Insulin demand regulates β cell number via the unfolded protein response

J Clin Invest. 2015 Oct 1;125(10):3831-46. doi: 10.1172/JCI79264. Epub 2015 Sep 21.


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 types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factor 6 / antagonists & inhibitors
  • Activating Transcription Factor 6 / biosynthesis
  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / physiology
  • Adaptation, Physiological
  • Animals
  • Biomarkers
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Cell Division
  • Cells, Cultured
  • Endoplasmic Reticulum Stress / physiology
  • Endoplasmic Reticulum, Rough / ultrastructure
  • Gene Expression Regulation
  • Glycosylation
  • Humans
  • Hyperglycemia / physiopathology
  • Insulin / genetics
  • Insulin / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Models, Biological
  • Obesity / genetics
  • Obesity / physiopathology
  • Proinsulin / genetics
  • Protein Processing, Post-Translational / drug effects
  • Receptors, Leptin / deficiency
  • Recombinant Fusion Proteins / metabolism
  • Unfolded Protein Response / physiology*


  • ATF6 protein, human
  • Activating Transcription Factor 6
  • Atf6 protein, mouse
  • Biomarkers
  • Insulin
  • Receptors, Leptin
  • Recombinant Fusion Proteins
  • leptin receptor, mouse
  • Proinsulin