Transcriptional mechanisms of pancreatic β-cell maturation and functional adaptation

Lineage determining transcription factors (LDTFs) are required for β-cell differentiation, yet acquisition of β-cell identity is not sufficient for glucose-stimulated insulin secretion. Environmental signals that regulate signal-dependent transcription factors (SDTFs) govern acquisition and adaptation of glucose-stimulated insulin secretion. β-Cell function is acquired in a stepwise manner whereby LDTFs initiate expression of cell type-characteristic genes, then SDTFs fine-tune gene expression to confer metabolic and functional properties to β-cells. LDTFs guide the recruitment of SDTFs to provide cell type specificity to the transcriptional effects of environmental signals in neonatal and adult β-cells. Pancreatic β-cells secrete insulin commensurate to circulating nutrient levels to maintain normoglycemia. The ability of β-cells to couple insulin secretion to nutrient stimuli is acquired during a postnatal maturation process. In mature β-cells the insulin secretory response adapts to changes in nutrient state. Both β-cell maturation and functional adaptation rely on the interplay between extracellular cues and cell type-specific transcriptional programs. Here we review emerging evidence that developmental and homeostatic regulation of β-cell function involves collaboration between lineage-determining and signal-dependent transcription factors (LDTFs and SDTFs, respectively). A deeper understanding of β-cell SDTFs and their cognate signals would delineate mechanisms of β-cell maturation and functional adaptation, which has direct implications for diabetes therapies and for generating mature β-cells from stem cells. Pancreatic β-cells secrete insulin commensurate to circulating nutrient levels to maintain normoglycemia. The ability of β-cells to couple insulin secretion to nutrient stimuli is acquired during a postnatal maturation process. In mature β-cells the insulin secretory response adapts to changes in nutrient state. Both β-cell maturation and functional adaptation rely on the interplay between extracellular cues and cell type-specific transcriptional programs. Here we review emerging evidence that developmental and homeostatic regulation of β-cell function involves collaboration between lineage-determining and signal-dependent transcription factors (LDTFs and SDTFs, respectively). A deeper understanding of β-cell SDTFs and their cognate signals would delineate mechanisms of β-cell maturation and functional adaptation, which has direct implications for diabetes therapies and for generating mature β-cells from stem cells. the capability to express insulin and genes that participate in insulin processing, granule formation, and exocytosis. genes selectively repressed in islets or β-cells compared with other tissues. an increase or decrease of the insulin secretory response per β-cell. acquisition of glucose-responsive insulin secretion and reduction of basal insulin secretion by the β-cell. a blanket term referring to both β-cell functional adaptation and functional maturation. a constitutively active, sequence-specific transcription factor (TF) exhibiting a restricted expression pattern that is typically required for differentiation and maintenance of cell identity. a TF broadly expressed or induced in diverse cell types that is activated by extracellular stimuli.