Islet Biology/Insulin Secretion

duces proinflammatory lipids that exacerbate β cell dysfunction and death. Inhibition of 12/15-LOX thereby provides a potential therapeutic approach to prevent glycemic deterioration in T1D, but to date no specific inhibitors have been tested T1D. Here we assessed the efficacy and mechanism of a novel and specific 12/15-LOX inhibitor, ML351. Using cultured β cells in vitro, ML351 exhibited no apparent toxicity across a range of concentration and led to improved survival in response to pro-inflammatory cytokines (PIC), which mimic the stress observed in T1D. In isolated mouse islets in vitro, ML351 inhibited production of the pro-inflammatory lipid mediator 12-hydroxyeicosatetraenoic acid, and in luciferase assays it dose-dependently increased activity of the anti-oxidant transcription factor Nrf2. Following oral or intraperitoneal administration of ML351 in mice penetrance of the drug was observed in multiple organs, including pancreas, fat, liver and brain. In the low-dose streptozotocin model of T1D in mice, ML351 administration prevented development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β oxidative stress, and preservation of β cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 in the prediabetic phase prevented glycemic deterioration and reduced invasive insulitis. In conclusion, our 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. Supported By: National Institutes of Health (T32DK064466), (R01DK105588 to R.G.M., J.L.N.); Diabetes Research Center (P30DK097512)