Division of Diabetes and Endocrinology, Department of Internal Medicine, and.
Division of Metabolism and Disease, Department of Biophysics, Kobe University Graduate School of Health Science, Kobe, Japan.
JCI Insight. 2020 May 7;5(9):128820. 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.
EIF2AK4 编码氨基酸缺乏感应蛋白 GCN2，它被认为是日本人群 2 型糖尿病的易感基因。然而，GCN2 影响葡萄糖稳态的机制尚不清楚。在这里，我们发现携带 EIF2AK4 风险等位基因的个体胰岛素分泌减少，并且在高脂肪饮食下维持 GCN2 缺陷型小鼠会导致胰岛β细胞质量的丧失。我们的数据表明，GCN2 在β细胞中感知氨基酸缺乏，并限制机械靶标雷帕霉素复合物 1 的信号传导，以防止在高脂肪饮食消耗期间β细胞衰竭。
