Effects of isoxazole (ISX) on long-term cultured human islets

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

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Kalwat MA, Huang Z, Wichaidit C, McGlynn K, Earnest S, Savoia C, Dioum EM, Schneider JW, Hutchison MR, Cobb MH