Type 1 diabetes (T1D) is characterized by the loss of insulin producing β cells precipitated by infiltration of the pancreas by autoimmune T lymphocytes. We have shown that there is a parallel loss of function in the mass of β cells still remaining when T1D is diagnosed. This project aims to better understand how and why the remaining β cells stop working in people with T1D. Our main goal is to characterize the changes in the islet metabolism that cause these β cells to fail and the spatial and temporal relationship between these changes and the infiltration by T cells. In the first part of the study, we will look at how β cells lose their ability to produce insulin in response to glucose. We believe this is caused by early problems in how β cells sense sugar levels and transduce the signal to secrete the appropriate amount of insulin. Using donated human pancreas tissue, we will track these changes at the molecular level using advanced techniques like spatial metabolomics and test whether we can restore normal function in the β cells. The second part of the study will explore how the immune system interacts with β cells during disease development. We will compare β cell function in islets with different levels of immune cell activity using high thoughput encoding of islet function. Even when immune cells aren’t actively attacking, they may leave behind signs of previous damage. We will relate islet function with markers of active and past immune activity in the tissue samples. Finally, we will attempt to build a model of T1D in slices by co-culturing slices from non-diabetic donors with T cells transduced with diabetogenic T cell receptors. Together, these studies will provide a clearer picture of how and when β cells begin to fail in T1D. Our expert team combines strengths in imaging, metabolism, and immunology to work toward new ways to detect, prevent, or treat this disease.
