title: 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.
authors.affiliation: Department of Medicine, Vanderbilt University, School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA.
authors.forename: Claudia E
authors.initials: CE
authors.lastname: Ramirez
authors.affiliation: Department of Medicine, Vanderbilt University, School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Shuey
authors.affiliation: Department of Medicine, Vanderbilt University, School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA.
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.affiliation: Department of Medicine, Vanderbilt University, School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gilbert
authors.affiliation: Department of Biostatistics, Vanderbilt University, School of Medicine, 2525 West End, Nashville, TN 37203, USA.
authors.forename: Nian
authors.initials: N
authors.lastname: Hui
authors.affiliation: Department of Biostatistics, Vanderbilt University, School of Medicine, 2525 West End, Nashville, TN 37203, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Medicine, Vanderbilt University, School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Luther
authors.affiliation: Department of Medicine, Vanderbilt University, School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA. Electronic address: Nancy.j.brown@vanderbilt.edu.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000328:Adult; D001095:Arachidonic Acids / Q000097:blood / Q000378:metabolism*; D015992:Body Mass Index; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004851:Epoxide Hydrolases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000502:physiology*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D001095:Arachidonic Acids; D007328:Insulin; D004247:DNA; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human
keywords: Epoxyeicosatrienoic acids; Insulin sensitivity; Metabolic syndrome; Soluble epoxide hydrolase