Kaiwen Ma1, An Xiao1, So Hyun Park1, Lindsey Glenn1, Laura Jackson1, Tatvam Barot1, Jessica R Weaver2, David A Taylor-Fishwick2, Diane K Luci3, David J Maloney3, Raghavendra G Mirmira4,5,6, Yumi Imai1,7, Jerry L Nadler1. 1. Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia 23507. 2. Department of Microbiology & Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia 23507. 3. National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850. 4. Department of Pediatrics, IU Center for Diabetes and Metabolic Disease, Indiana University School of Medicine, Indianapolis, Indiana 46202. 5. Departments of Biochemistry and Molecular Biology, Medicine, and Cellular and Integrative Physiology, IU Center for Diabetes and Metabolic Disease, Indiana University School of Medicine, Indianapolis, Indiana 46202. 6. Indiana Biosciences Research Institute, Indianapolis, Indiana 46202. 7. Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
Abstract
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.
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.
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