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

Sustained stimulation and elevations in intracellular Ca2+ concentrations due to metabolic stress in pre-diabetic states triggers gene expression changes contributing to the loss of pancreatic β-cell function. To establish a temporal relationship between β-cell stimulation and perturbations in Ca2+-dependent transcription, islet Ca2+ dynamics and gene expression was analysed in cultured mouse islets that were stimulated by membrane depolarization with tolbutamide, a sulfonylurea that blocks the ATP-dependent potassium (KATP) channel. By varying the timing and nature of the experimental stimulory conditions, we defined temporal transcriptional dynamics of islets in responce to stimulation, identified immediate early response genes and transcriptional regulators that drive these transcriptional changes and defined a set of physiologically relevant Ca2+-regulated genes with sustained changes 24 hours post-stimulation. Ca2+-dependent changes resulting from chronic stimulation include an increase in β-cell stress response and dedifferentiation genes, and a decrease in critical β-cell identity genes.