Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UK.
Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK.
Nat Commun. 2021 Jan 29;12(1):674. doi: 10.1038/s41467-020-20632-z.
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 PDX1 and MAFA β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1 and MAFA 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 Ca 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.
转录成熟和不成熟的β细胞共存于成人胰岛中。这种多样性如何促进胰岛素释放仍知之甚少。本文显示，使用 PDX1 和 MAFA 表达定义的β细胞成熟度的细微差异会影响胰岛的功能。对包含比例更高的 PDX1 和 MAFA β细胞的啮齿动物和人类胰岛进行功能映射，揭示了代谢、离子通量和胰岛素分泌的缺陷。在转录组水平上，增加 PDX1 和 MAFA β细胞的数量会导致参与代谢过程的基因途径失调。使用化学遗传破坏策略表明，PDX1 和 MAFA 表达的差异取决于胰岛 Ca 信号模式。在代谢应激期间，可以通过纠正整个β细胞群体中 PDX1 和 MAFA 水平之间的平衡来恢复胰岛功能。因此，维持 PDX1 和 MAFA 表达的异质性，更广泛地说，维持β细胞成熟的异质性，对于维持胰岛功能可能很重要。
