Cytochrome P450 Epoxygenase-Derived Epoxyeicosatrienoic Acids Contribute to Insulin Sensitivity in Mice and in Humans

Aims/hypothesis: Insulin resistance is frequently associated with hypertension and type 2 diabetes. The P450 arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analyzing mice lacking Cyp2c44, a
major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans.

Methods: We assessed insulin sensitivity in wild-type (WT) and Cyp2c44(-/-) mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscles. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated-perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry.

Results: Cyp2c44(-/-) mice showed decreased insulin sensitivity compared to WT controls. Although glucose uptake was diminished in Cyp2c44(-/-) mice in vivo, insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular KATP-induced relaxation was impaired in isolated Cyp2c44(-/-) vessels, suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human subjects.

Conclusions/Interpretation: CYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension.