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

J Clin Endocrinol Metab. 2017 Aug 1;102(8):2789-2797. doi: 10.1210/jc.2017-00267.


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.

MeSH terms

  • Adult
  • Case-Control Studies
  • Diabetes Mellitus, Type 2 / metabolism*
  • Female
  • Glucose / pharmacology*
  • Humans
  • In Vitro Techniques
  • Inflammation
  • Insulin / metabolism*
  • Insulin Secretion
  • Interferon-gamma / pharmacology
  • Interleukin-1beta / pharmacology
  • Islets of Langerhans / drug effects*
  • Lipoxygenase Inhibitors / pharmacology*
  • Male
  • Middle Aged
  • Oxygen Consumption / drug effects*
  • Sulfonamides / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Young Adult


  • Insulin
  • Interleukin-1beta
  • Lipoxygenase Inhibitors
  • ML355
  • Sulfonamides
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Glucose