Epoxyeicosatrienoic acids and glucose homeostasis in mice and men

Abstract

Epoxyeicosatrienoic acids (EETs) are formed from arachidonic acid by the action of P450 epoxygenases (CYP2C and CYP2J). Effects of EETs are limited by hydrolysis by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. Studies in rodent models provide compelling evidence that epoxyeicosatrienoic acids exert favorable effects on glucose homeostasis, either by enhancing pancreatic islet cell function or by increasing insulin sensitivity in peripheral tissues. Specifically, the tissue expression of soluble epoxide hydrolase appears to be increased in rodent models of obesity and diabetes. Pharmacological inhibition of epoxide hydrolase or deletion of the gene encoding soluble epoxide hydrolase (Ephx2) preserves islet cells in rodent models of type 1 diabetes and enhances insulin sensitivity in models of type 2 diabetes, as does administration of epoxyeicosatrienoic acids or their stable analogues. In humans, circulating concentrations of epoxyeicosatrienoic acids correlate with insulin sensitivity, and a loss-of-function genetic polymorphism in EPHX2 is associated with insulin sensitivity.

Keywords: Diabetes; Epoxyeicosatrienoic acids; Glucose; Insulin; Soluble epoxide hydrolase.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Figure 1

Possible mechanisms through which epoxyeicosatrienoic acids (EETs) improve glucose homeostasis. EETs are produced by the actions of epoxygenases CYP2C and CYP2J on arachidonic acid. EETs improve insulin signaling in muscle, liver and adipose tissue. Genetic deletion of Ephx2 or pharmacologic inhibition of soluble epoxide hydrolase increases insulin-induced tyrosyl phosphorylation of the insulin receptor and tyrosyl phosphorylation of (IRS)-1 as well as AKT phosphorylation in insulin-sensitive tissues.[, , –33] EETs also improve insulin sensitivity by increase capillary volume and microvascular blood flow in insulin sensitive tissues such as muscle.[33] The increase in capillary blood volume appears to be nitric oxide-independent, whereas increases in microvascular blood flow are nitric oxide-dependent. Not shown, EETs also preserve islet cell function and increase insulin secretion, particularly in rodent models of type 1 diabetes. The actions of EETs are limited by hydrolysis by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). sEH activity is often measured as the ratio of dihydroxyoctadecenoic acid (DiHOME) to epoxy-9Z-octadecenoic acid (EpOME). AKT, protein kinase B; IRS, insulin receptor substrate; G6Pase, glucose 6 phosphatase; glut 4, glucose transporter type 4; PDE, phosphodiesterase; PI3K, phosphoinositide 3-kinase

Figure 2

Plasma epoxyeicosatrienoic acids (EETs) in individuals without (N=28) and with (N=12) metabolic syndrome.[35] EETs were measured using UPLC/MS/MS. *P

Figure 3

Spearman’s correlation between plasma epoxyeicosatrienoic acid (EET) concentrations and insulin sensitivity index (ISI) calculated from hyperglycemic clamp.[35] Solid circles depict individuals with metabolic syndrome (MetSyn) and open circles those without MetSyn. Reprinted with permission.

Figure 4

Linear regression model fitted for log-transformed insulin sensitivity index (ISI) on genotype with adjustment for body mass index (BMI), as well as the interaction between genotype and BMI, in patients with or without metabolic syndrome. A smooth relationship was assumed for BMI using restricted cubic regression splines with three knots. Presented are predicted ISI as a function of BMI for Arg/Gln and Arg/Arg with metabolic syndrome set to overall mean; shaded area are 95% confidence intervals.