Abstract
Genetic and environmental factors together cause islet β-cell failure, leading to Type 2 diabetes (T2D). Yet how they integrate to regulate β-cells remains largely unclear. Here, we examined how two members of the Myelin transcription factor family (MYT1, 2, and 3) prevent human β-cell failure under obesity-related stress. We have reported that obesity-related nutrient levels induce these factors. They prevent β-cell failure in mouse islets and human β-cell lines. Their variants are all associated with human T2D, and their downregulation accompanies β-cell dysfunction. By knocking down MYT1 or MYT3 separately in primary human donor islets, we show here that they have overlapping but distinct functions. Under normal culture conditions, MYT1-knockdown (KD) causes β-cell death, while MYT3-KD compromises glucose-stimulated insulin secretion. Under obesity-induced metabolic stress in vivo, MYT3-KD also causes β-cell death. Accordingly, these TFs regulate common and unique genes, with MYT1-KD de-regulating several genes in cell death and Ca(2+) binding, while MYT3-KD de-regulating genes involved in mitochondria, ER, etc. Intriguingly, the MYT1 and MYT3-regulated genes are enriched for T2D-associated genes. These findings suggest that the MYT TFs complement each other to serve as a node that integrates genetic and environmental factors to prevent β-cell failure and T2D.