GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels

JCI Insight. 2020 May 7;5(9):e128820. doi: 10.1172/jci.insight.128820.


EIF2AK4, which encodes the amino acid deficiency-sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear. Here, we show that insulin secretion is reduced in individuals harboring the risk allele of EIF2AK4 and that maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic β cell mass. Our data suggest that GCN2 senses amino acid deficiency in β cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent β cell failure during the consumption of a high-fat diet.

Keywords: Endocrinology; Insulin signaling; Islet cells; Metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acids / analysis*
  • Animals
  • Cell Line, Tumor
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetes Mellitus, Type 2* / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Insulin Secretion
  • Insulin-Secreting Cells* / metabolism
  • Insulin-Secreting Cells* / pathology
  • Liver* / metabolism
  • Liver* / pathology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Knockout
  • Middle Aged
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / physiology
  • Rats


  • Amino Acids
  • EIF2AK4 protein, human
  • Protein Serine-Threonine Kinases