ANTIOXIDANT & HYPERGLYCEMIA INDUCED PROCOAGULANT STATE

描述(申请人提供)：糖尿病与 早期动脉粥样硬化性血管疾病的发病率和流行率 死亡率。造成这种情况的原因尚不清楚，但很可能是 至少部分地与糖尿病中存在的促凝血状态有关。我们 最近有研究表明，长期高血糖/高胰岛素血症(约200 Mg/dl×18-72小时)，但不是正血糖-高血糖激活组织因子 健康青年男性凝血(Tf)途径的升高 血浆凝血因子V1a和凝血因子VII的活性及Tf的升高 途径抑制物和FVHL，这表明急性 当凝血机制由以下因素触发时，高血糖期间的血栓形成 强烈暴露于组织因子，例如在斑块破裂期间。在 提出的项目，我们计划检验以下假设：1)选择性 高血糖与高血糖-高胰岛素血症一样有效地激活 转铁蛋白途径；2)高血糖诱导单核细胞表达IF；3)在 非糖尿病受试者高血糖介导的血管紧张素转换酶途径激活 抗氧化剂可以预防或减少血液凝固；4) 糖尿病患者的促凝血状态至少部分是由高血糖引起的 可以通过严格的血糖控制或使用抗氧化剂(在 并存的高血糖)。我们将测试这些假设1)在肥胖和 非肥胖型非糖尿病和肥胖型糖尿病受试者 延长(48小时)高血糖(约200 mg/d1)对IF途径因子(V1a， VIIC、TF途径抑制物)和其他凝血蛋白(第VIII因子)和 凝血酶生成的标志物(凝血酶原片段1+2、凝血酶-抗凝血酶 复合体)服用和不服用抗氧化剂(维生素C或维生素 E)和2)通过确定STRIGN对II型糖尿病患者的影响 正常血糖控制(为期5天)的IF途径活性。 我们认为这种长期高血糖的模型(有或没有) 高胰岛素血症)特别适合于体内治疗效果的研究 干预措施，包括降低血糖和服用 抗氧化维生素，在凝血的转铁蛋白途径上。

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.