Serum soluble epoxide hydrolase related oxylipins and major depression in patients with type 2 diabetes

Natasha Z Anita; Nubaira Forkan; Radia Kamal; Michelle M Nguyen; Di Yu; Chelsi Major-Orfao; Sophie K Wong; Krista L Lanctôt; Nathan Herrmann; Paul I Oh; Baiju R Shah; Jeremy Gilbert; Angela Assal; Ilana J Halperin; Theresa L Pedersen; Ameer Y Taha; Walter Swardfager

doi:10.1016/j.psyneuen.2021.105149

Serum soluble epoxide hydrolase related oxylipins and major depression in patients with type 2 diabetes

Psychoneuroendocrinology. 2021 Apr:126:105149. doi: 10.1016/j.psyneuen.2021.105149. Epub 2021 Jan 19.

Authors

Natasha Z Anita¹, Nubaira Forkan², Radia Kamal², Michelle M Nguyen¹, Di Yu², Chelsi Major-Orfao³, Sophie K Wong¹, Krista L Lanctôt⁴, Nathan Herrmann⁵, Paul I Oh⁶, Baiju R Shah⁷, Jeremy Gilbert⁸, Angela Assal⁸, Ilana J Halperin⁸, Theresa L Pedersen⁹, Ameer Y Taha¹⁰, Walter Swardfager¹¹

Affiliations

¹ Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada.
² Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
³ Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada.
⁴ Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada; Department of Psychiatry - University of Toronto, 250 College Street 8th floor, Toronto, Ontario M5T 1R8, Canada.
⁵ Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Department of Psychiatry - University of Toronto, 250 College Street 8th floor, Toronto, Ontario M5T 1R8, Canada; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
⁶ University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada.
⁷ Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
⁸ Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
⁹ Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, Davis, CA, USA.
¹⁰ Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, Davis, CA, USA; NIH-West Coast Metabolomics Center, Genome Center, University of California - Davis, Davis, CA, USA.
¹¹ Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada. Electronic address: [email protected].

PMID: 33503568
DOI: 10.1016/j.psyneuen.2021.105149

Abstract

Background: People with type 2 diabetes mellitus (T2DM) are at increased risk for depression. Both conditions are associated with disturbances in polyunsaturated fatty acids. Omega-3 and omega-6 fatty acids can be converted into bioactive epoxides by cytochrome P450s (CYP450), which play pro-resolving roles in the inflammatory response; however, soluble epoxide hydrolase (sEH) metabolizes epoxides into diols, which lack pro-resolving functions and can be cytotoxic. Here, we survey serum CYP450- and sEH-derived metabolite concentrations in people with T2DM with and without a major depressive episode.

Methods: Sunnybrook Type 2 Diabetes Study (NCT04455867) participants experiencing a major depressive episode (research version of the Structured Clinical Interview for DSM-5 criteria) were matched 1:1 for gender, glycosylated hemoglobin A1c and body mass index to participants without a current depressive episode. Depression severity was assessed using the Beck Depression Inventory 2nd Edition (BDI-II). From fasting morning blood, unesterified serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry following solid phase extraction, and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay.

Results: Between 20 depressed and 20 non-depressed participants (mean age 58.9 ± 8.5 years, 65% women) with T2DM, several sEH-derived fatty acid diols, but not IL-6, were higher among those with a depressive episode (effect sizes up to d = 0.796 for 17,18-DiHETE, a metabolite of eicosapentaenoic acid [EPA]; t = 2.516, p = 0.016). Among people with a depressive episode, two epoxides were correlated with lower BDI-II scores: 12(13)-EpOME (ρ = -0.541, p = 0.014) and 10(11)-EpDPE (ρ = -0.444, p = 0.049), metabolites of linoleic acid and docosahexaenoic acid (DHA), respectively, while the ratio of 12,13-DiHOME/12(13)-EpOME was correlated with higher BDI-II scores (ρ = 0.513, p = 0.021).

Conclusions: In people with T2DM, major depressive episodes and depressive symptom severity were associated with an oxylipin profile consistent with elimination of pro-resolving lipid mediators by sEH.

Keywords: Depression; Inflammation; Omega-3 fatty acid; Oxylipin; Soluble epoxide hydrolase; Type 2 diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Depressive Disorder, Major* / blood
Diabetes Mellitus, Type 2* / complications
Epoxide Hydrolases* / blood
Female
Humans
Male
Middle Aged
Oxylipins* / blood

Substances

Oxylipins
Epoxide Hydrolases

Associated data

ClinicalTrials.gov/NCT04455867

Grants and funding

PJT-159711/CIHR/Canada