Dynamic Ca²⁺-dependent transcription links metabolic stress to impaired β-cell identity

By augmenting ATP-sensitive K⁺ (K_ATP) channel-induced membrane depolarization, chronic metabolic stress in pre-diabetes may increase intracellular Ca²⁺ concentrations in pancreatic β-cells and cause a loss of cell identity and function. Here, we describe studies of the temporal transcriptomic dynamics induced by sulfonylurea-induced membrane depolarization. Gene expression in isolated islets is highly dynamic, with changes occurring within 30 minutes of membrane depolarization. Initially, the changes are adaptive and driven mainly by signaling through CREB and several other CREB-dependent transcription factors. However, within several hours, there is a progressive decline in islet function that correlates with the diminished expression of islet identity genes and the expression of dedifferentiation markers, consistent with the responses having become maladaptive. The gene expression adaptations cluster into 19 distinct response patterns driven by multiple transcription factors. We also identify a set of high glucose/Ca²⁺-regulated genes and modules of co-expressed genes that are enriched for type 2 diabetes risk genes. Together, these findings establish a close temporal link between membrane depolarization, changes in intracellular Ca²⁺ concentrations, alterations in the islet transcriptome, and impairments of β-cell identity and function.