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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.

Original publication

DOI

10.1038/s41467-020-20632-z

Type

Journal article

Journal

Nat Commun

Publication Date

29/01/2021

Volume

12

Keywords

Animals, Calcium, Cells, Cultured, Diabetes Mellitus, Type 2, Female, Gene Knock-In Techniques, Homeodomain Proteins, Humans, Insulin Secretion, Insulin-Secreting Cells, Maf Transcription Factors, Large, Male, Mice, Mice, Transgenic, Models, Animal, Primary Cell Culture, Trans-Activators