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Transcriptionally mature and immature beta-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in beta-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1(HIGH) and MAFA(HIGH) beta-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1(HIGH) and MAFA(HIGH) beta-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 Ca(2+) signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the beta-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in beta-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

2021

Volume

12

Keywords

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