Clinical and Molecular-Genetic Insights into the Role of Oxidative Stress in Diabetic Retinopathy: Antioxidant Strategies and Future Avenues

Abstract

Reactive oxygen species (ROS) overproduction and ROS-signaling pathways activation attack the eyes. We evaluated the oxidative stress (OS) and the effects of a daily, core nutritional supplement regimen containing antioxidants and omega 3 fatty acids (A/ω3) in type 2 diabetics (T2DM). A case-control study was carried out in 480 participants [287 T2DM patients with (+)/without (-) diabetic retinopathy (DR) and 193 healthy controls (CG)], randomly assigned to a daily pill of A/ω3. Periodic evaluation through 38 months allowed to outline patient characteristics, DR features, and classic/OS blood parameters. Statistics were performed by the SPSS 24.0 program. Diabetics displayed significantly higher circulating pro-oxidants (p = 0.001) and lower antioxidants (p = 0.0001) than the controls. Significantly higher plasma malondialdehyde/thiobarbituric acid reactive substances (MDA/TBARS; p = 0.006) and lower plasma total antioxidant capacity (TAC; p = 0.042) and vitamin C (0.020) was found in T2DM + DR versus T2DM-DR. The differential expression profile of solute carrier family 23 member 2 (SLC23A2) gene was seen in diabetics versus the CG (p = 0.001), and in T2DM + DR versus T2DM - DR (p < 0.05). The A/ω3 regime significantly reduced the pro-oxidants (p < 0.05) and augmented the antioxidants (p < 0.05). This follow-up study supports that a regular A/ω3 supplementation reduces the oxidative load and may serve as a dietary prophylaxis/adjunctive intervention for patients at risk of diabetic blindness.

Keywords: antioxidants; candidate biomarkers; omega-3 fatty acids; oxidative stress; prevention of blindness; retinopathy; type 2 diabetes mellitus.

Figure 1

Flowchart of the recruitment, classification, and random assignation of the nutraceutical regimen in the study participants.

Figure 2

Oral supplement formula.

Figure 3

Ocular Fundus imaging. (A) Standard color fundus retinography showing 30° of the posterior eye pole (including the optic nerve head and the macula) of the RE from a participant of the CG (P: Optic nerve papilla; M: Macula; A: Retinal artery; V: Retinal vein). (B) Standard color fundus retinography showing 30° of the posterior eye pole of the RE displaying the clinical microvascular angiopathy manifestations of a T2DM patient with nonproliferative diabetic retinopathy (NPDR). Note the microaneurysms and abundant microhemorrhages (arrowthin), as well as macrohemorrhages (arrowhead). Scarce hard exudates (●) and cotton-wool spots (*) (being the latter grey-white discolored plaques located in the retinal nerve fiber layer, corresponding to local ischemic areas) were detected. The same abbreviations reflected in A for the main retinal structures can be detected in this pathologic image. No macular alterations were detected in this NPDR retinography. (C) Spectral Domain Optical Coherence tomography (SD-OCT) of a CG participant. Normal macular structural details of the same healthy participant as referred to in A. Among other retinal structures, the retinal nerve fiber layer (RNFL), retinal ganglion cell (RGC), and the retinal pigment epithelium (RPE)/Bruch’s membrane complex can be identified. (D) The microaneurysms and the hemorrhages (identified as hypo-reflective lesions) were present in the SD-OCT scans of the above diabetic patient, as referred in B. No macular changes and no neovascularization were detected in the NPDR images. (E) Central Macular Thickness in the right eye (RE) and left eye (LE) of the T2DM participants, as compared to the CG.

Figure 4

Plasmatic SLC23A2 relative expression at baseline. (A) T2DM vs. CG; (B) T2DM + DR vs. T2DM − DR vs. CG. (SLC23A2: Solute Carrier Family 23 Member 2 gene; T2DM: Type 2 diabetes mellitus, +/−DR: With/without diabetic retinopathy, CG: Control group. *: p < 0.05 statistically significant).