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Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.

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

Author information

1
Department of Medicine, Vanderbilt University, School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA.
2
Department of Biostatistics, Vanderbilt University, School of Medicine, 2525 West End, Nashville, TN 37203, USA.
3
Department of Medicine, Vanderbilt University, School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA. Electronic address: Nancy.j.brown@vanderbilt.edu.

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

[Indexed for MEDLINE]
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