Pseudotime Ordering of Single Human Beta-Cells Reveals States of Insulin Production and Unfolded Protein Response

We report the pseudotime ordering of single non-diabetic human beta-cells detected by large-scale RNA sequencing. We identified major states with 1) low UPR and low insulin gene expression, 2) low UPR and high insulin gene expression or 3) high UPR and low insulin gene expression. The latter state was enriched for proliferating cells. Stressed human beta-cells do not dedifferentiate and show little propensity for apoptosis. These data suggest that human beta-cells transition between states with high rates of biosynthesis to fulfill the body's insulin requirements to maintain normal blood glucose levels and UPR-mediated recovery from ER stress due to high insulin production. Overall design: Single-cell RNA sequencing of human pancreatic islets