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CYP2C44 is expressed in the vascular endothelium, kidney and liver and its disruption reduces EET production, alters sodium handling and causes hypertension in response to dietary sodium or potassium loading. EETs act as endothelium-derived vasodilators and in mice multiple isoforms possess EET synthase activity (e.g. EETs are hydrolysed to less biologically active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). The CYP arachidonic acid monooxygenases oxidise arachidonic acid either to 5,6-, 8,9-, 11,12- or 14,15-EET via CYP2 isoforms or to 19- or 20-hydroxyeicosatetraenoic acid (HETE) via CYP4 isoforms. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure via renal and vascular actions and may also improve glucose homeostasis. Compensatory hyperinsulinaemia in insulin-resistant individuals has been associated with cardiovascular events and has been implicated in the development of hypertension. Obesity, hypertension, and type 2 diabetes are linked by insulin resistance and endothelial dysfunction, although the aetiology of these associations remains unclear. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension. Conclusions/interpretationĬYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants. 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. Although glucose uptake was diminished in Cyp2c44 −/− mice in vivo (gastrocnemius R g 16.4 ± 2.0 vs 6.2 ± 1.7 μmol 100 g −1 min −1, p < 0.01) insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. ResultsĬyp2c44 −/− mice showed decreased glucose tolerance (639 ± 39.5 vs 808 ± 37.7 mmol/l × 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). Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry. Vascular function was tested in isolated perfused mesenteric vessels. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets.
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We assessed insulin sensitivity in wild-type (WT) and Cyp2c44 −/− mice using hyperinsulinaemic–euglycaemic clamps and isolated skeletal muscle.
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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. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. Insulin resistance is frequently associated with hypertension and type 2 diabetes.