12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets.

Publication/Presentation Date

8-1-2017

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.

Volume

102

Issue

8

First Page

2789

Last Page

2797

ISSN

1945-7197

Disciplines

Medicine and Health Sciences

PubMedID

28609824

Department(s)

Department of Emergency Medicine, Department of Emergency Medicine Residents, Fellows and Residents

Document Type

Article

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