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

Beta-cells of pancreatic islets of Langerhans release insulin in response to rising blood glucose levels. This release of insulin is essential towards maintaining appropriate blood sugar levels. In disease state, as in type 2 diabetes, insulin release is improperly regulated and decreases dramatically with progression of the disease. We will investigate the role of a novel regulatory protein PI3K-gamma, as a regulator of insulin secretion. We have previously shown this protein to be a positive regulator of insulin secretion, and have shown that its inhibition leads to a decrease in insulin containing granules at the plasma membrane, which also correlates to an increase in cortical actin structure. We will now determine the molecular mechanism by which PI3K-gamma modulates actin remodeling, and further elucidate the mechanism by which PI3K-gamma controls insulin release. We will combine state of the art imaging and electrophysiological techniques with molecular biology and whole animal studies. We will investigate electrical function, exocytosis, insulin secretion and signal transduction in beta-cells in which PI3K-gamma has been genetically up- or down- regulated, or inhibited pharmacologically. Understanding how insulin secretion is regulated will lead to the findings of potential sites of dysfunction and targets for the therapeutic treatment of type 2 diabetes.