Myelin transcription factors 1 and 3 have overlapping but distinct roles in insulin secretion and survival of human β cells

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 MYT1 or MYT3 separately in primary human donor islets, we show here that these TFs have distinct functions. Under normal physiological conditions, high MYT1 expression is required for β-cell survival, while high MYT3 expression is needed for glucose-stimulated insulin secretion. Under obesity-induced metabolic stress, MYT3 is also necessary for β-cell survival. Accordingly, these TFs regulate different genes, with MYT1-KD de-regulating several in protein translation and Ca ²⁺ binding, while MYT3-KD de-regulating genes involved in mitochondria, ER, etc. These findings highlight not only the family member-specific functions of each TF but also the multilayered protective function of these factors in human β-cell survival under different levels of metabolic stress.