High glucose and fatty acid levels impair pancreatic beta cell function. We have recently shown that palmitate-induced loss of INS-1E insulinoma cells is related to increased reactive oxygen species (ROS) production as both toxic effects are prevented by palmitoleate. Here we show that palmitate-induced ROS are mostly mitochondrial: oxidation of MitoSOX, a mitochondria-targeted superoxide probe, is increased by palmitate, whilst oxidation of the equivalent non-targeted probe is unaffected. Moreover, mitochondrial respiratory inhibition with antimycin A stimulates palmitate-induced MitoSOX oxidation. We also show that palmitate does not change the level of mitochondrial uncoupling protein-2 (UCP2) and that UCP2 knockdown does not affect palmitate-induced MitoSOX oxidation. Palmitoleate does not influence MitoSOX oxidation in INS-1E cells ±UCP2 and largely prevents the palmitate-induced effects. Importantly, UCP2 knockdown amplifies the preventive effect of palmitoleate on palmitate-induced ROS. Consistently, viability effects of palmitate and palmitoleate are similar between cells ±UCP2, but UCP2 knockdown significantly augments the palmitoleate protection against palmitate-induced cell loss at high glucose. We conclude that UCP2 neither mediates palmitate-induced mitochondrial ROS generation and the associated cell loss, nor protects against these deleterious effects. Instead, UCP2 dampens palmitoleate protection against palmitate toxicity.



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Publication Title

Redox Biol



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Organisational Unit

School of Biomedical Sciences


Cytoprotection, Glucolipotoxicity, INS-1E insulinoma cells, Mitochondrial dysfunction, Non-esterified fatty acids, Obesity, Pancreatic beta cells, Reactive oxygen species, Type 2 diabetes, Uncoupling protein-2 (UCP2), Antimycin A, Cell Count, Cell Line, Tumor, Fatty Acids, Monounsaturated, Glucose, Humans, Insulin, Insulin-Secreting Cells, Insulinoma, Ion Channels, Mitochondria, Mitochondrial Proteins, Oxidation-Reduction, Pancreatic Neoplasms, Reactive Oxygen Species, Uncoupling Protein 2