Project 446710

Type 1 diabetes (T1D), often diagnosed in children, affects >300,000 Canadians. In T1D, the immune system targets and destroys a special type of cell called a beta cell which makes insulin. It is becoming clear that problems within beta cells and changes to the insulin gene are important in T1D. Beta cells balance the stress of making large amounts of insulin with the demands of controlling blood sugar. Even subtle changes to insulin production might tip beta cells into an unhealthy state, leading to cell death or attack by the immune system. The goal of our research is to figure out which steps of insulin production push beta cells into an unhealthy state. We will study beta cells from both men and women, and from male and female mice. Men aged 15-34 have a higher risk of T1D than women. Our team and other scientists have shown that beta cells in males are more fragile. Unfortunately, because beta cells from women and female mice are understudied, we do not fully understand why female beta cells are more resilient. Our team includes experts on each stage of insulin production and quality control, and an expert on how male and female insulin-producing cells are different. Based on the clues from our recent work, we have designed experiments in human beta cells to interfere with specific steps of insulin synthesis, processing, and quality control to see how this affects stress in beta cells from both men and women. In experiments that are only possible in mice, we will delete genes involved in each stage of insulin synthesis and measure changes in beta cell stress and health in each sex. This knowledge will help us find new ways of maintaining healthy beta cells, an objective that is relevant for improving existing treatments for T1D and other forms of diabetes. This information will also help us figure out how male and female beta cells are different. Eventually, the knowledge we generate will lead to new ways of treating T1D that are effective in both sexes.