Single-nucleus RNA-sequencing reveals singular gene signatures of human ductal cells during adaptation to insulin resistance.


Adaptation to increased insulin demand is mediated by β-cell proliferation and neogenesis among other mechanisms. Although it is known that pancreatic β-cells can arise from ductal progenitors, these observations have been limited mostly to the neonatal period. We have recently reported that the duct is a source of insulin secreting cells in adult insulin resistant states. To further explore the signaling pathways underlying the dynamic β-cell reserve during insulin resistance we undertook human islet and duct transplantations under the kidney capsule of immunodeficient NOD SCID gamma (NSG) mouse models that were either pregnant, insulin resistant or had insulin resistance superimposed upon pregnancy (pregnancy+insulin resistance), followed by single-nucleus RNA-sequencing (snRNA-seq) on snap-frozen graft samples. We observed an upregulation of proliferation markers (e.g., NEAT1), expression of islet endocrine cell markers (e.g., GCG and PPY) as well as mature β-cell markers (e.g., INS), in transplanted human duct grafts in response to high insulin demand. We also noted downregulation of ductal cell identity genes (e.g., KRT19 and ONECUT2) coupled with upregulation of β-cell development and insulin signaling pathways. These results indicate that subsets of ductal cells are able to gain β-cell identity and reflect a form of compensation during the adaptation to insulin resistance in both physiological and pathological states.

Last updated on 07/15/2022