Emerging Mechanisms Underlying Dedifferentiation and Transdifferentiation in Pancreatic B Cell

Type 2 diabetes (T2D) has long been viewed as a disease driven primarily by progressive loss of pancreatic β-cells resulting from chronic metabolic stress and apoptosis. Increasing evidence, however, indicates that impaired insulin secretion frequently arises from disruption of β-cell identity rather than extensive cellular depletion. Under diabetic conditions, mature β-cells may relinquish their differentiated phenotype through dedifferentiation, acquiring progenitor-like characteristics, or undergo transdifferentiation toward alternative endocrine cell fates, particularly α-cell-like phenotypes. These observations have shifted the current understanding of T2D toward a disorder characterized by β-cell plasticity and altered cell-state dynamics. In this review, we examine evidence from human pancreatic tissues, lineage-tracing studies, single-cell transcriptomic analyses, and experimental models to summarize the molecular mechanisms responsible for β-cell dedifferentiation and transdifferentiation. Particular emphasis is placed on the contribution of glucotoxicity, lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory signaling, and epigenetic regulation in destabilizing β-cell identity. To complement the published literature, we performed an integrated systems-level bioinformatics analysis of ten established regulators of β-cell identity, including PDX1, MAFA, NKX6.1, FOXO1, ALDH1A3, NEUROG3, BACH2, TCF7L2, UHRF1, and SMOC1. Functional enrichment and interaction network analyses revealed extensive coordination among pathways involved in pancreatic development, endocrine differentiation, glucose homeostasis, chromatin regulation, and diabetes-associated signaling, highlighting the interconnected molecular framework that maintains β-cell fate. We further discuss emerging concepts of endocrine plasticity, including β-to-α-cell conversion, hybrid endocrine cell states, and the growing evidence that β-cell dedifferentiation may be reversible. Finally, we evaluate current and emerging therapeutic strategies aimed at restoring β-cell identity through metabolic interventions, incretin-based therapies, epigenetic modulation, and regenerative approaches, emphasizing the potential of preserving or re-establishing endogenous β-cell function rather than simply enhancing insulin secretion.