Regulated and adaptive in vivo insulin secretion from islets only containing ß-cells

The activity of pancreatic islets' insulin-producing ß-cells is closely regulated by systemic cues and, locally, by adjacent islet hormone-producing “non-ß-cells” (namely a-, d- and ?-cells). Still, it is unclear whether the presence of the non-ß-cells is a requirement for accurate insulin secretion. Here, we generated and studied a mouse model in which adult islets are exclusively composed of ß-cells, and human pseudoislets containing only primary ß-cells. Mice lacking non-ß-cells had optimal blood glucose regulation. They exhibited enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under high-fat diet. The insulin secretion dynamics in islets composed of only ß-cells was like in intact islets, both in homeostatic conditions and upon extreme insulin demand. Similarly, human ß-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of human islets comprising all four cell types. Together, the findings indicate that non-ß-cells are dispensable for blood glucose homeostasis and ß-cell function. This is particularly relevant in diabetes, where non-ß-cells become dysfunctional and worsen the disease's pathophysiology. These results support efforts aimed at developing diabetes treatments by generating ß-like cell clusters devoid of non-ß-cells, as for example from human embryonic stem cells and/or by in situ conversion of non-ß-cells into insulin producers. Overall design: Comparative gene expression profiling analysis of RNA-seq data for FAC-sorted pancreatic beta-cells of control mice with intact islets and DT-treated beta-only mice, both under 2-hour refed or 8-hour fasting conditions.