Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada; KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, ON, Canada.
Sunnybrook Research Institute, Toronto, ON, Canada; KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, ON, Canada.
J Lipid Res. 2023 Jul;64(7):100395. doi: 10.1016/j.jlr.2023.100395. Epub 2023 May 26.
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 (F = 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 (F = 7.222, P = 0.008 and F = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F = 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.
2 型糖尿病（T2DM）会增加认知能力下降和痴呆的风险。有报道称，T2DM、肥胖和认知障碍患者的细胞色素 P450-可溶性环氧化物水解酶（CYP450-sEH）途径存在紊乱。我们研究了亚油酸（LA）衍生的 CYP450-sEH 氧化脂素与 T2DM 中的认知功能，并探讨了肥胖和非肥胖个体之间的潜在差异。该研究纳入了 51 名肥胖和 57 名非肥胖（平均年龄 63.0±9.9 岁，49%为女性）T2DM 患者。采用 Stroop 颜色-单词干扰测试、FAS 言语流畅性测试、数字符号替代测试和 Trails 制作测试 B 评估执行功能。采用加利福尼亚言语学习测试，第二版评估言语记忆。通过超高压液相色谱/质谱分析了 4 种 LA 衍生的氧化脂素，12,13-二羟基十八碳单烯酸（12,13-DiHOME）被认为是主要的研究物种。模型控制了年龄、性别、BMI、糖化血红蛋白 A1c、糖尿病病程、抑郁、高血压和教育。sEH 衍生的 12,13-DiHOME 与较差的执行功能评分相关（F=7.513，P=0.007）。CYP450 衍生的 12(13)-环氧十八碳单烯酸（12(13)-EpOME）与较差的执行功能和言语记忆评分相关（F=7.222，P=0.008 和 F=4.621，P=0.034）。肥胖与 12,13-DiHOME/12(13)-EpOME 比值之间存在交互作用（F=5.498，P=0.021），肥胖与 9(10)-环氧十八碳单烯酸（9(10)-EpOME）浓度之间存在交互作用（F=4.126，P=0.045），这些交互作用表明，在肥胖个体中，这些关系更为强烈。这些发现表明，CYP450-sEH 途径可能是 T2DM 认知能力下降的潜在治疗靶点。对于某些标志物，关系可能依赖于肥胖。
