Wenjun Xu

Human embryonic stem cell-derived β cells (SC-β cells) hold great promise for treatment of diabetes, yet how to achieve functional maturation and protect them against metabolic stresses such as glucotoxicity and lipotoxicity remains elusive. Our single-cell RNA-seq analysis reveals that ZnT8 loss of function (LOF) accelerates the functional maturation of SC-β cells. As a result, ZnT8 LOF improves glucose-stimulated insulin secretion (GSIS) by releasing the negative feedback of zinc inhibition on insulin secretion. Furthermore, we demonstrate that ZnT8 LOF mutations endow SC-β cells with resistance to lipotoxicity/glucotoxicity-triggered cell death by alleviating endoplasmic reticulum (ER) stress through modulation of zinc levels. Importantly, transplantation of SC-β cells with ZnT8 LOF into mice with preexisting diabetes significantly improves glycemia restoration and glucose tolerance. These findings highlight the beneficial effect of ZnT8 LOF on the functional maturation and survival of SC-β cells that are useful as a potential source for cell replacement therapies.

Abstract Obesity, a growing global health concern, is closely linked to depression. However, the neural mechanism of association between obesity and depression remains poorly understood. In this study, neural‐specific WFS1 deficiency exacerbates the vicious cycle of obesity and depression in mice fed a high‐fat diet (HFD), positioning WFS1 as a crucial factor in this cycle. Through human pluripotent stem cells (hESCs) neural differentiation, it is demonstrated that WFS1 regulates Zn 2+ homeostasis and the apoptosis of neural progenitor cells (NPCs) and cerebral organoids by inhibiting the zinc transporter ZnT3 under the situation of dysregulated lipid metabolism. Notably, riluzole regulates ZnT3 expression to maintain zinc homeostasis and protect NPCs from lipotoxicity‐induced cell death. Importantly, riluzole, a therapeutic molecule targeting the nervous system, in vivo administration prevents HFD‐induced obesity and associated depression. Thus, a WFS1‐ZnT3‐Zn 2+ axis critical is demonstrated for the vicious cycle of obesity and depression and that riluzole may have the potential to reverse this process against obesity and depression.

Zinc is an essential trace element that participates in a wide range of physiological processes. Cellular zinc homeostasis is tightly controlled by two families of transporters: the Zrt/Irt-like protein (ZIP/ SLC39) family, which mediates zinc influx into the cytoplasm, and the zinc transporter (ZnT/ SLC30) family, which facilitates zinc efflux or sequestration into intracellular organelles. Growing evidence implicates dysregulated expression or function of zinc transporters in the onset and progression of diverse pathological conditions. In this review, we provide a comprehensive overview of the molecular regulation and recent advances on ZIPs and ZnTs in diabetes and related disorders, including obesity, neurodegenerative diseases, cancers, and immune dysregulation. We also discuss ongoing scientific controversies regarding the mechanistic roles of zinc transporters, particularly ZnT8, in the pathogenesis of diabetes. Finally, we provide perspectives on the translational potential of zinc transporter-targeted strategies in precision medicine.

Pancreatic β cell loss by cellular stress contributes to diabetes pathogenesis. Nevertheless, the fundamental mechanism of cellular stress regulation remains elusive. Here, it is found that elevated zinc transportation causes excessive cellular stress in pancreatic β cells in diabetes. With gene-edited human embryonic stem cell-derived β cells (SC-β cells) and human primary islets, the results reveal that elevated zinc transportation initiates the integrated stress response (ISR), and ultimately leads to β cell death. By contrary, genetic abolishment of zinc transportation shields β cells from exacerbated endoplasmic reticulum stress (ER stress) and concurrent ISR. To target excessive zinc transportation with a chemical inhibitor, an isogenic SC-β cells based drug-screening platform is established. Surprisingly, independent of its traditional role as protein synthesis inhibitor at a high-dose (10 µm), low-dose (25 nm) anisomycin significantly inhibits zinc transportation and effectively prevents β cell loss. Remarkably, in vivo administration of anisomycin in mice demonstrates protective effects on β cells and prevents type 2 diabetes induced by high-fat diet. Overall, elevated zinc transportation is identified as a crucial driver of β cell loss and low-dose anisomycin as a potential therapeutic molecule for diabetes.

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.