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

Novel strategies are needed to modulate
β-cell differentiation
and function as potential β-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 β-cells was
incompletely defined. We find that isoxazole induces genes that support
neuroendocrine and β-cell phenotypes and suppresses genes important
for proliferation. Isoxazole alters β-cell metabolites and protects
glucose-responsive signaling pathways under lipotoxic conditions.
Finally, we show that isoxazole improves glycemia in a mouse model
of β-cell regeneration. Isoxazole is a prime candidate to alter
cell fate in different contexts.