Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

Diabetes. 2017 Nov;66(11):2875-2887. doi: 10.2337/db17-0215. Epub 2017 Aug 25.


Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / genetics
  • Arachidonate 12-Lipoxygenase / metabolism*
  • Arachidonate 15-Lipoxygenase / genetics
  • Arachidonate 15-Lipoxygenase / metabolism*
  • Blood Glucose
  • Cells, Cultured
  • Computer Simulation
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Female
  • Humans
  • Hydroxyquinolines / chemistry
  • Hydroxyquinolines / pharmacology*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Mice
  • Mice, Inbred NOD
  • Molecular Structure
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Oxidative Stress
  • Protein Binding
  • Software
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*


  • 12-15-lipoxygenase
  • Blood Glucose
  • Hydroxyquinolines
  • Isoxazoles
  • Lipoxygenase Inhibitors
  • ML127 compound
  • ML351 compound
  • Naphthalenes
  • Thiophenes
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase