| First Author | Hernandez-Perez M | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 11 | Pages | 2875-2887 |
| PubMed ID | 28842399 | Mgi Jnum | J:245084 |
| Mgi Id | MGI:5915500 | Doi | 10.2337/db17-0215 |
| Citation | Hernandez-Perez M, et al. (2017) Inhibition of 12/15-Lipoxygenase Protects Against beta-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes. Diabetes 66(11):2875-2887 |
| abstractText | Islet beta-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 beta-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate beta-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 beta-cell oxidative stress, and preservation of beta-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced beta-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 beta-cell dysfunction and glycemic deterioration in models of T1D. |
