GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels
Ayumi Kanno, … , Masato Kasuga, Yoshiaki Kido
Ayumi Kanno, … , Masato Kasuga, Yoshiaki Kido
Published May 7, 2020
Citation Information: JCI Insight. 2020;5(9):e128820. https://doi.org/10.1172/jci.insight.128820.
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Research Article Endocrinology Metabolism

GCN2 regulates pancreatic β 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 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.

Authors

Ayumi Kanno, Shun-ichiro Asahara, Ayuko Furubayashi, Katsuhisa Masuda, Risa Yoshitomi, Emi Suzuki, Tomoko Takai, Maki Kimura-Koyanagi, Tomokazu Matsuda, Alberto Bartolome, Yushi Hirota, Norihide Yokoi, Yuka Inaba, Hiroshi Inoue, Michihiro Matsumoto, Kenichi Inoue, Takaya Abe, Fan-Yan Wei, Kazuhito Tomizawa, Wataru Ogawa, Susumu Seino, Masato Kasuga, Yoshiaki Kido

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Figure 2

GCN2-KO mice exhibit glucose intolerance and reduced pancreatic β cell mass when fed a high-fat diet (HFD).

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GCN2-KO mice exhibit glucose intolerance and reduced pancreatic β cell m...
(A) Immunoblot analysis of GCN2 and β-actin in tissues of 12-week-old WT mice (upper) and the relative GCN2/β-actin ratio (lower). Data are the mean ± SEM (n = 4). Quantative data for 4 independent experiments are shown. (B) Immunoblot analysis of GCN2 in tissues from 12-week-old GCN2+/+, GCN2+/–, and GCN2–/– mice. (C–E) Blood glucose (C) and serum insulin concentrations (D) during an OGTT and immunostaining of insulin (red) and glucagon (green) in pancreatic sections (E, right) from 24-week-old normal chow diet–fed (NCD-fed) GCN2+/+ and GCN2–/– mice. Quantified pancreatic β cell mass (E, left). (F) Immunoblot analysis of phosphorylated and total GCN2 in the islets of 12- or 24-week-old WT mice fed a NCD or HFD. (G–I) Blood glucose (G), serum insulin levels (H) during an OGTT, and immunostaining of insulin (red) and glucagon (green) in pancreatic sections (I, right) from 24-week-old HFD-fed GCN2+/+ and GCN2–/– mice. Quantified pancreatic β cell mass (I, left). (J–L) Blood glucose (J), serum insulin levels (K) during an OGTT and immunostaining of insulin (red) and glucagon (green) in pancreatic sections (L, right) from 24-week-old HFD-fed βGCN2+/+ and βGCN2–/– mice. Quantified pancreatic β cell mass (L, left). Scale bars: 100 μm (E, I, and L ). Quantitative data in C–E and G–L are the mean ± SEM (n = 6–11). *P < 0.05, **P < 0.01 (2-tailed Student’s t test).