Islet β-cell dysfunction, loss of identity, and death, together known as β-cell failure, lead to reduced inulin output and Type 2 diabetes (T2D). Understanding how β-cells avoid this failure holds the key to preventing or delaying the development of this disease. Here, we examine the roles of two members of the Myelin transcription factor family (including MYT1, 2, and 3) in human β-cells. We have reported that these factors together prevent β-cell failure by repressing the overactivation of stress response genes in mice and human β-cell lines. Single-nucleotide polymorphisms in MYT2 and MYT3 are associated with human T2D. These findings led us to examine the roles of these factors individually in primary human β-cells. By knocking down