Nordt T K, Peter K, Bode C, Sobel B E
Department of Internal Medicine III, University of Freiburg Medical School, Germany.
J Clin Endocrinol Metab. 2000 Apr;85(4):1563-8. doi: 10.1210/jcem.85.4.6525.
Troglitazone, a novel oral insulin sensitizer, normalizes increased plasma activity of plasminogen activator inhibitor type 1 (PAI-1) in hyperinsulinemic patients such as women with polycystic ovary syndrome and patients with type 2 diabetes mellitus. However, underlying mechanisms have not yet been fully elucidated. Human hepatic and vascular cells, the main sources of circulating PAI-1, were studied in cell culture. In human hepatic cells, PAI-1 accumulated in conditioned medium by 23% within 24 h after exposure to 3 microg/mL troglitazone (P = 0.001). The accumulation depended on the concentration of troglitazone, but not that of insulin (known to stimulate PAI-1 synthesis). By contrast, in human aortic smooth muscle cells, 3 microg/mL troglitazone decreased basal PAI-1 expression by 23% (P = 0.037) and decreased transforming growth factor-beta-induced expression by 34% (P = 0.026). Concomitant insulin had no effect. Tissue-type plasminogen activator was decreased by 38% (P = 0.002). In human endothelial cells, PAI-1 was diminished by 32% (P < 0.001), whereas tissue-type plasminogen activator was unaffected. The results suggest that the reduction in plasma activity of PAI-1 induced by troglitazone in patients may reflect both directly mediated diminution of its elaboration from vessel walls and indirectly mediated reduction of its hepatic synthesis secondary to attenuation of hyperinsulinemia (known to increase the hepatic synthesis of PAI-1).
曲格列酮是一种新型口服胰岛素增敏剂，可使高胰岛素血症患者（如多囊卵巢综合征女性和2型糖尿病患者）升高的血浆纤溶酶原激活物抑制剂1（PAI-1）活性恢复正常。然而，其潜在机制尚未完全阐明。本研究在细胞培养中对循环PAI-1的主要来源——人肝细胞和血管细胞进行了研究。在人肝细胞中，暴露于3μg/mL曲格列酮后24小时内，条件培养基中PAI-1的积累增加了23%（P = 0.001）。这种积累取决于曲格列酮的浓度，而不取决于胰岛素的浓度（已知胰岛素可刺激PAI-1合成）。相比之下，在人主动脉平滑肌细胞中，3μg/mL曲格列酮使基础PAI-1表达降低了23%（P = 0.037），并使转化生长因子-β诱导的表达降低了34%（P = 0.026）。同时存在的胰岛素没有影响。组织型纤溶酶原激活物降低了38%（P = 0.002）。在人内皮细胞中，PAI-1减少了32%（P < 0.001），而组织型纤溶酶原激活物未受影响。结果表明，曲格列酮在患者中诱导的PAI-1血浆活性降低可能既反映了其从血管壁直接介导的生成减少，也反映了继发于高胰岛素血症减轻（已知高胰岛素血症会增加肝脏PAI-1合成）的肝脏合成间接介导的减少。
