β-cell dedifferentiation in type 2 diabetes: Interplay of metabolic stress, endoplasmic reticulum dysfunction, and forkhead box protein O1 inhibition
Abstract
In this editorial, we highlight the study by Wang et al published in a recent issue of the World Journal of Diabetes. Type 2 diabetes is increasingly recognized as a β-cell dysfunction disorder, with apoptosis and dedifferentiation being key factors in insulin secretion loss. β-cell dedifferentiation is a regression from a mature insulin-secretory phenotype to a progenitor-like state, characterized by the loss of key transcription factors such as pancreatic and duodenal homeobox 1 and MAF bZIP transcription factor A, and the ectopic expression of developmental markers such as neurogenin 3 and aldehyde dehydrogenase 1 family member A3. This editorial discusses the key role of metabolic stress-saturated fatty acids and high glucose-in triggering dedifferentiation through endoplasmic reticulum (ER) stress and repression of the forkhead box protein O1 (FoxO1) transcription factor. The study by Wang et al demonstrated how ER dysfunction and FoxO1 suppression collaborate to destabilize β-cell identity. Notably, evidence suggests that this process can be reversed under certain circumstances, with potential for therapies aiming to redifferentiate β-cells or prevent identity loss. We also outline the therapeutic potential of modulating ER stress pathways, controlling FoxO1 activity, and developing biomarkers to track β-cell plasticity in patients. Overall, β-cell dedifferentiation knowledge and manipulation offer new avenues for the treatment of diabetes by restoring functional…
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