Hyperglycemia and Hyperinsulinemia Induced Procoagulant State

描述(由申请人提供)：糖尿病与动脉粥样硬化性血管疾病的风险增加数倍相关。增加风险的一个主要因素是众所周知的事实，即糖尿病患者的血液往往比非糖尿病患者的血液更容易形成血栓。凝血的组织因子(TF)途径是启动凝血的主要生理机制，因此引起了人们的极大兴趣。我们最近发现，高糖和高胰岛素，特别是高糖和高胰岛素(HI/HG)的联合作用，可显著增加正常志愿者血液中膜结合型组织因子促凝活性(TF-PCA)，并进一步增加2型糖尿病(T2 DM)患者已升高的循环TF-PCA。此外，我们还发现，将健康受试者的血糖和胰岛素水平提高到T2 DM患者中常见的水平，循环中的TF-PCA在24小时内增加了8.6倍，生长抑素(SMS)几乎完全抑制了这种HG/HI诱导的TF-PCA的增加，而TF抗原仅有轻微的下降(~28%)。目前的提议有两个主要目标。目标1是将我们的研究扩展到长期血糖和/或胰岛素水平升高的情况，即T1 DM、T2 DM、IGT患者和胰岛素抵抗的非糖尿病患者。具体地说，我们计划调查血糖控制的急剧恶化和改善以及胰岛素抵抗的长期降低对TF-PCA和TF-抗原的影响。目的2确定正常人和2型糖尿病患者血液中基础、HG/HI刺激和丹参抑制循环Tf-Pca和蛋白的性质和来源。我们推测，HG/HI可诱导循环中高度促凝血的微粒子(MP)的增加，这些微粒子可与多种细胞分离，包括单核细胞、血小板和内皮细胞。我们将列举MP、它们的细胞来源和促凝活性。我们推测，丹参能抑制HG/HI诱导的MP形成。我们希望，在糖尿病领域拥有多年经验的PI和著名的凝血领域专家Co-Pi之间的成功合作的继续，将为T2 DM已知存在的凝血障碍的性质提供新的信息，并将有助于降低他们发生血管事故的风险。

DESCRIPTION (provided by applicant): Diabetes is associated with a several-fold increased risk for atherosclerotic vascular disease. A major contributor to the increased risk is the well-known fact that blood of diabetic patients tends to form blood clots more easily than blood of non-diabetic individuals. The tissue factor (TF) pathway of blood coagulation, which is the primary physiological mechanism of initiation of blood coagulation, has therefore become of intense interest. We have recently shown that high glucose and high insulin, but especially the combination of high glucose and high insulin (HI/HG), greatly increased membrane-bound tissue factor procoagulant activity (TF-PCA) in blood of normal volunteers and increased further the already elevated circulating TF- PCA in patients with type 2 diabetes (T2DM). Moreover, we have found that raising glucose and insulin levels in healthy subjects to levels commonly seen in patients with T2DM, increased circulating TF-PCA 8.6- fold within 24 h and that somatostatin (SMS) almost completely inhibited this HG/HI induced increase in TF- PCA with only a modest reduction (~28%) in the TF-antigen. The current proposal has two major objectives. Objective 1 is to expand our studies to conditions with chronically elevated glucose and/or insulin levels, i.e., to patients with T1DM, T2DM, IGT and insulin resistant, non-diabetic individuals. Specifically, we plan to investigate effects of acutely worsening and improving glycemic control and of longterm lowering of insulin resistance on TF-PCA and TF-antigen. Objective 2 is to determine the nature and the origin of basal, HG/HI stimulated and of SMS suppressed circulating TF-PCA and protein in blood of healthy volunteers and of patients with T2DM. We hypothesize, that HG/HI induces an increase in circulating microparticles (MP) which are highly procoagulant, bearTF and segregate from various cells, including monocytes, platelets and endothelial cells. We will enumerate MP, their cellular origin and procoagulant activity. We hypothesize that SMS inhibits HG/HI-induced MP formation. We hope that continuation of the successful collaboration between the PI, who has many years of experience in diabetes and the Co-Pi, who is a well-known expert in the area of blood coagulation, will provide new information on the nature of the coagulation disorder known to exist in T2DM and will help to reduce their risk for vascular accidents.