Insulin demand regulates β cell number via the unfolded protein response Academic Article uri icon


MeSH Major

  • Insulin
  • Insulin-Secreting Cells
  • Unfolded Protein Response


  • Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic β cell number expands in response to an increase in insulin demand. Lineage tracing shows that new β cells are generated from proliferation of mature, differentiated β cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the β cell unfolded protein response (UPR), which senses insulin production, as a regulator of β cell proliferation. Using genetic and physiologic models, we determined that among the population of β cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand-induced β cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human β cells, suggesting that therapeutic UPR modulation has potential to expand β cell mass in people at risk for diabetes. Together, this work defines a stem cell-independent model of tissue homeostasis, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand.

publication date

  • October 2015



  • Academic Article



  • eng

PubMed Central ID

  • PMC4607122

Digital Object Identifier (DOI)

  • 10.1172/JCI79264

PubMed ID

  • 26389675

Additional Document Info

start page

  • 3831

end page

  • 46


  • 125


  • 10