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。众所周知，糖尿病患者的血液比非糖尿病患者的血液更容易形成血栓，这是导致风险增加的一个主要原因。凝血的组织因子（TF）途径是凝血起始的主要生理机制，因此成为人们关注的热点。我们最近的研究表明，高糖和高胰岛素，尤其是高糖和高胰岛素的结合（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活性（TF-PCA），并进一步增加了2型糖尿病（T2DM）患者血液中已经升高的循环TF-PCA。此外，我们发现，将健康受试者的葡萄糖和胰岛素水平提高到T2DM患者常见的水平，24小时内循环TF-PCA增加8.6倍，并且生长抑素（SMS）几乎完全抑制HG/HI诱导的TF-PCA增加，而TF抗原仅适度降低（约28%）。目前的提案有两个主要目标。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T1DM， T2DM， IGT和胰岛素抵抗的非糖尿病患者。具体来说，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T2DM患者血液中基础、HG/HI刺激和SMS抑制循环TF-PCA和蛋白质的性质和来源。我们假设，HG/HI诱导了循环微粒（MP）的增加，这些微粒是高促凝剂，可以从包括单核细胞、血小板和内皮细胞在内的各种细胞中分离出来。我们将列举MP，它们的细胞起源和促凝活性。我们假设SMS抑制HG/ hi诱导的MP形成。我们希望，具有多年糖尿病治疗经验的PI和凝血领域知名专家Co-Pi之间的成功合作将继续提供关于T2DM患者凝血功能障碍性质的新信息，并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.