12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets.
CONTEXT: 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.
Published In/Presented At
Ma, K., Xiao, A., Park, S. H., Glenn, L., Jackson, L., Barot, T., Weaver, J. R., Taylor-Fishwick, D. A., Luci, D. K., Maloney, D. J., Mirmira, R. G., Imai, Y., & 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. https://doi.org/10.1210/jc.2017-00267
Medicine and Health Sciences
Department of Emergency Medicine, Department of Emergency Medicine Residents, Fellows and Residents