Insulin Promoter-Driven <i>Gaussia</i> Luciferase-Based Insulin Secretion Biosensor Assay for Discovery of β‑Cell Glucose-Sensing Pathways

High throughput screening of insulin secretion is intractable with current methods. We developed a secreted insulin–luciferase system (Ins-GLuc) in β cells that is rapid, inexpensive, and amenable to 96- and 384-well formats. We treated stable Ins-GLuc-expressing MIN6 cells overnight with 6298 marine natural product fractions. The cells were then washed to remove media and chemicals, followed by stimulation with glucose in the diazoxide paradigm. These conditions allowed the discovery of many insulin secretion suppressors and potentiators. The mechanisms of action of these natural products must be long-lasting given the continuance of secretory phenotypes in the absence of chemical treatment. We anticipate that these natural products and their target pathways will lead to a greater understanding of glucose-stimulated insulin secretion

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

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

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

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

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