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.

Serum soluble epoxide hydrolase related oxylipins and major depression in patients with type 2 diabetes.

BACKGROUND: People with type 2 diabetes mellitus (T2DM) are at increased risk for depression. Both conditions are associated with disturbances in polyunsaturated fatty acids. Omega-3 and omega-6 fatty acids can be converted into bioactive epoxides by cytochrome P450s (CYP450), which play pro-resolving roles in the inflammatory response; however, soluble epoxide hydrolase (sEH) metabolizes epoxides into diols, which lack pro-resolving functions and can be cytotoxic. Here, we survey serum CYP450- and sEH-derived metabolite concentrations in people with T2DM with and without a major depressive episode. METHODS: Sunnybrook Type 2 Diabetes Study (NCT04455867) participants experiencing a major depressive episode (research version of the Structured Clinical Interview for DSM-5 criteria) were matched 1:1 for gender, glycosylated hemoglobin A1c and body mass index to participants without a current depressive episode. Depression severity was assessed using the Beck Depression Inventory 2nd Edition (BDI-II). From fasting morning blood, unesterified serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry following solid phase extraction, and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay. RESULTS: Between 20 depressed and 20 non-depressed participants (mean age 58.9 ± 8.5 years, 65% women) with T2DM, several sEH-derived fatty acid diols, but not IL-6, were higher among those with a depressive episode (effect sizes up to d = 0.796 for 17,18-DiHETE, a metabolite of eicosapentaenoic acid [EPA]; t = 2.516, p = 0.016). Among people with a depressive episode, two epoxides were correlated with lower BDI-II scores: 12(13)-EpOME (ρ = -0.541, p = 0.014) and 10(11)-EpDPE (ρ = -0.444, p = 0.049), metabolites of linoleic acid and docosahexaenoic acid (DHA), respectively, while the ratio of 12,13-DiHOME/12(13)-EpOME was correlated with higher BDI-II scores (ρ = 0.513, p = 0.021). CONCLUSIONS: In people with T2DM, major depressive episodes and depressive symptom severity were associated with an oxylipin profile consistent with elimination of pro-resolving lipid mediators by sEH.

Serum osteocalcin is associated with subjective stress in people with depression and type 2 diabetes.

BACKGROUND: Low serum osteocalcin is a risk factor for type 2 diabetes mellitus (T2DM), and osteocalcin release from bone is associated with an acute stress response in mice. Both diabetes and stress are associated with depression. Here, we assess relationships between serum osteocalcin, depression and subjective stress in people with T2DM. METHODS: Participants with T2DM (HbA1c above 6.4 %, impaired fasting glucose or impaired glucose tolerance) were assessed for a major depressive episode using the research version of the Structured Clinical Interview for DSM-5 depression criteria (SCID-5RV). Subjective stress over the past month was assessed using the Perceived Stress Scale (PSS). Serum carboxylated (cOCN) and fully decarboxylated (dcOCN) osteocalcin were assayed from fasting morning blood by commercial enzyme-linked immunosorbent assay. RESULTS: Among 95 participants (mean age 62.4 ± 9.9, 51 % women), 22 % were experiencing a depressive episode (9 men, 12 women). The presence of a depressive episode was not associated with dcOCN or cOCN concentrations; however, higher concentrations of cOCN were associated with higher PSS scores in participants with depression (r = 0.585, p = 0.005). In an analysis of covariance model controlling for age, sex, body mass index, glycemic control (glycosylated hemoglobin), insulin resistance (homeostatic model), depression, and antidepressant use, cOCN was associated with PSS scores (F=10.302, p = 0.002), and this relationship was stronger in those with depression (depression × cOCN interaction F=4.978, p = 0.028). Although associations between dcOCN concentrations and PSS scores did not reach significance, the same trend seen with cOCN concentrations was observed in participants with depression for dcOCN (r=0.365, p=0.10), and for a depression × dcOCN interaction associated with PSS scores in the whole group (F=2.165, p = 0.15). CONCLUSIONS: Osteocalcin is a neuroendocrine marker associated with perceived chronic stress among people with T2DM experiencing a depressive episode.