Alterations in Epoxyeicosatrienoic Acids Metabolism in Type 2 Diabetes Mellitus and Potential Association with...

Epoxyeicosatrienoic acids (EETs), synthesized by cytochrome P450 epoxygenases (mainly CYP2C9, CYP2J2, and CYP2S1), are vasoprotective lipid mediators that are rapidly degraded by soluble epoxide hydrolase (sEH). This study aimed to examine changes in EET metabolism in T2DM patients with and without DR to understand its potential role in disease pathogenesis and progression.

Two hundred T2DM patients (without DR), 100 with non-proliferative DR (NPDR), 100 with proliferative DR (PDR), and 200 matched healthy controls were enrolled in the study. Plasma EET levels were quantified using LC-MS/MS, and mRNA and protein levels of CYP2J2, CYP2C9, CYP2S1, and sEH were measured using qPCR and ELISA, respectively.

Compared to the controls, T2DM without DR and NPDR groups, patients with PDR had significantly higher EET levels (p < 0.05). In contrast, the T2DM without DR and NPDR groups exhibited remarkably lower EET levels than controls, although this was not significant. In both groups, CYP2J2 and CYP2S1 mRNA and/or protein levels were significantly lower, suggesting suppressed EET biosynthesis. However, CYP2C9 protein levels were higher in NPDR and PDR groups than in the control group. Furthermore, in the comparison between NPDR and PDR, CYP2J2 and CYP2S1 mRNA levels were higher in PDR, whereas CYP2C9 and EPHX2 expression did not differ significantly.

Plasma EET concentrations showed a tendency to be lower in the T2DM without DR and NPDR groups compared with healthy controls; however, these differences did not reach statistical significance. In contrast, patients with PDR exhibited significantly higher EET levels, suggesting stage-dependent alterations in EET metabolism during the progression of DR.

Altered EET metabolism may play a dual role in DR, influencing both early microvascular impairment and late-stage angiogenic progression.