Type 2 diabetes (T2D) is one of the most common chronic conditions worldwide, affecting hundreds of millions of people. It develops when the pancreas cannot produce enough insulin and/or when the body no longer responds to insulin effectively. While it is clear that insulin–producing β–cells fail in T2D, the reasons for this failure remain poorly understood. Increasing evidence suggests that other parts of the pancreas, including the surrounding exocrine tissue and immune cells, may play a crucial role in this process. Our project will generate the comprehensive “atlas” of the human pancreas in T2D. Using advanced single–nucleus and spatial technologies, we will study pancreatic tissues from people with and without T2D at unprecedented resolution. This approach will allow us to examine not only the islet cells, but also the exocrine, stromal, and immune compartments of the pancreas. By mapping how these cell types interact and change in T2D, we hope to uncover the networks and pathways that lead to β–cell dysfunction. To interpret these large datasets, we will employ cutting–edge artificial intelligence and machine learning methods. These tools will help us disentangle how the local pancreatic environment shapes disease and will enable us to predict which cellular interactions might be driving β–cell failure. We will then confirm key findings directly in human tissue sections and in pancreatic slice models. In addition to T2D, we will study pancreatic samples from people with cystic fibrosis (CF). Many adults with CF develop a form of diabetes caused by changes in the pancreatic environment. Comparing T2D and CF will provide unique insight into how exocrine disease contributes to β–cell stress and failure, and will highlight shared or distinct mechanisms across conditions. Ultimately, this project will produce a valuable resource for the scientific community and help guide the development of therapies aimed at protecting and restoring insulin–producing cells.
