Cytochrome P450-soluble epoxide hydrolase derived linoleic acid oxylipins and cognitive performance in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been reported in T2DM, obesity and cognitive impairment. We examine linoleic acid (LA)-derived CYP450-sEH oxylipins and cognition in T2DM and explore potential differences between obese and nonobese individuals. The study included 51 obese and 57 nonobese participants (mean age 63.0 ± 9.9, 49% women) with T2DM. Executive function was assessed using the Stroop Color-Word Interference Test, FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B. Verbal memory was assessed using the California Verbal Learning Test, second Edition. Four LA-derived oxylipins were analyzed by ultra-high-pressure-LC/MS, and the 12,13-dihydroxyoctadecamonoenoic acid (12,13-DiHOME) considered the main species of interest. Models controlled for age, sex, BMI, glycosylated hemoglobin A1c, diabetes duration, depression, hypertension, and education. The sEH-derived 12,13-DiHOME was associated with poorer executive function scores (F1,98 = 7.513, P = 0.007). The CYP450-derived 12(13)-epoxyoctadecamonoenoic acid (12(13)-EpOME) was associated with poorer executive function and verbal memory scores (F1,98 = 7.222, P = 0.008 and F1,98 = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F1,97 = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F1,97 = 4.126, P = 0.045), predicting executive function such that relationships were stronger in obese individuals. These findings suggest that the CYP450-sEH pathway as a potential therapeutic target for cognitive decline in T2DM. For some markers, relationships may be obesity dependent.

Cytochrome P450-soluble epoxide hydrolase oxylipins, depression and cognition in type 2 diabetes.

AIMS: This study examined serum cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) oxylipins and depressive symptoms together in relation to cognitive performance in individuals with type 2 diabetes mellitus (T2DM). METHODS: Clinically cognitively normal T2DM individuals were recruited (NCT04455867). Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II; total scores ≤13 indicated minimal depressive symptoms and ≥ 14 indicated significant depressive symptoms). Executive function and verbal memory were assessed. Fasting serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass-spectrometry. RESULTS: The study included 85 participants with minimal depressive symptoms and 27 with significant symptoms (mean age: 63.3 ± 9.8 years, 49 % women). In all participants, higher concentrations of linoleic acid derived sEH (12,13-dihydroxyoctadecamonoenoic acid; DiHOME) and CYP450 (12(13)-epoxyoctadecamonoenoic acid; EpOME) metabolites were associated with poorer executive function (F1,101 = 6.094, p = 0.015 and F1,101 = 5.598, p = 0.020, respectively). Concentrations of multiple sEH substrates interacted with depressive symptoms to predict 1) poorer executive function, including 9(10)-EpOME (F1,100 = 12.137, p < 0.001), 5(6)-epoxyeicosatrienoic acid (5(6)-EpETrE; F1,100 = 6.481, p = 0.012) and 11(12)-EpETrE (F1,100 = 4.409, p = 0.038), and 2) verbal memory, including 9(10)-EpOME (F1,100 = 4.286, p = 0.041), 5(6)-EpETrE (F1,100 = 6.845, p = 0.010), 11(12)-EpETrE (F1,100 = 3.981, p = 0.049) and 14(15)-EpETrE (F1,100 = 5.019, p = 0.027). CONCLUSIONS: Associations of CYP450-sEH metabolites and depressive symptoms with cognition highlight the biomarker and therapeutic potential of the CYP450-sEH pathway in T2DM.