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个体的血液更容易形成血栓。组织因子（TF）凝血途径，这是启动血液凝固的主要生理机制，因此已成为强烈的兴趣。我们最近已经表明，高葡萄糖和高胰岛素，但特别是高葡萄糖和高胰岛素的组合（HI/HG），大大增加了正常志愿者血液中的膜结合组织因子促凝血活性（TF-PCA），并进一步增加了2型糖尿病（T2 DM）患者中已经升高的循环TF-PCA。此外，我们已经发现，将健康受试者中的葡萄糖和胰岛素水平升高至T2 DM患者中常见的水平，在24小时内使循环TF-PCA增加8.6倍，并且生长抑素（SMS）几乎完全抑制了这种HG/HI诱导的TF-PCA增加，TF抗原仅适度减少（~28%）。目前的建议有两个主要目标。目的1是将我们的研究扩展到具有慢性葡萄糖和/或胰岛素水平升高的情况，即，T1 DM、T2 DM、IGT和胰岛素抵抗患者、非糖尿病个体。具体而言，我们计划研究急性恶化和改善血糖控制以及长期降低胰岛素抵抗对TF-PCA和TF-抗原的影响。目的2是确定健康志愿者和2型糖尿病患者血液中基础的、HG/HI刺激的和SMS抑制的循环TF-PCA和蛋白质的性质和来源。我们假设，HG/HI诱导循环微粒（MP）的增加，所述循环微粒是高度促凝的、携带TF的并且与包括单核细胞、血小板和内皮细胞在内的各种细胞分离。我们将列举MP，其细胞来源和促凝血活性。我们推测SMS抑制HG/HI诱导的MP形成。我们希望，具有多年糖尿病经验的PI与凝血领域知名专家Co-Pi之间的成功合作将继续提供有关T2 DM中已知凝血障碍性质的新信息，并将有助于降低其血管意外风险。

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.