12-Lipoxygenase inhibitor improves functions of cytokine-treated human islets and type 2 diabetic islets

Kaiwen Ma, An Xiao, So Hyun Park, Lindsey Glenn, Laura Jackson, Tatvam Barot, Jessica R. Weaver, David A. Taylor-Fishwick, Diane K. Luci, David J. Maloney, Raghavendra G. Mirmira, Yumi Imai, Jerry L. Nadler

Research output: Contribution to journalArticle

3 Scopus citations

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-g 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.

Original languageEnglish (US)
Pages (from-to)2789-2797
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number8
DOIs
StatePublished - Aug 1 2017

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ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

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. Journal of Clinical Endocrinology and Metabolism, 102(8), 2789-2797. https://doi.org/10.1210/jc.2017-00267