A hallmark of type 2 diabetes (T2D) is endocrine islet β-cell failure, which can occur via cell dysfunction, loss of identity, and/or death. How each is induced remains largely unknown. We used mouse β-cells deficient for myelin transcription factors (Myt TFs; including Myt1, -2, and -3) to address this question. We previously reported that inactivating all three Myt genes in pancreatic progenitor cells (MytPancΔ) caused β-cell failure and late-onset diabetes in mice. Their lower expression in human β-cells is correlated with β-cell dysfunction, and single nucleotide polymorphisms in MYT2 and MYT3 are associated with a higher risk of T2D. We now show that these Myt TF-deficient postnatal β-cells also dedifferentiate by reactivating several progenitor markers. Intriguingly, mosaic Myt TF inactivation in only a portion of islet β-cells did not result in overt diabetes, but this created a condition where Myt TF-deficient β-cells remained alive while activating several markers of Ppy-expressing islet cells. By transplanting MytPancΔ islets into the anterior eye chambers of immune-compromised mice, we directly show that glycemic and obesity-related conditions influence cell fate, with euglycemia inducing several Ppy+ cell markers and hyperglycemia and insulin resistance inducing additional cell death. These findings suggest that the observed β-cell defects in T2D depend not only on their inherent genetic/epigenetic defects but also on the metabolic load.
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 Ca2+ 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.
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