Ma, KaiwenXiao, AnPark, So HyunGlenn, LindseyJackson, LauraBarot, TatvamWeaver, Jessica R.Taylor-Fishwick, David A.Luci, Diane K.Maloney, David J.Mirmira, Raghavendra G.Imai, YumiNadler, Jerry L.2019-05-092019-05-092017-08-01Ma, K., Xiao, A., Park, S. H., Glenn, L., Jackson, L., Barot, T., … Nadler, J. L. (2017). 12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets. The Journal of clinical endocrinology and metabolism, 102(8), 2789–2797. doi:10.1210/jc.2017-00267https://hdl.handle.net/1805/19205Context: The 12-lipoxygenase (12-LO) pathway produces proinflammatory metabolites, and its activation is implicated in islet inflammation associated with type 1 and type 2 diabetes (T2D). Objectives: We aimed to test the efficacy of ML355, a highly selective, small molecule inhibitor of 12-LO, for the preservation of islet function. Design: Human islets from nondiabetic donors were incubated with a mixture of tumor necrosis factor α , interluekin-1β, and interferon-γ to model islet inflammation. Cytokine-treated islets and human islets from T2D donors were incubated in the presence and absence of ML355. Setting: In vitro study. Participants: Human islets from organ donors aged >20 years of both sexes and any race were used. T2D status was defined from either medical history or most recent hemoglobin A1c value >6.5%. Intervention: Glucose stimulation. Main Outcome Measures: Static and dynamic insulin secretion and oxygen consumption rate (OCR). Results: ML355 prevented the reduction of insulin secretion and OCR in cytokine-treated human islets and improved both parameters in human islets from T2D donors. Conclusions: ML355 was efficacious in improving human islet function after cytokine treatment and in T2D islets in vitro. The study suggests that the blockade of the 12-LO pathway may serve as a target for both form of diabetes and provides the basis for further study of this small molecule inhibitor in vivo.en-USPublisher PolicyDiabetes Mellitus -- Type 2GlucoseInsulinInterferon-gammaLipoxygenase InhibitorsOxygen ConsumptionArticle