Harnessing Gut Endocrine Cell Plasticity to Restore Insulin Production

Type 1 diabetes (T1D) results from autoimmune-mediated destruction of pancreatic β-cells, leading to insulin deficiency and chronic hyperglycemia. β-cell replacement represents a promising therapeutic strategy, yet the identification of a sustainable and immune-compatible cell source remains a major challenge. Here, we explore the potential of the gastrointestinal (GI) epithelium as an alternative source of β-cells through in vivo cellular reprogramming. Given the large size and highly regenerative nature of the GI tract, partial reprogramming could provide a renewable source of insulin-producing (insulin⁺) cells. We demonstrate that ectopic expression of Pax4 is sufficient to convert gut endocrine L-cells into insulin⁺ cells in vivo. Phenotypic analyses reveal that these gut-derived cells express key β-cell markers, components of the glucose-sensing machinery, and properly process proinsulin into mature insulin. Functional studies using organoids derived from Pax4-expressing gut epithelium further demonstrate that these cells display glucose-responsive insulin secretion. Collectively, our findings highlight the plasticity of gut endocrine cells and support the feasibility of generating β-like cells from the GI epithelium, providing a potential avenue for the development of alternative cell-based therapies for T1D.