Deregulated translation of the transcription factor Myt3 predisposes islet β cells to dysfunction under obesity-induced metabolic stress

In response to obesity-related metabolic stress, islet β 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 β-cell failure and overt type 2 diabetes. We have previously shown that transcription factor Myt3 (St18) and its paralogs, Myt1 and Myt2 (Myt1l), prevent β-cell failure. Myt3 was induced at post-transcriptional levels by obesity-related stress in both mouse and human β cells. Its downregulation, at both protein and transcript levels, accompanied human β-cell dysfunction during type 2 diabetes development. Single-nucleotide polymorphisms in MYT3 were associated with an increased risk of human diabetes. We now show that disrupting an upstream ORF that overlaps with the main Myt3 ORF can enhance Myt3 translation without metabolic stress but decreases it under high-fat diet challenges in islet β cells. Consequently, this deregulation results in β-cell dysfunction and glucose intolerance in mice, accompanied by compromised expression of several β-cell function genes under high-fat diet challenge. These findings suggest that stress-induced Myt3 translation is a part of the compensation mechanism that prevents β-cell failure in mice.