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.

Background: SPARC is a matricellular protein that is increased in type 2 diabetes patients. Results: SPARC is expressed by stromal cells within islets and inhibits growth factor responses and islet survival. Conclusion:The matricellular protein SPARC is a novel regulator of islet survival. Significance: The regulation of stromal-derived matricellular proteins represents a novel approach to promoting islet growth or survival.

Highlights d Vitamin-D-binding protein (DBP) is highly expressed in pancreatic a cells d Glucagon secretion and insulin tolerance are altered in mice lacking DBP d DBP-null a cells possess an abnormal actin cytoskeleton and are dysfunctional d DBP levels are decreased in a cells of donors with late-onset type 1 diabetes