Abstract
Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.
Highlights
Mature and immature β-cells co-exist within the adult islet
Immature β-cells are operationally defined as expressing low levels of the transcription factors PDX1 and MAFA based upon fluorescent immunostaining
We investigated whether a reduction in PDX1LOW/MAFALOW cells would lead to a decline in functional subpopulations shown to drive islet dynamics, some of which possess an immature or energetic phenotype
Summary
Mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. One of the subpopulations, termed hubs, was found to display lowered expression of β-cell maturity markers and insulin, but increased expression of glucose-sensing enzymes, including glucokinase[21,22] These studies provide the first glimpse that immature cells with similar characteristics might contribute to the regulation of insulin release across the islet. Heterogeneity in PDX1 and MAFA is encoded at the individual β-cell level by the islet Ca2+ signaling network, and maintaining a balance between PDX1LOW/MAFALOW:PDX1HIGH/MAFAHIGH β-cells restores Ca2+ fluxes during metabolic stress. Together, these results show that differences in PDX1 and MAFA levels, and more broadly in β-cell maturity, contribute to islet function
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