Atherothrombotic vascular disease is the leading cause of morbidity and mortality in type 2 diabetes. Despite a greater understanding of the pathophysiologic mechanisms responsible for the development of type 2 diabetes, the mechanisms responsible for the excess vascular risk in type 2 diabetes are unclear. Impaired fibrinolytic function occurring in the obese/insulin resistant prediabetic stage is thought to contribute to the accelerated rate of atherothrombosis in type 2 diabetes. However, the underlying mechanisms responsible for the hypofibrinolytic state in obesity/insulin resistance are not well understood. Indeed, it is currently unknown whether the capacity of the vascular endothelium to release tissue-type plasminogen activator (t-PA) is impaired in obesity/insulin resistance. This is critically important because it is the local endothelial release rate of t-PA, the key enzyme in initiating fibrinolysis, and not circulating plasma fibrinolytic concentrations that determines endogenous thrombolysis potential. Accordingly, the specific aims of the present proposal will be to determine: 1) if the capacity of the vascular endothelium to release tissue-type plasminogen activator is reduced in obese/insulin resistant adult humans; 2) if the postulated decrease in endothelial tissue-type plasminogen activator release with obesity/insulin resistance is due to increased oxidative stress; and 3) if the postulated decrease in endothelial tissue-type plasminogen activator release with obesity/insulin resistance is associated with chronic subclinical inflammation. To address these aims, 48 middle-aged obese/insulin resistant and non-obese/insulin sensitive adults will be studied. Capacity of the vascular endothelium to locally release t-PA will be assessed, in vivo, in response to intrabrachial infusions of bradykinin (12.5-50 ng/100 mL tissue/min) and sodium nitroprusside (1.0-4.0 ml/100 ml tissue/min). Net release/uptake of t-PA across the forearm vasculature to each pharmacological stimulus will be calculated as the product of the arteriovenous concentration gradient and forearm plasma flow. To determine the effects of oxidative stress on endothelial t-PA release, the bradykinin and sodium nitroprusside dose response curves will be repeated with a coinfusion of the antioxidant vitamin C (12 mg/100 mL tissue/min). The relation between plasma biomarkers of inflammation and t-PA release will also be examined. The expected results should provide mechanistic insight into the excess risk of atherothrombosis observed in the obese/insulin resistant prediabetic state, and experimental support for future antioxidant supplementation trials aimed at reducing/preventing cardiovascular complications associated with type 2 diabetes.
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