By augmenting ATP-sensitive K+ channel–induced membrane depolarization, chronic metabolic stress in prediabetes 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 min 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-concentration glucose/Ca2+-regulated genes and modules of coexpressed 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.
- This study was undertaken to establish a temporal link between an increase in intracellular Ca2+ concentration and the loss of pancreatic β-cell identity.
- We profiled the alterations in Ca2+ dynamics and gene transcription that occur in freshly isolated islets following membrane depolarization.
- We show that initially adaptive Ca2+-dependent transcription changes, mediated largely by CREB and CREB-dependent transcription factors, rapidly become maladaptive, causing the loss of β-cell identity and function.
- We also show that many effector genes linked to nearby human type 2 diabetes susceptibility loci are regulated by Ca2+-dependent mechanisms.
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