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

Abstract

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