575-P: Serum Soluble Epoxide Hydrolase-Related Oxylipins Are Associated with Depression and Increased Symptom Severity in T2DM

Depression in T2DM is associated with inflammation (e.g., interleukin-6 [IL-6]), but specific inflammatory pathways, and depressive symptoms involved, have not been identified. Cytochrome P450s (CYP450s) convert dietary fatty acids into pro-resolving epoxides but soluble epoxide hydrolase (sEH) metabolizes these into inactive diols, thereby limiting their anti-inflammatory benefits. We hypothesized that sEH oxylipins (diols and epoxides) will be associated with depression and increased symptom severity in T2DM. Patients with T2DM were diagnosed with depression (Structured Clinical Interview, DSM-5) and matched 1:1 to non-depressed patients for sex, HbA1c and BMI. Fasting serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry. All analyses controlled for IL-6, measured by ELISA. Diol/epoxide ratios were calculated to estimate sEH pathway flux. Among 20 depressed and 20 non-depressed patients (mean age 58.9±8.5, mean HbA1c 7.0±0.9%, 65% women), the 17,18 sEH derived eicosapentaenoic acid (EPA) diol was higher in depressed participants (F(1,37)=5.753, p=0.022). Somatic, negative affective, and anhedonic symptoms were screened (Center for Epidemiological Studies-Depression Scale). Three diol/epoxide oxylipin ratios were associated with higher somatic symptoms in the depressed group: the 16,17 docosahexaenoic acid (DHA) derived ratio (β=0.489, p=0.007), and both linoleic acid derived ratios (9,10 [β=0.549, p=0.017] and 12,13 [β=0.547, p=0.003]). The 14,15 arachidonic acid derived ratio was associated with higher negative affective symptoms (β=0.559, p=0.006). These associations were not found in non-depressed T2DM. This increased flux of omega-3 and omega-6 fatty acids through the sEH pathway associated with depression and symptom severity suggests the potential role of sEH inhibitors for T2DM-related depressive symptoms.