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

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journal contribution
posted on 01.02.2016 by Michael A. Kalwat, Zhimin Huang, Chonlarat Wichaidit, Kathleen McGlynn, Svetlana Earnest, Claudia Savoia, Elhadji M. Dioum, Jay W. Schneider, Michele R. Hutchison, Melanie H. Cobb
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.