Transcriptional mechanisms of pancreatic β-cell maturation and functional adaptation

Abstract

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.

Keywords: adaptation; insulin secretion; maturation; metabolism; transcription factors; β-cell.

Figure 1.. Mechanisms of transcriptional regulation of β-cell identity and functional plasticity

(A) Defining properties of lineage-determining transcription factors (LDTFs) and signal-dependent transcription factors (SDTFs). Although it is possible for TFs to exhibit characteristics of both classes, these rules classify the vast majority of TFs studied in the context of β-cells (see Table 1). Top left, LDTFs are expressed in restricted numbers of cell types. Bottom left, LDTFs are required for differentiation of specific cell types. Right, activity or expression of SDTFs are dynamically regulated by extracellular signals. PTM, post-translational modification. (B) β-cell-characteristic genes are activated in a stepwise manner during development and maturation first involving establishment of gene regulatory programs by LDTFs followed by fine-tuning of transcription in response to environmental signals by SDTFs. (C) LDTFs provide cell type specificity to the response to environmental signals by directing SDTFs to cell type-specific gene regulatory elements. This figure was created using BioRender (https://biorender.com/).

Figure 2.. Transcriptional regulation of β-cell maturation.

(A) The relationship between insulin secretion and glucose concentration for mature and immature β-cells, approximated from observations in [16, 30]. (B) Schematic of the metabolic and functional changes of β-cells during maturation. MCFs, metabolic coupling factors. (C) Signals and their cognate signal-dependent transcription factors (SDTFs) involved in β-cell maturation. OxPhos, oxidative phosphorylation.

Figure 3.. Transcriptional regulation in the β-cell during functional adaptation.

(A) The relationship between insulin secretion and glucose concentration during compensation for insulin resistance relative to normal β-cells, based on observations in [50, 51]. (B) Schematic of the metabolic and functional changes in β-cells during compensation for insulin resistance. MCFs, metabolic coupling factors. (C) Signals and their cognate signal-dependent transcription factors (SDTFs) involved in compensation for insulin resistance. ROS, reactive oxygen species; ER, endoplasmic reticulum.

Figure I.

LDTFs and SDTFs co-bind islet-specific regulatory elements of the Pcx gene.