢，因此我们表征了DPP-4抑制作用和天然完整与DPP-4裂解的GLP-1在流量依赖性血栓形成中的作用。在老鼠和人类的血液中。方法和结果：采用体外全血微流模型研究体内血栓形成，并通过多参数分析研究剪切流条件下胶原依赖性血小板粘附，活化和血栓形成。在小鼠体内，DPP-4（Dpp4-/-）的体内抑制作用或基因缺陷，但不是GLP-1受体（Glp1r-/-）抑制了流量依赖性血小板聚集。在人的血液中，GLP-1（7-36），而不是DPP-4裂解的GLP-1（9-36），在低/静脉和高/动脉血栓形成中将血栓量减少了32％，并损害了全血血栓形成墙剪率。这些效应在ADP共刺激时得以增强，并且独立于血浆因子和白细胞而发生。人血小板不含有可检测水平的GLP-1受体转录物。同样，GLP-1（7-36）在血小板搅拌或停滞的条件下也不能抑制胶原蛋白诱导的聚集，这表明其具有明显的血流依赖性。结论天然，完整的GLP-1是生理流条件下血栓生长的天然抑制剂，