(DCP075) LINOLEIC ACID-DERIVED OXYLIPIN SPECIES AND COGNITIVE FUNCTION IN TYPE 2 DIABETES MELLITUS

Background: People with type 2 diabetes mellitus (T2DM) are at an increased risk of developing cognitive decline and dementia. While the underlying mechanisms remain unclear, cognitive impairment in T2DM has been associated with systemic inflammation. The cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway, which generates oxylipins (diols and epoxides), has been hypothesized to play a role in both T2DM and cognitive decline. Polyunsaturated fatty acids can be converted by CYP450s into epoxides that are anti-inflammatory and help resolve inflammation; however their beneficial effects are limited when metabolized by sEH into inactive or cytotoxic diols. We investigated serum oxylipins and executive function in individuals with T2DM. Obesity was also studied as it has been associated with altered oxylipin profiles and is common but not ubiquitous in this population.

METHODS AND RESULTS: T2DM participants (glycosylated hemoglobin [HbA1c] > 6.4%, impaired fasting glucose, and/or glucose intolerance) were recruited and divided into obese and non-obese groups (based on BMI ≥ 30 kg/m2). 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. Depression was diagnosed using the Structured Clinical Interview for DSM-5 criteria Research Version. Four linoleic acid-derived oxylipin species were analyzed by ultra-high pressure liquid chromatography tandem mass spectrometry. Diol/epoxide ratios were calculated to estimate overall sEH activity. All analyses were controlled for age, sex, BMI, HbA1c, diabetes duration, depression, hypertension, and years of education. To test interaction effects between oxylipins and obesity on executive function scores, analyses controlling for the same covariates except BMI were used, wherein obesity status and an obesity×oxylipin interaction were added. Among 108 T2DM participants (age 63.0±9.9, 49% women, 47% obese), the 12,13-diol was associated with lower executive function scores (F1,98=7.513, p=0.007). The 12(13)-epoxide was associated with poorer executive function (F1,98=7.222, p=0.008). There were interactions between obesity and the 12,13-diol/12(13)-epoxide ratio (F1,97=5.498, p=0.021), and between obesity and 9(10)-epoxide concentrations (F1,97=4.126, p=0.045) predicting executive function such that relationships were stronger in obese individuals.

Conclusion: The current findings suggest that perturbations in peripheral oxylipin concentrations may be associated with executive dysfunction in T2DM, and that obesity may also affect these mechanisms. Greater understanding of this pathway, and its relationships with metabolic symptoms, may prevent future complications. sEH inhibitors might be considered as a potential target for T2DM-related cognitive symptoms.