Department of Pharmacology & Toxicology, Temerty Faculty of Medicine - University of Toronto, Canada; Sunnybrook Research Institute, Toronto, Ontario, Canada; KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Canada.
Sunnybrook Research Institute, Toronto, Ontario, Canada; Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Psychiatry - University of Toronto, Canada.
J Diabetes Complications. 2024 Sep;38(9):108826. doi: 10.1016/j.jdiacomp.2024.108826. Epub 2024 Jul 22.
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).
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.
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 (F = 6.094, p = 0.015 and F = 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 (F = 12.137, p < 0.001), 5(6)-epoxyeicosatrienoic acid (5(6)-EpETrE; F = 6.481, p = 0.012) and 11(12)-EpETrE (F = 4.409, p = 0.038), and 2) verbal memory, including 9(10)-EpOME (F = 4.286, p = 0.041), 5(6)-EpETrE (F = 6.845, p = 0.010), 11(12)-EpETrE (F = 3.981, p = 0.049) and 14(15)-EpETrE (F = 5.019, p = 0.027).
Associations of CYP450-sEH metabolites and depressive symptoms with cognition highlight the biomarker and therapeutic potential of the CYP450-sEH pathway in T2DM.
本研究旨在探讨 2 型糖尿病（T2DM）患者血清细胞色素 P450 可溶性环氧化物水解酶（CYP450-sEH）氧化脂素与抑郁症状共同与认知表现的关系。
本研究招募了临床认知正常的 T2DM 个体（NCT04455867）。使用贝克抑郁量表第二版（BDI-II；总分为≤13 表示轻度抑郁症状，≥14 表示重度抑郁症状）评估抑郁症状严重程度。使用执行功能和言语记忆评估进行评估。通过超高效液相色谱串联质谱法定量测定空腹血清氧化脂素。
本研究包括 85 名轻度抑郁症状患者和 27 名重度抑郁症状患者（平均年龄：63.3±9.8 岁，49%为女性）。在所有参与者中，较高浓度的亚油酸衍生的 sEH（12,13-二羟基十八碳单烯酸；DiHOME）和 CYP450（12（13）-环氧十八碳单烯酸；EpOME）代谢物与执行功能较差相关（F=6.094，p=0.015 和 F=5.598，p=0.020）。多个 sEH 底物的浓度与抑郁症状相互作用，预测 1）执行功能较差，包括 9（10）-环氧十八碳三烯酸（9（10）-EpOME；F=12.137，p<0.001）、5（6）-环氧二十碳三烯酸（5（6）-EpETrE；F=6.481，p=0.012）和 11（12）-环氧二十碳三烯酸（11（12）-EpETrE；F=4.409，p=0.038），以及 2）言语记忆较差，包括 9（10）-EpOME（F=4.286，p=0.041）、5（6）-EpETrE（F=6.845，p=0.010）、11（12）-EpETrE（F=3.981，p=0.049）和 14（15）-环氧二十碳四烯酸（14（15）-EpETrE；F=5.019，p=0.027）。
CYP450-sEH 代谢物和抑郁症状与认知的关联突出了 CYP450-sEH 途径在 T2DM 中的生物标志物和治疗潜力。
