TY - JOUR
T1 - GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels
AU - Kanno, Ayumi
AU - Asahara, Shun Ichiro
AU - Furubayashi, Ayuko
AU - Masuda, Katsuhisa
AU - Yoshitomi, Risa
AU - Suzuki, Emi
AU - Takai, Tomoko
AU - Kimura-Koyanagi, Maki
AU - Matsuda, Tomokazu
AU - Bartolome, Alberto
AU - Hirota, Yushi
AU - Yokoi, Norihide
AU - Inaba, Yuka
AU - Inoue, Hiroshi
AU - Matsumoto, Michihiro
AU - Inoue, Kenichi
AU - Abe, Takaya
AU - Wei, Fan Yan
AU - Tomizawa, Kazuhito
AU - Ogawa, Wataru
AU - Seino, Susumu
AU - Kasuga, Masato
AU - Kido, Yoshiaki
N1 - Funding Information:
We thank M. Nagano, M. Oya, A. Tanida, and S. Hirahara for technical assistance. This research was supported by a grant for the Cooperative Network of Unique Science and Technology for Economic Revitalization from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (to MK); a grant-in-aid for creative scientific research from MEXT (18GS0317 to MK); grants-in-aid for creative scientific research from MEXT (22590981, 25461352, and 17H01966 to YK); grants-in-aid for creative scientific research from MEXT (26461382 and 17K09882 to SIA); grants-in-aid for creative scientific research from MEXT (24790944, 26750040, and 16K09803 to MKK); a grant-in-aid for creative scientific research from MEXT (16K16277 to AK); grants from Hyogo Science and Technology Association (to YK); grants from The Naito Foundation (to YK); grants from The Food Science Institute Foundation (to SIA); and grants from Mishima Kaiun Memorial Foundation (to AK).
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/5/7
Y1 - 2020/5/7
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.128820
DO - 10.1172/jci.insight.128820
M3 - Article
C2 - 32376799
AN - SCOPUS:85084386143
SN - 2379-3708
VL - 5
JO - JCI insight
JF - JCI insight
IS - 9
M1 - e128820
ER -
