Epoxyeicosatrienoic acids (EETs) are formed from arachidonic acid by the action 
of P450 epoxygenases (CYP2C and CYP2J). Effects of EETs are limited by 
hydrolysis by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic 
acids. Studies in rodent models provide compelling evidence that 
epoxyeicosatrienoic acids exert favorable effects on glucose homeostasis, either 
by enhancing pancreatic islet cell function or by increasing insulin sensitivity 
in peripheral tissues. Specifically, the tissue expression of soluble epoxide 
hydrolase appears to be increased in rodent models of obesity and diabetes. 
Pharmacological inhibition of epoxide hydrolase or deletion of the gene encoding 
soluble epoxide hydrolase (Ephx2) preserves islet cells in rodent models of type 
1 diabetes and enhances insulin sensitivity in models of type 2 diabetes, as 
does administration of epoxyeicosatrienoic acids or their stable analogues. In 
humans, circulating concentrations of epoxyeicosatrienoic acids correlate with 
insulin sensitivity, and a loss-of-function genetic polymorphism in EPHX2 is 
associated with insulin sensitivity.