# Variation in Soluble Epoxide Hydrolase Activity and Human Insulin Sensitivity

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $467,438

## Abstract

PROJECT SUMMARY
The World Health Organization estimates that 422 million adults or 8.5% of the world’s adult population
has diabetes. Despite the development of promising new treatments for the prevention and treatment of
diabetes, the expense and inconvenience of newer therapies, coupled with new side effect profiles,
mandate that we continue to develop novel strategies to direct therapies to those at greatest risk of
developing type 2 diabetes mellitus (T2DM) and to identify potential new drug targets. This proposal
addresses the contribution of the epoxyeicosatrienoic acids (EETs)/ soluble epoxide hydrolase (sEH)
pathway to insulin sensitivity/resistance in humans. The EETs, P450 metabolites of arachidonic acid, are
well-established naturally occurring vasodilators and anti-inflammatory lipids. Hydrolysis by sEH limits
the activity of EETs, and reducing the hydrolysis of EETs by sEH prevents vascular, cardiovascular, and
renal injury in rodent models. Expression and activity of sEH are increased in rodent models of obesity
and diabetes. Studies in rodent models further suggest that decreasing the activity of sEH improves
insulin sensitivity either by increasing signaling in insulin-sensitive tissues or by enhancing capillary
recruitment. Our group has found that humans who carry a loss-of-function variant of the gene encoding
for sEH (EPHX2, rs751141 or Arg287Gln) have decreased vascular resistance and increased insulin
sensitivity, but we do not yet know the mechanism for increased insulin sensitivity and have not
assessed insulin sensitivity using the most rigorous methods. In addition, we do not know the effect of
human obesity on sEH activity. The purpose of the present proposal is to test the overarching
hypothesis that genetic or pharmacological factors that decrease sEH activity improve insulin
sensitivity, increase insulin-stimulated vasodilation, and increase tissue insulin signaling in
obese individuals. In Aim 1, we will test the hypothesis that the loss-of-function EPHX2 variant is
associated with increased insulin sensitivity measured using hyperinsulinemic-euglycemic clamp,
enhanced insulin-stimulated vasodilation, and increased insulin-signaling in muscle and adipose tissue in
obesity. We will assess the effect of genotype on tissue sEH activity and EET concentrations. In Aim 2,
we will test the hypothesis that a novel orally bioavailable specific small molecule inhibitor of sEH will
improve insulin sensitivity in obese individuals with prediabetes. This small molecule inhibitor of sEH,
GSK2256294, has already been tested safely in over one hundred people and we hold an IND for its
use. These studies promise to elucidate the physiological role of the EETs/sEH pathway in glucose
homeostasis and insulin sensitivity in humans. Moreover, these studies could lead to strategies to
identify those at highest risk of developing T2DM, as well as to the development of new pharmacological
targets for the prevention and treatment of T2DM.

## Key facts

- **NIH application ID:** 10170332
- **Project number:** 5R01DK117875-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Nancy J. Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $467,438
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170332

## Citation

> US National Institutes of Health, RePORTER application 10170332, Variation in Soluble Epoxide Hydrolase Activity and Human Insulin Sensitivity (5R01DK117875-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10170332. Licensed CC0.

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