Festa A, D'Agostino R, Mykkänen L, Tracy R P, Zaccaro D J, Hales C N, Haffner S M
Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, TX 78284-7873, USA.
Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):562-8. doi: 10.1161/01.atv.19.3.562.
Hyperinsulinemia is associated with the development of coronary heart disease. However, the underlying mechanisms are still poorly understood. Hypercoagulability and impaired fibrinolysis are possible candidates linking hyperinsulinism with atherosclerotic disease, and it has been suggested that proinsulin rather than insulin is the crucial pathophysiological agent. The aim of this study was to investigate the relationship of insulin and its precursors to markers of coagulation and fibrinolysis in a large triethnic population. A strong and independent relationship between plasminogen activator inhibitor-1 (PAI-1) antigen and insulin and its precursors (proinsulin, 32-33 split proinsulin) was found consistently across varying states of glucose tolerance (PAI-1 versus fasting insulin [proinsulin], r=0.38 [r=0.34] in normal glucose tolerance; r=0.42 [r=0.43] in impaired glucose tolerance; and r=0.38 [r=0.26] in type 2 diabetes; all P<0.001). The relationship remained highly significant even after accounting for insulin sensitivity as measured by a frequently sampled intravenous glucose tolerance test. In a stepwise multiple regression model after adjusting for age, sex, ethnicity, and clinic, both insulin and its precursors were significantly associated with PAI-1 levels. The relationship between fibrinogen and insulin and its precursors was significant in the overall population (r=0.20 for insulin and proinsulin; each P<0.001) but showed a more inconsistent pattern in subgroup analysis and after adjustments for demographic and metabolic variables. Stepwise multiple regression analysis showed that proinsulin (split products) but not fasting insulin significantly contributed to fibrinogen levels after adjustment for age, sex, clinic, and ethnicity. Decreased insulin sensitivity was independently associated with higher PAI-1 and fibrinogen levels. In summary, we were able to demonstrate an independent relationship of 2 crucial factors of hemostasis, fibrinogen and PAI-1, to insulin and its precursors. These findings may have important clinical implications in the risk assessment and prevention of macrovascular disease, not only in patients with overt diabetes but also in nondiabetic subjects who are hyperinsulinemic.
高胰岛素血症与冠心病的发生有关。然而，其潜在机制仍知之甚少。高凝状态和纤维蛋白溶解功能受损可能是将高胰岛素血症与动脉粥样硬化疾病联系起来的因素，并且有人提出胰岛素原而非胰岛素是关键的病理生理介质。本研究的目的是在一个大型三族裔人群中调查胰岛素及其前体与凝血和纤维蛋白溶解标志物之间的关系。在不同的糖耐量状态下，始终发现纤溶酶原激活物抑制剂-1（PAI-1）抗原与胰岛素及其前体（胰岛素原、32-33裂解胰岛素原）之间存在强烈且独立的关系（在糖耐量正常时，PAI-1与空腹胰岛素[胰岛素原]的相关系数r=0.38[r=0.34]；糖耐量受损时，r=0.42[r=0.43]；2型糖尿病时，r=0.38[r=0.26]；所有P<0.001）。即使在通过频繁采样静脉葡萄糖耐量试验测量胰岛素敏感性后，这种关系仍然高度显著。在调整年龄、性别、种族和诊所因素后的逐步多元回归模型中，胰岛素及其前体均与PAI-1水平显著相关。纤维蛋白原与胰岛素及其前体之间的关系在总体人群中显著（胰岛素和胰岛素原的r=0.20；各P<0.001），但在亚组分析以及调整人口统计学和代谢变量后显示出更不一致的模式。逐步多元回归分析表明，在调整年龄、性别、诊所和种族因素后，胰岛素原（裂解产物）而非空腹胰岛素对纤维蛋白原水平有显著贡献。胰岛素敏感性降低与较高的PAI-1和纤维蛋白原水平独立相关。总之，我们能够证明止血的两个关键因素纤维蛋白原和PAI-1与胰岛素及其前体之间存在独立关系。这些发现可能对大血管疾病的风险评估和预防具有重要的临床意义，不仅适用于显性糖尿病患者，也适用于高胰岛素血症的非糖尿病受试者。
