Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications

Pharmacol Ther. 2019 Mar:195:100-110. doi: 10.1016/j.pharmthera.2018.10.010. Epub 2018 Oct 19.


12-lipoxygenase (12-LOX) is one of several enzyme isoforms responsible for the metabolism of arachidonic acid and other poly-unsaturated fatty acids to both pro- and anti-inflammatory lipid mediators. Mounting evidence has shown that 12-LOX plays a critical role in the modulation of inflammation at multiple checkpoints during diabetes development. Due to this, interventions to limit pro-inflammatory 12-LOX metabolites either by isoform-specific 12-LOX inhibition, or by providing specific fatty acid substrates via dietary intervention, has the potential to significantly and positively impact health outcomes of patients living with both type 1 and type 2 diabetes. To date, the development of truly specific and efficacious inhibitors has been hampered by homology of LOX family members; however, improvements in high throughput screening have improved the inhibitor landscape. Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors.

Keywords: Inflammation; Lipoxygenase; Lipoxygenase inhibitors; Type 1 diabetes; Type 2 diabetes-related complications.

Publication types

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

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / metabolism*
  • Arachidonate 15-Lipoxygenase / metabolism
  • Diabetes Complications / enzymology*
  • Diabetes Mellitus, Type 1 / enzymology*
  • Diabetes Mellitus, Type 2 / enzymology*
  • Humans
  • Insulin-Secreting Cells / enzymology
  • Lipoxygenase Inhibitors / pharmacology
  • Signal Transduction


  • Lipoxygenase Inhibitors
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase