GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans

Abstract

Supplemental Digital Content is available in the text. Epoxyeicosatrienoic acids (EETs) reduce blood pressure by acting in the vasculature and kidney, and interventions to increase circulating EETs improve insulin sensitivity and prevent diabetes in animal models. Inhibition of EET hydrolysis with a sEH (soluble epoxide hydrolase) inhibitor is an attractive approach for hypertension and diabetes. We tested the hypothesis that sEH inhibition increases circulating EETs, reduces blood pressure, and improves insulin sensitivity, blood flow, and inflammation in a randomized, double-blind, placebo-controlled crossover study. Sixteen participants with obesity and prediabetes were randomized to GSK2256294 10 mg QD or placebo for 7 days, insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and adipose and muscle tissues biopsies were performed to assess insulin-stimulated Akt phosphorylation. We assessed tissue and plasma EETs and their respective diol concentrations and sEH activity within plasma, muscle, and adipose tissues. GSK2256294 reduced circulating and adipose tissue sEH activity, but blood pressure, circulating EET, and tissue EETs were unchanged. Plasma sEH activity correlated with muscle and adipose tissue sEH activity. Insulin sensitivity assessed during hyperinsulinemic clamps, as well as adipose and muscle phosphorylated-Akt/Akt expression were similar during GSK2256294 and placebo. sEH inhibition with GSK2256294 reduced plasma F2-isoprostanes (50.7±15.8 versus 37.2±17.3 pg/mL; P=0.03) but not IL (interleukin)-6. Resting blood pressure, forearm blood flow, and renal plasma flow were similar during GSK2256294 and placebo. We demonstrate that GSK2256294 administration for 7 days effectively inhibits sEH activity in plasma, muscle, and adipose tissue and reduces F2-isoprostanes—a marker of oxidative stress—but does not improve insulin sensitivity or blood pressure.