Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β-Cells

Novel strategies are needed to modulate beta-cell differentiation and function as potential beta-cell replacement or restorative therapies for diabetes. We previously demonstrated that small molecules based on the isoxazole scaffold drive neuroendocrine phenotypes. The nature of the effects of isoxazole compounds on beta-cells was incompletely defined. We find that isoxazole induces genes that support neuroendocrine and beta-cell phenotypes and suppresses genes important for proliferation. Isoxazole alters beta-cell metabolites and protects glucose-responsive signaling pathways under lipotoxic conditions. Finally, we show that isoxazole improves glycemia in a mouse model of beta-cell regeneration. Isoxazole is a prime candidate to alter cell fate in different contexts.