Workload-induced changes to cell state contribute to β-cell failure in diabetes

Insufficient insulin secretion relative to insulin demand is a key feature of type 2 diabetes (T2D). While the defects of insulin-producing β-cells in T2D are well defined, little is known about how β-cells progress from the functionally normal state to the decompensated state during the natural history of this disease. Here, we provide evidence that workload-induced β-cell overstimulation precipitates β-cell failure in T2D. We employ scRNA-seq to define workload-induced changes to β-cell transcriptional states, identifying a novel compensating state that is distinct from the stressed state of decompensated β-cells. We demonstrate a key role for the chromatin-modifying enzyme Lysine-specific demethylase 1 (Lsd1) in restraining workload-induced β-cell state transitions, indicating epigenomic control of β-cell state. Experimental manipulations that promote the compensating state accelerate β-cell failure in mouse models of diabetes. Altogether, these findings show that the compensatory response of the β-cell to increased workload becomes maladaptive over time and contributes to the pathogenesis of T2D.