Activating transcription factor 4 (ATF4) is a regulator of the unfolded protein response and integrated stress response (ISR), which are known as adaptive mechanisms to endoplasmic reticulum (ER) stress. Previous reports demonstrated that dysregulation of the ISR showed development of severe diabetes. However, the roles of ATF4 in pancreatic β-cells remain unclear. First, we investigated the therapeutic effect of ISR enhancer Sephin1 on an animal model of diabetes using Akita mice. Sephin1 improved glucose metabolism and increased ATF4 expression in Akita mice. Next, we established β-cell-specific ATF4 knockout (βAtf4-KO) mice, which were then crossed with Akita mice. Akita/βAtf4-KO mice showed hyperglycemia and diabetic death caused by ketoacidosis. Interestingly, numbers of α-, δ-, and PP-cells were increased in the islets of Akita/βAtf4-KO mice, suggesting that ATF4-deleted β-cells are more vulnerable to dedifferentiation under ER stress condition. Finally, we identified ATOH8 as a downstream factor of ATF4, and showed that the downregulation of ATOH8 increased expressions of undifferentiation markers, Nanog and Oct4. These results indicated that the ATF4 contributes to maintaining β-cell identity and that ISR modulation could be a promising approach in the treatment of diabetes.