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

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 largely induced genes that support neuroendocrine and β-cell phenotypes, and suppressed a set of 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 for altering cell fate in different contexts. Overall design: We analyzed 3 pairs of long-term cultured human islet cells treated with either DMSO or ISX (20uM) for 7 days prior to RNA extraction using the Affymetrix GeneChip Human Transcriptome Array 2.0 platform. Data was analyzed in the Affymetrix Expression Console and Transcriptome Analysis Console v2.0. No technical replicates were performed.