Pro-oxidant/antioxidant balance controls pancreatic β-cell differentiation through the ERK1/2 pathway

Cell Death Dis. 2014 Oct 23;5(10):e1487. doi: 10.1038/cddis.2014.441.


During embryogenesis, the intrauterine milieu affects cell proliferation, differentiation, and function by modifying gene expression in susceptible cells, such as the pancreatic β-cells. In this limited energy environment, mitochondrial dysfunction can lead to overproduction of reactive oxygen species (ROS) and to a decline in β-cell function. In opposition to this toxicity, ROS are also required for insulin secretion. Here we investigated the role of ROS in β-cell development. Surprisingly, decreasing ROS production in vivo reduced β-cell differentiation. Moreover, in cultures of pancreatic explants, progenitors were highly sensitive to ROS stimulation and responded by generating β-cells. ROS enhanced β-cell differentiation through modulation of ERK1/2 signaling. Gene transfer and pharmacological manipulations, which diminish cellular ROS levels, also interfered with normal β-cell differentiation. This study highlights the role of the redox balance on β-cell development and provides information that will be useful for improving β-cell production from embryonic stem cells, a step in cell therapy for diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Antioxidants / pharmacology*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
  • Catalase / metabolism
  • Cell Differentiation / drug effects*
  • Embryo, Mammalian / cytology
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Female
  • Hydrogen Peroxide / toxicity
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / enzymology*
  • MAP Kinase Signaling System / drug effects*
  • Nerve Tissue Proteins / metabolism
  • Oxidants / toxicity*
  • Phosphorylation / drug effects
  • Rats, Wistar


  • Antioxidants
  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Neurog3 protein, rat
  • Oxidants
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Hydrogen Peroxide
  • Catalase
  • Acetylcysteine