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

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

J Clin Endocrinol Metab. 2017 05 10;:

Authors: Ma K, Park SH, Lindsey G, Laura J, Tatvam B, Weaver JR, Taylor-Fishwick DA, Luci DK, Maloney DJ, Mirmira RG, Imai Y, Nadler JL

Abstract
Context: 12-lipoxygenase (12-LO) pathway produces pro-inflammatory metabolites and its activation is implicated in islet inflammation associated with type 1 and type 2 diabetes (T1D, T2D).
Objectives: We aimed to test the efficacy of ML355, a new highly selective small molecule inhibitor of 12-LO, for the preservation of islet function.
Design: Human islets from non-diabetic donors were incubated with the mixture of TNFα, 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.
Settings: In vitro study
Participants: Human islets from organ donors age over 20-years-old of both sex and any race were used. T2D status was defined either from medical history or most recent hemoglobin A1c above 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 is efficacious in improving human islet function after cytokine treatment and in T2D islets in vitro. The study supports that the blockade of 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.

PMID: 28609824 [PubMed - as supplied by publisher]

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