Schneider D J, Sobel B E
Department of Medicine, University of Vermont College of Medicine, Burlington 05405, USA.
Coron Artery Dis. 1996 Nov;7(11):813-7. doi: 10.1097/00019501-199611000-00004.
Plasminogen activator inhibitor type-1 (PAI-1) implicated as a determinant of thrombosis, and possibly of atherosclerosis, is increased approximately four-fold in the blood of subjects with type II diabetes, and the increase is closely correlated with concentrations of insulin. Insulin can stimulate expression of PAI-1 in vitro, but infusions of insulin in human subjects have not increased PAI-1 in blood in acute, euglycemic clamp studies.
To determine whether the dichotomy reflects interactions between insulin and both very-low-density lipoprotein (VLDL)-bound triglycerides (VLDL-TG) and albumin-bound nonesterified (free) fatty acids (FFA) affecting PAI-1 elaboration.
HepG2 cells (human hepatoma cell line) were exposed to insulin, VLDL, and FFA alone and in selected combinations for 24 h.
Striking synergistic effects were observed. Thus, compared with control, pathophysiologic concentrations of insulin increased PAI-1 accumulation in conditioned media modestly, as did VLDL, but the combination elicited a marked nine-fold increase (control PAI-130 +/- 2 ng/ml, PAI-1 with 400 mg/dl VLDL-TG 97 +/- 6 ng/ml; with 4 nmol/1 insulin 45 +/- 6 ng/ml, with 400 mg/dl VLDL-TG plus 4 nmol/1 insulin 276 +/- 47 ng/ml; P < 0.01 for the combination compared with control or with either agent alone). Similarly, a modest increase was found either with insulin or with FFA alone, but a synergistic increase was evident when they were combined (control 27 +/- 3 ng/ml; 1 mmol/l FFA 36 +/- 2 ng/ml; 10 nmol/l insulin 59 +/- 6 ng/ml; 1 mmol/l FFA plus 10 nmol/l insulin 82 +/- 1 ng/ml; P < 0.01 for the combination compared with control or with either agent alone).
The combination of increased insulin with elevated VLDL-TG and increased FFA appears to cause the increase in PAI-1 in blood of subjects with type II diabetes mellitus and other insulin-resistant states, providing novel and promising targets for normalizing altered fibrinolytic system potential and thereby ameliorating the associated predisposition to persistent thrombosis and possibly atherosclerosis.
纤溶酶原激活物抑制剂-1（PAI-1）被认为是血栓形成的一个决定因素，可能也是动脉粥样硬化的决定因素，在II型糖尿病患者的血液中其水平大约升高四倍，且这种升高与胰岛素浓度密切相关。胰岛素在体外可刺激PAI-1的表达，但在人体受试者的急性、血糖正常的钳夹研究中，输注胰岛素并未使血液中的PAI-1增加。
确定这种差异是否反映了胰岛素与极低密度脂蛋白（VLDL）结合的甘油三酯（VLDL-TG）以及白蛋白结合的非酯化（游离）脂肪酸（FFA）之间的相互作用，这些相互作用影响PAI-1的产生。
将HepG2细胞（人肝癌细胞系）单独或按选定组合暴露于胰岛素、VLDL和FFA中24小时。
观察到显著的协同效应。因此，与对照组相比，生理病理浓度的胰岛素适度增加了条件培养基中PAI-1的积累，VLDL也有同样的作用，但二者组合可使PAI-1显著增加九倍（对照组PAI-1 30±2 ng/ml，含400 mg/dl VLDL-TG时PAI-1为97±6 ng/ml；含4 nmol/l胰岛素时为45±6 ng/ml，含400 mg/dl VLDL-TG加4 nmol/l胰岛素时为276±47 ng/ml；组合组与对照组或任一单独试剂组相比，P<0.01）。同样，单独使用胰岛素或FFA时PAI-1有适度增加，但二者联合使用时则有协同增加（对照组27±3 ng/ml；1 mmol/l FFA时为36±2 ng/ml；10 nmol/l胰岛素时为59±6 ng/ml；1 mmol/l FFA加10 nmol/l胰岛素时为82±1 ng/ml；组合组与对照组或任一单独试剂组相比，P<0.01）。
胰岛素水平升高与VLDL-TG升高及FFA增加的组合似乎导致了II型糖尿病患者和其他胰岛素抵抗状态患者血液中PAI-1的增加，为使改变的纤溶系统潜能正常化从而改善相关的持续血栓形成倾向以及可能的动脉粥样硬化倾向提供了新的、有前景的靶点。
