Immunometabolic reprogramming and β-cell dedifferentiation: Integrated mechanisms driving type 2 diabetes progression

Type 2 diabetes is increasingly recognised as a condition driven by sustained metabolic overload and chronic low-grade inflammation rather than a simple decline in insulin secretion. Findings from single-cell transcriptomics, human islet studies, and metabolic profiling show that pancreatic β-cells undergo progressive alterations in identity when exposed to glucotoxic, lipotoxic, oxidative, and inflammatory stress. In parallel, cytokines, lipid intermediates, adipose-derived factors, hepatokines, myokines, and gut microbial metabolites generate an immunometabolic environment that accelerates β-cell dedifferentiation and promotes transitions toward progenitor-like or alternative endocrine states. Originally described through lineage-tracing studies in experimental models, β-cell dedifferentiation is now recognized as a dynamic and potentially reversible process shaped by immunometabolic stress in diabetes. This review synthesizes current evidence to illustrate how metabolic and immune pathways converge on key molecular regulators of β-cell fate. It further describes how interorgan communication reinforces these disturbances and contributes to the gradual shift of β-cells along a continuum of stress adaptation, functional decline, and identity loss. A conceptual framework, referred to as the beta-cell identity clock, is presented to capture the dynamic and potentially reversible nature of these transitions. Finally, emerging therapeutic strategies are discussed, including anti-inflammatory agents, metabolic modulators, epigenetic regulators, and regenerative approaches aimed at preserving or restoring β-cell identity in the context of modern metabolic stress.