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.
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