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Immune-mediated destruction of insulin-producing β cells causes type 1 diabetes (T1D). However, how β cells participate in their own destruction during the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in β cells of non-obese diabetic (NOD) mice by deleting the UPR sensor IRE1α prior to insulitis induced a transient dedifferentiation of β cells, resulting in substantially reduced islet immune cell infiltration and β cell apoptosis. Single-cell and whole-islet transcriptomics an