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

Pancreatic ß cell identity loss is increasingly recognized as a critical pathogenic contributor to ß cell failure in type 2 diabetes (T2D), but the specific mechanism remains to be elucidated. In this study, we demonstrate that zinc accumulation contributes to the ß 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-ß cells. This, in turn, initiates a cell-specific transcription factor ARX expression, resulting in the conversion from ß cells to a cells, forming a regulatory axis of zinc-ATF4-ARX. Moreover, similar to primary ß cells, SC-ß cells also undergo identity loss after transplantation into diabetic animals, which can be prevented by using an ISR inhibitor, resulting in improved glycemic control. Furthermore, both genetic depletion and chemical inhibition of zinc accumulation effectively safeguard SC-ß cells from identity loss and enhance their efficacy in diabetic animals. Pioneeringly, our study unveils a pathogenic mechanism of accumulated zinc-induced ß cell identity loss through lineage-tracing approaches and proposes a protective strategy to counteract this process. Overall design: We first generated human embryonic stem cell derived islet (SC-islet) with reporter gene labeling ß cell from hESCs by stepwise pancreatic differentiation. Next, we performed single-cell RNA sequencing (scRNA-seq) on SC-islets with or without zinc treatment with high glucose to mimic hyperglycemia in diabetes.