Mapping the association of beta cell longevity and cell senescence in type 1 diabetes

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Project Summary Type 1 diabetes (T1D) is caused by the functional collapse of insulin-producing beta cells in the pancreas. Most beta cells in the healthy pancreas can be as old as cortical neurons and are classified as long-lived cells. During T1D, beta cells become dysfunctional and/or are destroyed in an auto-immune reaction that can occur at any age. A recent study has linked the onset of beta cell senescence in a sub-set of beta cells with a paracrine pro- inflammatory response that exacerbates the functional impairment and death of T1D beta cells. Accordingly, clearance of senescent T1D beta cells is sufficient to improve beta cell survival and prevent the onset of T1D. Several studies now indicate the presence of beta cells in the pancreas of T1D patients, which indicates that T1D beta cells could also be long-lived. In addition, this data suggests that specific beta cells can survive this auto-immune attack and, thus, are able to survive for long periods in the human pancreas. However, it is currently unknown how these beta cells survive in the harsh T1D environment. Their specific molecular profiles that may predispose them for long-term survival also remain unknown. This project will establish both the longevity and molecular signatures of T1D pancreatic beta cells through utilization of high-resolution transcriptional sequencing and imaging technologies of individual beta cells in the pancreas of T1D mice and humans. The combination of these complementary techniques will overlay this high-dimensional data containing cell structure and molecular profiles at the transcriptional and proteome level with cell age and longevity. Understanding how long-lived beta cells maintain their long-term function and health will lead to new methods to promote and preserve beta cell function in T1D patients.