Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans

Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) 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 analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans. We assessed insulin sensitivity in wild-type (WT) and Cyp2c44 (-/-) mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscle. 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. Cyp2c44 (-/-) mice showed decreased glucose tolerance (639 +/- 39.5 vs 808 +/- 37.7 mmol/l x min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 +/- 0.02 vs 0.33 +/- 0.01 mmol kg(-1) min(-1) in WT and Cyp2c44 (-/-) mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 (-/-) mice in vivo (gastrocnemius R-g 16.4 +/- 2.0 vs 6.2 +/- 1.7 mu mol 100 g(-1) min(-1), p < 0.01) insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular K-ATP-induced relaxation was impaired in isolated Cyp2c44 (-/-) vessels (maximal response 39.3 +/- 6.5% of control, p < 0.001), suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants. 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.