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Publication
Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to
insulin sensitivity in mice and in humans.
Authors Gangadhariah MH, Dieckmann BW, Lantier L, Kang L, Wasserman DH, Chiusa M, Caskey
CF, Dickerson J, Luo P, Gamboa JL, Capdevila JH, Imig JD, Yu C, Pozzi A, Luther
JM
Submitted By Submitted Externally on 4/9/2018
Status Published
Journal Diabetologia
Year 2017
Date Published 6/1/2017
Volume : Pages 60 : 1066 - 1075
PubMed Reference 28352940
Abstract 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 × 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-1in
WT and Cyp2c44-/-mice respectively, p = 0.003). Although glucose uptake was
diminished in Cyp2c44-/-mice in vivo (gastrocnemius Rg16.4 ± 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. Capillary density was similar but
vascular KATP-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.




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