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<p>Pancreatic β-cell identity loss is increasingly recognized as a critical pathogenic contributor to β-cell failure in type 2 diabetes (T2D), but the specific mechanism remains to be characterized. In this study, we demonstrate that zinc accumulation contributes to β-cell identity loss during diabetes progression in both human and mouse islets. Using a model of human embryonic stem cell-derived islets (SC-islets), we reveal that accumulated zinc triggers the integrated stress response (ISR), with elevated ATF4 expression in SC-β cells. This, in turn, initiates expression of the α&#xa0;cell-specific transcription factor <i>ARX</i>, resulting in the conversion of β cells to α cells, thus forming a zinc-ATF4-ARX regulatory axis. Like primary β cells, SC-β cells also undergo identity loss after transplantation into diabetic animals, which can be prevented by an ISR inhibitor, resulting in improved glycemic control. Furthermore, both genetic depletion and chemical inhibition of zinc accumulation effectively safeguard SC-β cells from identity loss and enhance their efficacy in diabetic animals. Our study thus reveals a pathogenic mechanism in which zinc accumulation induces β-cell identity loss through lineage-tracing approaches and proposes a protective strategy to counteract this process.</p>

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Zinc accumulation-induced integrated stress response triggers β-cell identity loss

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月28日

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  • Qing Ma,
  • Wenjun Xu,
  • Xuan Wang,
  • Haoyu Nie,
  • Yukun Gao,
  • Rui Hu,
  • Zhihao Yang,
  • Xushu Wang,
  • Ta Na,
  • Xiangyi Chen,
  • Zhaoyue Wang,
  • Minglu Xu,
  • Li Shao,
  • Meng Guo,
  • Yanfang Liu,
  • Rongrong Le,
  • Shaorong Gao,
  • Weida Li

摘要

Pancreatic β-cell identity loss is increasingly recognized as a critical pathogenic contributor to β-cell failure in type 2 diabetes (T2D), but the specific mechanism remains to be characterized. In this study, we demonstrate that zinc accumulation contributes to β-cell identity loss during diabetes progression in both human and mouse islets. Using a model of human embryonic stem cell-derived islets (SC-islets), we reveal that accumulated zinc triggers the integrated stress response (ISR), with elevated ATF4 expression in SC-β cells. This, in turn, initiates expression of the α cell-specific transcription factor ARX, resulting in the conversion of β cells to α cells, thus forming a zinc-ATF4-ARX regulatory axis. Like primary β cells, SC-β cells also undergo identity loss after transplantation into diabetic animals, which can be prevented by an ISR inhibitor, resulting in improved glycemic control. Furthermore, both genetic depletion and chemical inhibition of zinc accumulation effectively safeguard SC-β cells from identity loss and enhance their efficacy in diabetic animals. Our study thus reveals a pathogenic mechanism in which zinc accumulation induces β-cell identity loss through lineage-tracing approaches and proposes a protective strategy to counteract this process.