Nordt T K, Sawa H, Fujii S, Sobel B E
Cardiovascular Division, Washington University School of Medicine, St. Louis, Mo.
Circulation. 1995 Feb 1;91(3):764-70. doi: 10.1161/01.cir.91.3.764.
Fasting hyperinsulinemia (reflected by elevations in immunoreactive "insulin") is typical of patients with non-insulin-dependent diabetes mellitus (NIDDM) and is often associated with obesity and hypertension. The elevated concentrations detected are indicative not only of insulin but also of its immunologically cross-reactive precursors, including proinsulin. Fasting hyperinsulinemia appears to be associated with decreased fibrinolytic activity in blood, which results from increased activity of plasminogen activator inhibitor type-1 (PAI-1), a potential independent risk factor for coronary artery disease. Patients who were given proinsulin in a previous clinical study by others exhibited an increased incidence of cardiovascular events. Thus, a "proinsulin-PAI-1 axis" may predispose to coronary thrombosis. To define the possible presence of such an axis, this study was designed to determine whether insulin, its precursors, or both increase the concentrations of PAI-1 in rabbits in vivo.
Equimolar proinsulin (n = 10), insulin (n = 11), C-peptide (n = 4), or vehicle alone (n = 10) was administered intravenously over 1 hour to euglycemic, conscious rabbits. Plasma PAI-1 activity increased 3.8-fold with proinsulin (P = .002) and 3.6-fold with insulin (P = .002). By contrast, no increase occurred after C-peptide or vehicle was administered. The increased PAI-1 activity was shown to be attributable to PAI-1 protein by reverse fibrin autography. As judged from changes in mRNA in tissues, proinsulin and insulin increased PAI-1 gene expression within 3 hours by 2.1- and 2.1-fold, respectively, in aorta (P = .025 each) and by 1.9- and 2.4-fold in liver (P = .015 and P = .001), with return of values to baseline within 24 hours (n = 4 experiments in each case).
These results extend our previous observations from studies in vitro and suggest that hyperinsulinemia attributable to augmented concentrations of proinsulin and insulin in plasma increase plasma PAI-1 activity and may contribute to acceleration of atherosclerosis and impairment of coronary thrombolysis in patients with NIDDM.
空腹高胰岛素血症（以免疫反应性“胰岛素”升高为指标）是非胰岛素依赖型糖尿病（NIDDM）患者的典型特征，常与肥胖和高血压相关。检测到的胰岛素浓度升高不仅表明胰岛素水平升高，还提示其免疫交叉反应性前体，包括胰岛素原水平也升高。空腹高胰岛素血症似乎与血液中纤溶活性降低有关，这是由纤溶酶原激活物抑制剂1型（PAI-1）活性增加所致，PAI-1是冠状动脉疾病的一个潜在独立危险因素。在之前他人进行的一项临床研究中，给患者注射胰岛素原后心血管事件的发生率增加。因此，“胰岛素原-PAI-1轴”可能易引发冠状动脉血栓形成。为确定是否存在这样一个轴，本研究旨在确定胰岛素、其前体或两者是否会在体内增加家兔PAI-1的浓度。
将等摩尔的胰岛素原（n = 10）、胰岛素（n = 11）、C肽（n = 4）或单独给予溶媒（n = 10）静脉注射给血糖正常、清醒的家兔，持续1小时。胰岛素原使血浆PAI-1活性增加3.8倍（P = .002），胰岛素使其增加3.6倍（P = .002）。相比之下，注射C肽或溶媒后未出现增加。反向纤维蛋白自显影显示，PAI-1活性增加归因于PAI-1蛋白。从组织中mRNA的变化判断，胰岛素原和胰岛素在3小时内分别使主动脉中PAI-1基因表达增加2.1倍和2.1倍（各P = .025），使肝脏中PAI-1基因表达增加1.9倍和2.4倍（P = .015和P = .001），24小时内各值恢复至基线水平（每种情况均为n = 4次实验）。
这些结果扩展了我们之前在体外研究中的观察结果，表明血浆中胰岛素原和胰岛素浓度增加所致的高胰岛素血症会增加血浆PAI-1活性，并可能促使NIDDM患者动脉粥样硬化加速和冠状动脉溶栓功能受损。
