Hyperglycemia and Hyperinsulinemia Induced Procoagulant State

高血糖和高胰岛素血症引起的促凝血状态

• 批准号: 8003649
• 负责人: Guenther Boden
• 金额: $ 0.7万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-23 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003649
• 关键词: Accidents; Address; Agonist; Antigens; Area; Atherosclerosis; Binding; Biological Assay; Blood; Blood Circulation; Blood Clot; Blood Coagulation Disorders; Blood Glucose; Blood Platelets; Blood Vessels; Blood coagulation; C-Peptide; Cells; Clinical; Collaborations; Diabetes Mellitus; Diabetic Angiopathies; Endothelial Cells; Fenofibrate; Figs - dietary; Glucose; Hour; Hyperglycemia; Hyperinsulinism; Individual; Infusion procedures; Inpatients; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Measures; Membrane; Methods; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Physiological; Plasma; Platelet Count measurement; Proteins; Relative (related person); Research Personnel; Risk; Secondary to; Serum; Sickle Cell Anemia; Somatostatin; Source; Testing; Thromboplastin; Time; Up-Regulation; Whole Blood; base; cell type; diabetic; diabetic patient; experience; glycemic control; healthy volunteer; improved; insulin secretion; interest; monocyte; non-diabetic; novel strategies; programs; response; rosiglitazone; volunteer

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.

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。血液凝固的组织因子（TF）途径是启动血液凝固的主要生理机制，因此引起了人们的强烈兴趣。我们最近发现，高葡萄糖和高胰岛素，特别是高葡萄糖和高胰岛素（HI/HG）的组合，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（T2DM）患者中已经升高的循环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，循环 TF-PCA 在 24 小时内增加 8.6 倍，生长抑素 (SMS) 几乎完全抑制 HG/HI 诱导的 TF-PCA 增加，而 TF-抗原仅适度减少 (~28%)。当前的提案有两个主要目标。目标 1 是将我们的研究扩展到葡萄糖和/或胰岛素水平长期升高的疾病，即 T1DM、T2DM、IGT 患者和胰岛素抵抗的非糖尿病个体。具体来说，我们计划研究急剧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。目标 2 是确定健康志愿者和 T2DM 患者血液中基础、HG/HI 刺激和 SMS 抑制的循环 TF-PCA 和蛋白质的性质和来源。我们假设，HG/HI 会诱导循环微粒 (MP) 的增加，这些微粒具有高度促凝血作用，可与各种细胞（包括单核细胞、血小板和内皮细胞）分离。我们将列举 MP、它们的细胞起源和促凝血活性。我们假设 SMS 抑制 HG/HI 诱导的 MP 形成。我们希望，拥有多年糖尿病治疗经验的 PI 和凝血领域知名专家 Co-Pi 之间的成功合作能够继续提供关于 T2DM 中已知的凝血障碍的性质的新信息，并有助于降低他们发生血管意外的风险。