PDX1(LOW) MAFA(LOW) beta-cells contribute to islet function and insulin release
Nasteska D., Fine NHF., Ashford FB., Cuozzo F., Viloria K., Smith G., Dahir A., Dawson PWJ., Lai YC., Bastidas-Ponce A., Bakhti M., Rutter GA., Fiancette R., Nano R., Piemonti L., Lickert H., Zhou Q., Akerman I., Hodson DJ.
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.