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.
- Arachidonic Acid
- Insulin Sensitivity
- Insulin Secretion in vitro and in vivo
- Hypertension, epoxygenases