Inhibition of 12/15-Lipoxygenase Protects Against ß Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

Islet ß-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 ß cells and macrophages during T1D and produces pro-inflammatory lipids and lipid peroxides that exacerbate ß-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 suggested reduced promiscuity of ML351 compared to ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of pro-inflammatory 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 ß-cell oxidative stress, and preservation of ß-cell mass. In the non-obese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced ß-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in the insulitis. Our data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of ß-cell dysfunction and glycemic deterioration in models of T1D. Overall design: RNA-seq of Mouse islets treated with vehicle, Proinflammatory cytokine cocktail, and/or ML351 for 24 hours