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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK062061-01
Application #
6513656
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2002-08-15
Project End
2004-06-30
Budget Start
2002-08-15
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$74,000
Indirect Cost
Name
University of Colorado at Boulder
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
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Van Guilder, Gary P; Hoetzer, Greta L; Greiner, Jared J et al. (2006) Influence of metabolic syndrome on biomarkers of oxidative stress and inflammation in obese adults. Obesity (Silver Spring) 14:2127-31
DeSouza, Christopher A; Van Guilder, Gary P; Greiner, Jared J et al. (2005) Basal endothelial nitric oxide release is preserved in overweight and obese adults. Obes Res 13:1303-6
Van Guilder, Gary P; Hoetzer, Greta L; Smith, Derek T et al. (2005) Endothelial t-PA release is impaired in overweight and obese adults but can be improved with regular aerobic exercise. Am J Physiol Endocrinol Metab 289:E807-13
Hoetzer, Greta L; Irmiger, Heather M; Keith, Rebecca S et al. (2005) Endothelial nitric oxide synthase inhibition does not alter endothelial progenitor cell colony forming capacity or migratory activity. J Cardiovasc Pharmacol 46:387-9

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