Project 461673

Type 1 Diabetes (T1D) is a disease that results when the immune system mistakenly destroys most of the insulin-producing beta cells in the body. Insulin is required for our bodies to use energy and due to the lack of enough beta cells, T1D is fatal without treatment. People living with T1D must take insulin every day in order to survive but this does not cure the disease and currently no therapy can sustainably prevent T1D. A better understanding of how T1D develops will give insights into how we can prevent this disease from occurring in those at risk. Although T1D has long been considered a disease of the immune system, recent work suggests that the beta cells are not passive targets, but active participants in the process. We discovered that before T1D occurs, some of the beta cells acquire a unique kind of cellular sickness rather than dying. This sickness allows them to accelerate the disease process. Sick beta cells accumulate during the development of T1D and are accomplices to the immune system, as they communicate signals that fuel the destruction process on healthy beta cells. Removal of these sick beta cells prevents T1D in an animal model, akin to throwing away rotten apples to save the rest. However, we do not understand what causes this beta cell sickness or how it alters the normal functions of beta cells. Addressing these questions will help us move therapies that target these sick cells towards the clinic for preventing T1D. In this project, we will tackle these fundamental questions by investigating the role that specific immune cell types play in the build up of these sick beta cells during T1D. We will determine how sick beta cells communicate with immune cells to accelerate T1D onset. Finally, we will explore how insulin production is altered by this beta cell sickness. Together these studies will give us a better understanding of how T1D develops and move this new approach of targeting sick beta cells towards the clinic.