Grant: CIHR Fellowship

Diabetes is a chronic disease, with devastating consequences and no cure. Type 2 diabetes (T2D), estimated to account for 90% of the 387 million diabetes cases worldwide, results when the insulin-producing beta-cells contained within pancreatic islets lose function, resulting in insufficient insulin levels and elevated blood sugar. The cause of beta-cell dysfunction in T2D is unclear, although it is tightly linked with obesity. An emerging perspective is that the immune system contributes to the development of beta-cell dysfunction in T2D. Ordinarily, the immune system acts to return the body to normalcy in response to stress; this function is not just limited to stresses such as infection or injury, but also over-nutrition. However, in response to chronic stress, over-activation of the immune system can have deleterious consequences, as is the case of inflammation (an immune-mediated response) in obesity. Pancreatic islets show increased inflammation in obesity and T2D, which can lead to decreased insulin secretion, impaired beta-cell function, and even beta-cell death. We recently found that a factor secreted by beta-cells, known as islet amyloid polypeptide (IAPP), may play a role in islet inflammation. In type 2 diabetic islets, IAPP forms insoluble aggregates, known as islet amyloid, which can activate an inflammatory response in immune cells, and attract pro-inflammatory immune cells to islets. Thus IAPP-induced inflammation may play a critical role in the development of beta-cell dysfunction in T2D. The aim of this research project is to elucidate the mechanism of the IAPP-induced islet inflammation, and to determine its contribution to beta-cell impairment and diabetes. This research will lead to a better understanding of the causes of beta-cell dysfunction, and may uncover new therapeutic targets that could be used to limit both the damaging effect of islet inflammation, and the development of T2D.