Therapeutic Strategies for Pancreatic β cell Regeneration in Type 1 Diabetes

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disorder characterized by the selective destruction of pancreatic β-cells, leading to absolute insulin deficiency and lifelong dependence on exogenous insulin therapy. Despite advances in glucose monitoring and insulin delivery, these approaches fail to restore endogenous β-cell mass or address disease progression. Consequently, regenerative strategies aimed at preserving, replacing, or regenerating functional β-cells have emerged as promising therapeutic alternatives. This review comprehensively discusses current and emerging therapeutic strategies for pancreatic β-cell regeneration in T1D. Key mechanisms of β-cell regeneration, including β-cell proliferation, neogenesis, transdifferentiation of non-β cells, and redifferentiation of dedifferentiated β-cells, are explored in detail. Pharmacological approaches targeting immune modulation, β-cell proliferation, survival, senescence, and incretin signaling are highlighted, along with advances in targeted drug delivery and combination therapies. In addition, stem cell–based strategies involving mesenchymal, pluripotent, hematopoietic stem cells, and stem cell-derived exosomes are examined for their regenerative and immunomodulatory potential. Gene therapy and gene-editing technologies, including CRISPR/Cas9-based approaches, are discussed as innovative tools for reprogramming non-β cells, enhancing β-cell survival, and correcting genetic defects. Finally, the review addresses current challenges and future directions, emphasizing the need to overcome autoimmune destruction, improve functional maturation, ensure long-term graft survival, and enhance clinical scalability.