Sex-Specific Associations between Fatty Acid-Derived Oxylipins and Executive Function in T2DM

T2DM increases the risk of cognitive decline, especially in women. Sex-specific associations between lipids and cognition have been reported, though underlying mechanisms remain unclear. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been linked to both T2DM and cognitive dysfunction. CYP450s convert long-chain polyunsaturated fatty acids into epoxides which are anti-inflammatory and help resolve inflammation, however sEH metabolizes these into inactive or cytotoxic diols, limiting their benefits. We hypothesized that oxylipin epoxides and diols of arachidonic acid (AA) and docosahexaenoic acid (DHA) would be associated with cognition in people with T2DM, particularly in women. Women and men with T2DM were recruited as part of the study. Twenty-two fasting serum free oxylipins were quantified by ultra-high performance liquid chromatography tandem mass spectrometry. Executive function was assessed using a composite z-score from the following tests: Stroop Colour-Word Interference Victoria Version, FAS Verbal Fluency, Digit Symbol Substitution, and Trails Making Test Part B. All analyses controlled for age, sex, BMI, HbA1c and years of education. Among 72 individuals with T2DM (mean age 61.8±9.2, mean HbA1c 7.4±0.1%, 53% women), demographic characteristics, oxylipin concentrations and cognitive performance did not differ between women and men. Some CYP450-derived epoxides of DHA and AA were associated with lower executive function scores in women, but with higher scores in men. Epoxide × sex interactions were found for 3 of 4 DHA epoxides (16(17) [F=20.2, p<0.001]; 13(14) [F=8.5, p=0.005]; and 10(11) [F=7.4, p=0.009]), and for the 14(15) AA epoxide [F=3.9, p<0.05]). Circulating concentrations of the corresponding diols were not associated with executive function. These associations between epoxides and executive function suggest a sex difference in the relevance of the CYP450 pathway to cognitive performance in T2DM. Disclosure S.Ryoo: None. B.R.Shah: None. J.Gilbert: Speaker's Bureau; Abbott, AstraZeneca, Amgen Canada, Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Sanofi, Dexcom, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Novo Nordisk Canada Inc. A.Assal: None. I.Halperin: Advisory Panel; Sanofi, Speaker's Bureau; 3Boehringer Ingelheim Canada Ltd./Ltée, Abbott Diabetes, Dexcom, Inc., Novo Nordisk. A.Taha: None. W.Swardfager: None. N.Z.Anita: None. C.Major-orfao: None. W.Lin: None. S.Noor: None. F.Kwan: None. K.L.Lanctôt: Consultant; Exciva, GW Pharmaceuticals, ICG Farma, Merck Sharp & Dohme Corp., Novo Nordisk, Sumitomo Pharma Co. Ltd., Other Relationship; BioXcel, Cerevel Therapeutics, H Lundbeck A/S. N.Herrmann: None. P.Oh: Advisory Panel; Novartis Canada. Funding Canadian Institutes of Health Research; Banting & Best Diabetes Centre; National Institute of Diabetes and Digestive and Kidney Diseases