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bioRxiv · 10.1101/2025.05.11.653323

Deregulated Myt3 translation predisposes islet β-cells to dysfunction under obesity-induced metabolic stress

Hu, R.·Wang, Y.·Yagan, M.·Xu, Y.·Simmons, A.·Lau, K.·Liu, Q.·Gu, G.
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Abstract

In response to obesity-related metabolic stress, islet {beta}-cells adapt (or compensate) by increasing their secretory function and mass. Yet, for unknown reasons, this compensation is reversed in some individuals at some point to induce {beta}-cell failure and overt type 2 diabetes (T2D). We have previously shown that transcription factor Myt3 (St18) and its paralogs, Myt1 and Myt2, prevent {beta}-cell failure. Myt3 was induced at post-transcriptional levels by obesity-related stress in both mouse and human {beta} cells and its downregulation accompanied {beta}-cell dysfunction during T2D development. Single-nucleotide polymorphisms in MYT3 were associated with an increased risk of developing human diabetes. We now demonstrate that Myt3 translation is regulated by an upstream open-reading frame that overlaps with the main Myt3 open-reading frame in mice. Disrupting this overlap enhances Myt3 translation in mouse {beta} cells without metabolic stress but decreases it under high-fat-diet challenges. Consequently, this deregulation results in {beta}-cell dysfunction and glucose intolerance in mice, accompanied by compromised expression of several {beta}-cell function genes. These findings suggest that stress-induced Myt3 translation is part of the compensation mechanism that prevents {beta}-cell failure.

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Hu, R., Wang, Y., Yagan, M., Xu, Y., Simmons, A., Lau, K., Liu, Q., Gu, G.. 2025-05-15. Deregulated Myt3 translation predisposes islet β-cells to dysfunction under obesity-induced metabolic stress. https://doi.org/10.1101/2025.05.11.653323

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