Grant: Team Grant: CIHR-JDRF Type 1 Diabetes and Precision Medicine

Type 1 diabetes (T1D) varies significantly from person to person in terms of time to onset, rate of progression and insulin use, but the reasons underlying these differences are not known. These knowledge gaps hamper the development of treatments that are tailored to individual patients. Our findings show that there are hierarchies in the function of individual insulin-secreting beta cells and between each 'islet of Langerhans', the small clusters of cells in the pancreas where beta cells live. Specialized "leader" and "hub" beta cells of each islet are like the conductors in an orchestra, coordinating the function of the rest of the cells in the islet. We propose that these critical cells, or the islets in which they are enriched, are particularly vulnerable to destruction by invading immune cells in T1D. This has clinical implications for understanding the variability between T1D patients and improving diagnosis, care and treatment. Our project uses a variety of state-of-the-art technologies, T1D mouse models and human T1D pancreas tissue to address this question. We will determine whether leader or hub cells are the first or last to be destroyed in T1D mouse models and use live pancreas tissue from human T1D donors to explore how the number of specialized beta cells changes as the disease evolves. We will establish a molecular "fingerprint" of the leader and hub cells and use this to track whether their numbers change across disease stages in human pancreas samples. We will examine the roles of genes known to influence T1D risk to see how they impact the function of the leader and hub cells. Finally, using a unique islet transplant mouse model, we will directly visualize whether immune cells selectively attack leader or hub cells during the development of T1D over time. Together these studies will help us understand why there is variability in beta cell loss between people with T1D and will pave the way to new therapies that are tailored to individual patients.