Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces β Cell Proliferation

Cell Metab. 2016 Jan 12;23(1):179-93. doi: 10.1016/j.cmet.2015.10.016. Epub 2015 Nov 25.


Pancreatic β cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive β cells into more pliable states with reduced cellular insulin levels, increased β cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ∼50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia. Transcriptome, proteome, and network analysis revealed alleviation of chronic endoplasmic reticulum (ER) stress, indicated by reduced Ddit3, Trib3, and Atf4 expression; reduced Xbp1 splicing; and reduced phospho-eIF2α. This state was associated with hyper-phosphorylation of Akt, which is negatively regulated by Trib3, and with cyclinD1 upregulation. Remarkably, β cell proliferation was increased 2-fold after reduced insulin production independently of hyperglycemia. Eventually, recombined cells mis-expressed glucagon in the hyperglycemic state. We conclude that the normally high rate of insulin production suppresses β cell proliferation in a cell-autonomous manner.

Keywords: ER stress; beta cells; dedifferentiation; diabetes; insulin; islets; metabolomic; proliferation; protein synthesis; proteomic; transcriptomic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • Cells, Cultured
  • Endoplasmic Reticulum Stress*
  • Insulin / biosynthesis*
  • Insulin-Secreting Cells / physiology*
  • Metabolome
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Protein Interaction Maps
  • Proteome / metabolism
  • Signal Transduction
  • Transcriptome


  • Insulin
  • Proteome