Grant: Doctoral: Vanier Canada Graduate Scholarships

Diabetes mellitus is a chronic disease that affects over 280 million people worldwide. At least two million Canadians currently live with the condition, a figure expected to double in the next ten years. Long-term complications include heart disease, stroke, kidney failure, and blindness. Type 2 diabetes accounts for at least 90% of cases and is currently treated with medications that have limited efficacy and significant side effects. Insulin is a hormone that lowers blood glucose levels and is released by beta cells in the pancreatic Islets of Langerhans. Patients with type 2 diabetes are unable to produce sufficient insulin to meet their peripheral demand. The majority of islets from type 2 diabetic patients contain amyloid deposits formed by aggregation of a small protein, islet amyloid polypeptide (IAPP). IAPP aggregates are toxic to beta cells and can impair insulin secretion. Type 2 diabetic islets also release increased levels of inflammatory proteins that recruit immune cells and directly inhibit beta cell function. Because potent pro-inflammatory effects have been attributed to protein aggregates found in other diseases, including Alzheimer's disease, we hypothesize that IAPP aggregation contributes to beta cell dysfunction by activating a local immune response. This project will determine the mechanisms of immune cell activation by IAPP and assess the effects of IAPP-induced inflammation on pancreatic islet function. We will evaluate potential therapeutic strategies for blocking IAPP-induced inflammation using mouse models of type 2 diabetes and islet transplantation, a potential curative therapy for type 1 diabetes that is also associated with amyloid formation. This work will contribute to our understanding of how protein aggregates interact with the immune system in multiple disease states. Furthermore, it may aid in the development of strategies to preserve beta cell function in both type 2 diabetic patients and islet transplant recipients.