PMID- 37245563 OWN - NLM STAT- MEDLINE DCOM- 20230807 LR - 20230808 IS - 1539-7262 (Electronic) IS - 0022-2275 (Print) IS - 0022-2275 (Linking) VI - 64 IP - 7 DP - 2023 Jul TI - Cytochrome P450-soluble epoxide hydrolase derived linoleic acid oxylipins and cognitive performance in type 2 diabetes. PG - 100395 LID - S0022-2275(23)00068-8 [pii] LID - 10.1016/j.jlr.2023.100395 [doi] LID - 100395 AB - 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(1,98) = 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 (F(1,98) = 7.222, P = 0.008 and F(1,98) = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F(1,97) = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F(1,97) = 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. CI - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Anita, Natasha Z AU - Anita NZ AD - 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. FAU - Kwan, Felicia AU - Kwan F AD - 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. FAU - Ryoo, Si Won AU - Ryoo SW AD - 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. FAU - Major-Orfao, Chelsi AU - Major-Orfao C AD - Sunnybrook Research Institute, Toronto, ON, Canada; KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, ON, Canada. FAU - Lin, William Z AU - Lin WZ AD - 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. FAU - Noor, Shiropa AU - Noor S AD - 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. FAU - Lanctot, Krista L AU - Lanctot KL AD - 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; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. FAU - Herrmann, Nathan AU - Herrmann N AD - Sunnybrook Research Institute, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto, ON, Canada. FAU - Oh, Paul I AU - Oh PI AD - KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, ON, Canada. FAU - Shah, Baiju R AU - Shah BR AD - Sunnybrook Research Institute, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto, ON, Canada. FAU - Gilbert, Jeremy AU - Gilbert J AD - Sunnybrook Health Sciences Centre, Toronto, ON, Canada. FAU - Assal, Angela AU - Assal A AD - Sunnybrook Health Sciences Centre, Toronto, ON, Canada. FAU - Halperin, Ilana J AU - Halperin IJ AD - Sunnybrook Health Sciences Centre, Toronto, ON, Canada. FAU - Taha, Ameer Y AU - Taha AY AD - Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, Davis, CA, USA; West Coast Metabolomics Center, Genome Center, University of California, Davis, Davis, CA, USA; Center for Neuroscience, University of California, Davis, Davis, CA, USA. FAU - Swardfager, Walter AU - Swardfager W AD - 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. Electronic address: w.swardfager@utoronto.ca. LA - eng GR - PJT-159711/CIHR/Canada PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230526 PL - United States TA - J Lipid Res JT - Journal of lipid research JID - 0376606 RN - 9KJL21T0QJ (Linoleic Acid) RN - 0 (Oxylipins) RN - EC 3.3.2.- (Epoxide Hydrolases) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) SB - IM MH - Humans MH - Female MH - Middle Aged MH - Aged MH - Male MH - *Linoleic Acid/metabolism MH - *Diabetes Mellitus, Type 2/complications MH - Oxylipins/metabolism MH - Epoxide Hydrolases/metabolism MH - Cognition MH - Cytochrome P-450 Enzyme System MH - Obesity/complications PMC - PMC10394387 OTO - NOTNLM OT - Alzheimer's disease OT - inflammation OT - lipids OT - obesity OT - oxidized lipids COIS- Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. B. R. S. of Sunnybrook Health Sciences Centre is funded by the University of Toronto as the Novo Nordisk Research Chair in Equitable Care of Diabetes and Related Conditions. J. G. of Sunnybrook Health Sciences Centre received speaker honoraria from Abbott, Ascencia, Amgen, Astra Zeneca, Boehringer, Dexcom, Eli Lilly, HLS, Insulet, Janssen, Merck, Novo Nordisk, and Sanofi. J. G. also performs advisory services to Abbott, Amgen, Astra Zeneca, Boehringer, Dexcom, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. A. A. of Sunnybrook Health Sciences Centre received speaker honoraria from Solutions Event Management. I. J. H. of Sunnybrook Health Sciences Centre received speaker honoraria from Dexcom, Abbott, Sanofi, and Boehringer Ingelheim. These roles are unrelated to the present work. The other authors declare no conflicts of interest. EDAT- 2023/05/29 00:42 MHDA- 2023/08/07 06:41 PMCR- 2023/05/26 CRDT- 2023/05/28 19:23 PHST- 2023/02/11 00:00 [received] PHST- 2023/05/03 00:00 [revised] PHST- 2023/05/21 00:00 [accepted] PHST- 2023/08/07 06:41 [medline] PHST- 2023/05/29 00:42 [pubmed] PHST- 2023/05/28 19:23 [entrez] PHST- 2023/05/26 00:00 [pmc-release] AID - S0022-2275(23)00068-8 [pii] AID - 100395 [pii] AID - 10.1016/j.jlr.2023.100395 [doi] PST - ppublish SO - J Lipid Res. 2023 Jul;64(7):100395. doi: 10.1016/j.jlr.2023.100395. Epub 2023 May 26.