Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Diabetes mellitus is a metabolic disorder in which plasma glucose is consistently elevated above normal. It can result from either an absolute deficiency of insulin secretion (type 1 diabetes) or the development of insulin resistance coupled with inadequate compensatory release of insulin (type 2 diabetes). This disorder currently affects more than 100 million people worldwide, and is a major risk factor for cardiovascular diseases such as heart failure and cardiomyopathy. Nitric oxide, a chemical produced in small amounts by endothelial-derived nitric oxide synthase (eNOS) within cells, mediates many essential physiological functions. Too much nitric oxide, however, can damage tissues. Previous studies have shown that high level of blood sugar characteristic of type 1 diabetes is associated with a large increase of nitric oxide synthesis in the heart and blood vessels due to activation of an inducible enzyme named iNOS. The aim of this study is to find out if increased blood sugar and/or plasma lipid levels in type 2 diabetes also activate iNOS thereby affecting cardiovascular function. To date, I have developed a new model of fructose-fed, streptozotocin-induced type 2 diabetes that exhibits hyperglycemia, hypertriglyceridemia and insulin resistance. Using this model, in vivo cardiac, hemodynamic and vascular functions are integrated with different biochemical and pharmacological approaches to examine the pathophysiological role of iNOS in type 2 diabetes. The proposed study will provide evidence that links cardiovascular dysfunction to activation of iNOS and/or other downstream biochemical abnormalities. This research will increase our understanding of the pathogenesis and complications of type 2 diabetes, and can lead to more effective therapeutic treatment for this complex, heterogeneous disorder.