Original Research ArticleArg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans
Introduction
An estimated 366 million people over the age of 20 years have type 2 diabetes worldwide and this number is predicted to grow to 552 million by 2030 [1]. Insulin resistance precedes the development of type 2 diabetes and can result from abnormalities in insulin signaling or from decreased perfusion of insulin-sensitive tissues. Type 2 diabetes results when insulin secretory capacity can no longer compensate for increased insulin requirements that result from resistance [2].
Studies in rodent models suggest that epoxyeicosatrienoic acids (EETs), epoxygenase metabolites of arachidonic acid, protect against the development of insulin resistance [3]. Cytochrome P450s (CYP2C and CYP2J) oxygenate arachidonic acid to form four different regioisomers of EETs [4], [5]. EETs are potent vasodilators [6], exert anti-inflammatory properties [7], and decrease sodium reabsorption in the kidney [8]. EETs are hydrolyzed to less biologically active dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolases, in particular soluble epoxide hydrolase (sEH) encoded for by the gene EPHX2 [9], [10].
In rodent models of obesity and insulin resistance, Cyp2c expression and EET levels are decreased [11], whereas adipose sEH expression is increased [12]. Conversely, treatment with a sEH inhibitor or disruption of Ephx2 improves insulin sensitivity and hepatic insulin signaling in high fat- or carbohydrate-fed rodents [3], [13], [14]. Studies in streptozotocin-treated [15] and high fat-fed mice [3] suggest that inhibition or deletion of sEH can also improve insulin secretion.
In humans, functional variants in EPHX2 encoding enzymes with increased (rs41507953 or Lys55Arg) or decreased (rs751141 or Arg287Gln) hydrolase activity have been associated with decreased and increased vasodilation, respectively [16], [17]. This study tested the hypothesis that functional variants in EPHX2 are associated with insulin sensitivity or secretion in individuals with and without the metabolic syndrome who underwent hyperglycemic clamp. We further examined the relationship between plasma EET concentrations and insulin sensitivity or the metabolic syndrome.
Section snippets
Subjects
We report data for subjects who participated in studies of metabolic function (NCT00732160, NCT00872599, NCT01409993, NCT01103245) and donated genomic DNA. All studies were approved by the Vanderbilt University Institutional Review Board and conducted in accordance with the Declaration of Helsinki. Informed consent was obtained for each study protocol and the collection of DNA.
Phenotyping
All subjects underwent a screening history and physical and blood was obtained after an overnight fast. Subjects were
Results
We found no relationship between EPHX2 Lys55Arg genotype and ISI, acute or late-phase glucose-stimulated insulin secretion, or DI (Supplemental Table 1). Thus, we focus on data analysis for EPHX2 Arg287Gln genotype.
Discussion
Soluble epoxide hydrolase, encoded for by EPHX2, hydrolyzes EETs to less biologically active DHETs. We report that carriers of a loss-of-function EPHX2 287Gln variant exhibit enhanced insulin sensitivity compared with carriers of the common allele. In addition, we report for the first time that circulating EET concentrations are decreased in individuals with the metabolic syndrome, and that EET concentrations correlate with insulin sensitivity. Taken together these data suggest that, as
Conclusions
The observation that a loss-of-function variant of EPHX2 and EETs are associated with higher insulin sensitivity has important clinical implications. Pharmacological inhibition of sEH increases cellular and circulating EET levels, potentiates vasodilation, and lowers blood pressure in preclinical models. Because of these properties, sEH inhibitors are currently under clinical development in humans. Studies are needed to determine whether pharmacological sEH inhibition improves insulin
Funding
This research was partly supported by DK038226, DK081662, HL060906, and UL1 RR024975 from the National Institutes of Health. This research was also partly supported by AHA09CRP2261428 from the American Heart Association. None of the funding sources had any role in the study design, analysis, or interpretation of the data or the preparation, review, or approval of the manuscript.
Author contributions
C.E.R. researched data, contributed to the discussion, wrote the manuscript, and reviewed and edited the manuscript. M.M.S. researched data, and reviewed the manuscript. K.G. researched data. H.N. data analysis, and reviewed the manuscript. C.Y. data analysis, and reviewed the manuscript. G.L.M. reviewed the manuscript. J.M.L. researched data, contributed to the discussion, and reviewed the manuscript. N.J.B. conceived the study, researched data, and reviewed and edited the manuscript. In
Acknowledgements
The authors wish to thank Dr. Bruce Hammock for his generosity in sharing methodology to measure DiHOME and EpOME. The authors thank Mrs. Loretta Byrne for assistance with subject recruitment, conduct of the research protocols, and data entry. The authors also thank Mr. Zhouzuo Wei and Mr. Anthony DeMatteo for laboratory assistance. The authors also thank Dr. Todd Edwards for his suggestions during the preparation of this manuscript.
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2021, EBioMedicineCitation Excerpt :Informed by these animal data, we hypothesized that higher plasma EETs were associated with lower risk of incident diabetes. Evidence for a role of EETs in diabetes in humans is limited to a handful of genetic studies [14–16]. A functional variant (287Gln) of sEH, encoded by EPHX2, is associated with greater insulin sensitivity in a study of 85 subjects without diabetes however, the genetic variant was not associated with plasma EETs [14].