Functional interrogation of immature β-cells reveals their role in insulin release

Immature β-cells are present in adult islets. However, their contribution to insulin release is not fully understood. Here we show that specific loss of immature β-cells induces failure throughout the β-cell complement. Functional mapping of the β-cell population in rodent and human loss-of-immaturity islets revealed defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, loss of immature β-cells led to dysregulation of gene pathways involved in glucose and carbohydrate-derivative metabolic processes. Using a chemogenetic disruption strategy, immature β-cells were found to depend on the islet signaling network for their phenotype. During metabolic stress, islet function could be restored by redressing the balance between immature and mature β-cells. We thus unveil immature β-cells as a critical component in islet operation. Preserving immature β-cells might be important for islet engineering efforts and more broadly the treatment of type 1 and type 2 diabetes. RIP7rtTA+/-;TetO-M3C+/- mice possess a gene cassette comprising of the mouse Pdx1, Mafa, Ngn3, and mCherry genes under the control of the Tet-On system. Upon addition of doxycycline these genes are overexpressed in β-cells leading to an increase in the ratio of mature/immature cells. Gene expression changes in these mice compared with littermate controls was assessed using RNA-sequencing of islets isolated from these mice.