Hernandez-Perez, MarimarChopra, GauravFine, JonathanConteh, Abass M.Anderson, Ryan M.Linnemann, Amelia K.Benjamin, ChanelleNelson, Jennifer B.Benninger, Kara S.Nadler, Jerry L.Maloney, David J.Tersey, Sarah A.Mirmira, Raghavendra G.2019-06-282019-06-282017-11Hernandez-Perez, M., Chopra, G., Fine, J., Conteh, A. M., Anderson, R. M., Linnemann, A. K., … Mirmira, R. G. (2017). Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes. Diabetes, 66(11), 2875–2887. doi:10.2337/db17-0215https://hdl.handle.net/1805/19743Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.en-USPublisher PolicyArachidonate 12-LipoxygenaseArachidonate 15-LipoxygenaseBlood GlucoseCells, CulturedComputer SimulationDiabetes Mellitus, Type 1HydroxyquinolinesInsulin-Secreting CellsIsoxazolesLipoxygenase InhibitorsMice, Inbred NODMolecular StructureNaphthalenesOxidative StressProtein BindingThiophenesArticle