Abstract 256: Loss-of-function Gln287 Variant in EPHX2 is Associated With Increased Insulin Sensitivity

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Epoxyeicosatrienoic acids (EETs) induce vasodilation via activation of calcium-sensitive potassium channels and smooth muscle cell hyperpolarization. Soluble epoxide hydrolase (sEH) hydrolyzes EETs to less biologically active metabolites. The variant Gln287 of EPHX2 encodes for a sEH enzyme with reduced hydrolase activity. In murine models of type 2 diabetes, inhibition of sEH or EPHX2 deletion results in improved insulin sensitivity. In humans, forearm blood flow is significantly increased in Gln287 variant allele carriers. Given that insulin sensitivity is influenced by vascular perfusion, we hypothesized that insulin sensitivity would be increased in Gln287-carriers compared with wild-type individuals. Insulin secretion and sensitivity were assessed in 63 volunteers (43 with metabolic syndrome, 34 females, 42.5 ± 13 years old, 15 black Americans) during hyperglycemic clamps. Statistical analyses were adjusted for BMI. Plasma total- (r=0.63, p=0.007), 14-15- (r=0.62, p=0.008), and 11-12- (r=0.57, p=0.02) EET concentrations correlated with insulin sensitivity. There was no effect of genotype on insulin secretion (not shown). In individuals without metabolic syndrome, insulin sensitivity was significantly increased in Gln287 variant carriers compared with wild-type individuals (Fig. A). Insulin sensitivity was decreased in individuals with the metabolic syndrome, but also trended higher in Gln287 variant carriers when compared with wild-type individuals (Fig. B). Taken together, these results suggest that the loss-of-function Gln287 variant of EPHX2 is associated with increased insulin sensitivity.

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