2689-P: Stat1 Activation in Pancreatic Beta Cells Links Cytokine Signaling to Type 1 Diabetes

Introduction and Objective: Type 1 diabetes (T1D) is an autoimmune disease characterized by the loss of pancreatic β-cell mass and function. Current treatments primarily focus on symptom management, such as insulin injections, or extending the partial remission period with therapies that limit immune cell function, inhibit cytokine signaling, or both. Cytokines secreted from such immune cells, such as interferon alpha (IFNα) and interferon gamma (IFNγ), are thought to be key contributors to the T1D disease pathology. Baricitinib inhibits these cytokine signals by limiting activation of the JAK/STAT pathway and has shown promise in preventing and delaying the progression of T1D in human study participants. However, the mechanisms underlying these clinically beneficial effects of baricitinib remain unclear. IFNγ and IFNα, secreted by immune cells, bind to cytokine receptors on pancreatic islet β-cells, activating intracellular JAK/STAT pathways. Baricitinib inhibits the JAK1/2 proteins in response to IFNγ signaling. Hence, we hypothesized that Baricitinib limits STAT1 activity in β-cells by Jak1/2 inhibition and that STAT1 regulates β-cell transcriptional outputs relevant to autoimmunity in response to IFNγ. Methods: Using unique molecular approaches, including STAT1 mutants (gain-of-function GOF and loss-of-function LOF), we conducted mechanistic analyses of STAT1 transcriptional activity using mouse islets and beta-cell lines. Results: Our results reveal that beta-cells respond directly to interferons via increased STAT1 transcriptional activity, leading to production of proteins that recruit immune cells. Additionally, Baricitinib suppresses STAT1 transcriptional activity in beta-cells in response to IFNγ. Conclusion: This work provides insights into molecular basis of effective therapeutic targets for T1D and demonstrates that the clinically effective drug baricitinib has effects directly at the islet beta-cell target cell population relevant to the pathophysiology of T1D. Disclosure H. Sun: None. H. Batdorf: None. T. Martin: None. S. Burke: None. J. Collier: None.