ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells

Cell Metab. 2016 Apr 12;23(4):622-34. doi: 10.1016/j.cmet.2016.03.005.


Pancreatic β cells undergo postnatal maturation to achieve maximal glucose-responsive insulin secretion, an energy intensive process. We identify estrogen-related receptor γ (ERRγ) expression as a hallmark of adult, but not neonatal β cells. Postnatal induction of ERRγ drives a transcriptional network activating mitochondrial oxidative phosphorylation, the electron transport chain, and ATP production needed to drive glucose-responsive insulin secretion. Mice deficient in β cell-specific ERRγ expression are glucose intolerant and fail to secrete insulin in response to a glucose challenge. Notably, forced expression of ERRγ in iPSC-derived β-like cells enables glucose-responsive secretion of human insulin in vitro, obviating in vivo maturation to achieve functionality. Moreover, these cells rapidly rescue diabetes when transplanted into β cell-deficient mice. These results identify a key role for ERRγ in β cell metabolic maturation, and offer a reproducible, quantifiable, and scalable approach for in vitro generation of functional human β cell therapeutics.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / therapy
  • Glucose / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Insulin / metabolism
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / transplantation
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, SCID
  • Mitochondria / metabolism
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Up-Regulation


  • ESRRG protein, human
  • Esrrg protein, mouse
  • Insulin
  • Receptors, Estrogen
  • Glucose