Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada.
Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Psychoneuroendocrinology. 2021 Apr;126:105149. doi: 10.1016/j.psyneuen.2021.105149. Epub 2021 Jan 19.
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.
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.
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).
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.
2 型糖尿病（T2DM）患者患抑郁症的风险增加。这两种情况都与多不饱和脂肪酸的紊乱有关。细胞色素 P450（CYP450）可将 ω-3 和 ω-6 脂肪酸转化为具有生物活性的环氧化物，在炎症反应中发挥促解决作用；然而，可溶性环氧化物水解酶（sEH）将环氧化物代谢为二醇，二醇缺乏促解决作用，并且具有细胞毒性。在这里，我们调查了 T2DM 患者伴或不伴重度抑郁症发作时的血清 CYP450 和 sEH 衍生代谢产物浓度。
Sunnybrook 2 型糖尿病研究（NCT04455867）参与者经历了重度抑郁症发作（DSM-5 标准的研究版结构化临床访谈），并根据性别、糖化血红蛋白 A1c 和体重指数与无当前抑郁发作的参与者进行 1:1 匹配。使用贝克抑郁量表 2 版（BDI-II）评估抑郁严重程度。从空腹晨血中，通过固相萃取后超高效液相色谱串联质谱法定量非酯化血清氧化脂，通过酶联免疫吸附试验定量白细胞介素 6（IL-6）。
在 20 名患有 T2DM 的抑郁组和 20 名非抑郁组参与者（平均年龄 58.9±8.5 岁，65%为女性）中，与抑郁发作相关的几种 sEH 衍生脂肪酸二醇，而非 IL-6，在抑郁组中较高（效应大小高达 d=0.796，用于评估 EPA 的 17,18-DiHETE；t=2.516，p=0.016）。在患有抑郁症的患者中，两种环氧化物与较低的 BDI-II 评分相关：12(13)-EpOME（ρ=-0.541，p=0.014）和 10(11)-EpDPE（ρ=-0.444，p=0.049），分别为亚油酸和二十二碳六烯酸（DHA）的代谢物，而 12,13-DiHOME/12(13)-EpOME 的比值与较高的 BDI-II 评分相关（ρ=0.513，p=0.021）。
在患有 T2DM 的患者中，重度抑郁症发作和抑郁症状严重程度与 sEH 消除促解决脂质介质的氧化脂谱一致。
