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.
Highlights
The increasing prevalence of type 2 diabetes mellitus (T2DM) constitutes a serious health burden worldwide
The insulin sensitivity index (Supplemental Figure 1A) and glucose infusion rate (Supplemental Figure 1B) during the glucose clamp test did not differ significantly between individuals with or without the risk allele in any of the 3 groups, indicative of similar insulin sensitivity. These data indicate that insulin secretion is reduced in carriers of the risk allele for rs2250402 with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) compared with corresponding individuals without the risk allele, and that the impairment of pancreatic β cell function in the carriers worsens with increasing BMI
We have shown that an single nucleotide polymorphisms (SNPs) of EIF2AK4 that is associated with T2DM in the Japanese population is associated with reduced insulin secretion
Summary
The increasing prevalence of type 2 diabetes mellitus (T2DM) constitutes a serious health burden worldwide. Analysis of single nucleotide polymorphisms (SNPs) in Japanese individuals implicated the gene for eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) as a candidate susceptibility gene for T2DM [5, 6]. The protein encoded by EIF2AK4 is known as general control nonderepressible 2 (GCN2), which — in yeast and mammals — is activated as a result of amino acid deficiency. During such a deficiency, uncharged transfer RNAs (tRNAs) bind to a regulatory region of GCN2 and induce its autophosphorylation [7, 8]. Activated GCN2 phosphorylates eukaryotic initiation factor 2α (eIF2α) and thereby suppresses the initiation of general protein translation [9]. ATF4 activates the transcription of various genes related to amino acid metabolism, transport, and synthesis [11]
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