ANTIOXIDANT & HYPERGLYCEMIA INDUCED PROCOAGULANT STATE

描述（由申请人提供）：糖尿病与增加的 过早动脉粥样硬化性血管疾病的发病率和患病率， mortality.其原因尚不清楚，但很可能是 至少部分地与存在于糖尿病中的促凝血状态相关。我们 最近表明，长期高血糖/高胰岛素血症（约200 mg/dl × 18-72 h），但正常血糖-高血糖未激活组织因子 (TF)健康年轻男性的凝血途径， 血浆中凝血因子VIla和凝血因子VII凝血活性以及升高的TF 途径抑制剂和FVHL这表明急性 高血糖症期间血栓形成，当凝血机制被 强烈暴露于组织因子，例如在斑块破裂期间。在 建议的项目，我们计划测试的假设，1）选择性 高血糖症与高血糖症-高胰岛素血症在激活 TF途径; 2）高血糖诱导单核细胞中IF的表达; 3）在 在非糖尿病受试者中，高血糖介导的TF途径激活， 抗氧化剂可以预防或减少血液凝固; 4） 糖尿病中的促凝血状态至少部分是由高血糖症引起的 并且可以通过严格的血糖控制或抗氧化剂（在 共存的高血糖症）。我们将测试这些假设1）在肥胖和 非肥胖非糖尿病和肥胖糖尿病受试者， 延长（48小时）的高血糖（约200 mg/d 1）对IF途径因子（VIla， VIIc，TF途径抑制剂）和其他凝血蛋白（因子VIII），以及 凝血酶生成标志物（凝血酶原片段1+2，凝血酶-抗凝血酶 复合物），同时给予和不给予抗氧化剂（维生素C或维生素 E）和2）在II型糖尿病患者中，通过确定严格的 正常血糖控制（5天）对IF通路活性的影响。 我们认为，这种长期高血糖模型（伴或不伴 高胰岛素血症）独特地适合于研究治疗性药物的体内作用。 干预措施，包括降低血糖和给予 抗氧化维生素，对血液凝固的TF途径。

DESCRIPTION (provided by applicant): Diabetes is associated with an increased incidence and prevalence of premature atherosclerotic vascular disease and mortality. The reason for this is not well understood, but is likely to be related, at least in part, to a procoagulant state existing in diabetes. We have recently shown that prolonged hyperglycemia/hyperinsulinemia (about 200 mg/dl x 18-72 h) but not euglycemia-hyperglycemia activated the tissue factor (TF) pathway of blood coagulation in healthy young men as evidenced by a rise in plasma factor VIla and factor VII coagulant activity and by elevated TF pathway inhibitor and FVHL This suggested an enhanced potential for acute thrombosis during hyperglycemia when coagulation mechanisms are triggered by intense exposure to tissue factor, such as during plaque rupture. In the proposed project, we plan to test the hypotheses that 1) selective hyperglycemia is as effective as hyperglycemia-hyperinsulinemia in activating the TF pathway; 2) hyperglycemia induces expression of IF in monocytes; 3) in non-diabetic subjects, hyperglycemia mediated activation of the TF pathway of blood coagulation can be prevented or reduced with antioxidants; 4) that the procoagulant state in diabetes is, at least partially, caused by hyperglycemia and can be reduced by either strict glycemic control or with antioxidants (at co-existing hyperglycemia). We will test these hypotheses 1) in obese and non-obese non-diabetic and obese diabetic subjects by determining effects of prolonged (48 h) hyperglycemia (about 200 mg/d1) on IF pathway factor (VIla, VIIc, TF pathway inhibitor) and other coagulation proteins (factor VIII) and markers of thrombin generation (prothrombin fragment 1+2, thrombin-antithrombin complex) with and without administration of antioxidants (Vitamin C or Vitamin E) and 2) in patients with Type II diabetes by determining effects of strict euglycemic control (for 5 days) on IF pathway activity. We believe that this model of prolonged hyperglycemia (with or without hyperinsulinemia) is uniquely suited to study in vivo effects of therapeutic interventions, including lowering of blood glucose and administration of antioxidant vitamins, on the TF pathway of blood coagulation.