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GCN2 regulates pancreatic ? cell mass by sensing intracellular amino acid levels.

ABSTRACT: 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 ? cell mass. Our data suggest that GCN2 senses amino acid deficiency in ? cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent ? cell failure during the consumption of a high-fat diet.

SUBMITTER: Kanno A

PROVIDER: S-EPMC7253016 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Kanno Ayumi A Asahara Shun-Ichiro SI Furubayashi Ayuko A Masuda Katsuhisa K Yoshitomi Risa R Suzuki Emi E Takai Tomoko T Kimura-Koyanagi Maki M Matsuda Tomokazu T Bartolome Alberto A Hirota Yushi Y Yokoi Norihide N Inaba Yuka Y Inoue Hiroshi H Matsumoto Michihiro M Inoue Kenichi K Abe Takaya T Wei Fan-Yan FY Tomizawa Kazuhito K Ogawa Wataru W Seino Susumu S Kasuga Masato M Kido Yoshiaki Y

JCI insight 20200507 9

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 defici ...[more]

PMID: 32376799

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