Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans

Abstract

Epoxyeicosatrienoic acids (EETs) protect against the development of insulin resistance in rodents. EETs are hydrolyzed to less biologically active diols by soluble epoxide hydrolase (encoded for by EPHX2). Functional variants of EPHX2 encode for enzymes with increased (Lys55Arg) or decreased (Arg287Gln) hydrolase activity. This study tested the hypothesis that variants of EPHX2 are associated with insulin sensitivity or secretion in humans. Subjects participating in metabolic phenotyping studies were genotyped. Eighty-five subjects underwent hyperglycemic clamps. There was no relationship between the Lys55Arg genotype and insulin sensitivity or secretion. In contrast, the EPHX2 287Gln variant was associated with higher insulin sensitivity index (p=0.019 controlling for body mass index and metabolic syndrome). Also, there was an interactive effect of EPHX2 Arg287Gln genotype and body mass index on insulin sensitivity index (p=0.029). There was no relationship between EPHX2 Arg287Gln genotype and acute or late-phase glucose-stimulated insulin secretion, but disposition index was higher in 287Gln carriers compared with Arg/Arg (p=0.022). Plasma EETs correlated with insulin sensitivity index (r=0.64, p=0.015 for total EETs) and were decreased in the metabolic syndrome. A genetic variant that results in decreased soluble epoxide hydrolase activity is associated with increased insulin sensitivity, as are higher EETs.

Trial registration: ClinicalTrials.gov NCT00732160 NCT00872599 NCT01103245 NCT01409993.

Keywords: Epoxyeicosatrienoic acids; Insulin sensitivity; Metabolic syndrome; Soluble epoxide hydrolase.

Copyright © 2014 Elsevier Inc. All rights reserved.

Figures

Figure 1

Relationship between EPHX2 Arg287Gln genotype and insulin sensitivity index (ISI) in individuals with and without the metabolic syndrome (MetSyn). ISI was calculated from hyperglycemic clamps. *P

Figure 2

A linear regression model was fitted for log-transformed ISI on genotype with adjustment for BMI, metabolic syndrome as well as the interaction between genotype and BMI. 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 (solid line) and Arg/Arg (dashed line) with metabolic syndrome set to overall mean; shaded area are 95% confidence intervals. Solid and empty circles are observed data for individual subjects.

Figure 3

Plasma epoxyeicosatrienoic acids (EETs) in individuals without (N=28) and with (N=12) the metabolic syndrome (MetSyn). EETs were measured using UPLC/MS/MS as described in the methods. *P

Figure 4

Correlation between plasma epoxyeicosatrienoic acid (EET) concentrations and insulin sensitivity index (ISI) calculated from hyperglycemic clamp. Solid circles depict individuals with metabolic syndrome (MetSyn) and open circles those without MetSyn.