Markers of systemic oxidative stress correlated with the development and worsening of diabetic retinopathy among patients with longstanding, inadequately controlled type 2 diabetes, researchers reported.
For example, the mean levels of products of lipid peroxidation such as malondialdehyde and 4-hydroxyalkenals were 1.42 µmol/L in patients with mild diabetic retinopathy compared with 0.98 µmol/L in healthy controls, according to Alejandra Guillermina Miranda-Diaz, MD, PhD, of the University of Guadalajara in Mexico, and colleagues.
And in those with moderate and severe retinal involvement, levels rose to 2.49 µmol/L and 3.29 µmol/L (P<0.017), respectively, the researchers reported online in the Journal of Diabetes.
"Because [lipid peroxidation] is a well established mechanism of cellular lesions, these findings suggest cellular and systemic oxidative stress," Miranda-Diaz and colleagues observed.
Hyperglycemia in diabetes can lead to death of vascular cells and neurons in the retina, through various mechanisms such as the conversion of reactive oxygen species to hydrogen peroxide and singlet oxygen, which then can lead to lipid peroxidation.
"Chronic hyperglycemia alters the homeostasis of vascular endothelial cells and causes changes in the expression of genes that incite [diabetic retinopathy], favoring early functional changes that augment the permeability of the basal membrane of the retina, with endothelial cell dysfunction and increased oxidative stress," they explained.
Nitric oxide also contributes through the oxidation of nitric oxide synthase and the production of reactive nitrogen species.
In addition, mitochondrial dysfunction can further accelerate retinal apoptosis through morphologic disturbances.
To quantify these changes and their ocular effects in diabetes, the researchers enrolled 270 adult patients who had not been diagnosed with diabetic retinopathy along with age- and sex-matched nondiabetic controls.
They identified 12 patients with mild, 18 with moderate, and 30 with severe nonproliferative diabetic retinopathy.
Mean age of affected patients was about 60, and mean duration of diabetes was 15 years.
Mean hemoglobin (Hb) A1c levels were 8.21%, 8.98%, and 9% in the mild, moderate, and severe groups, respectively.
Glucose levels also were high, at 123.66 mg/dL, 148.77 mg/dL, and 142 mg/dL in the three groups, as were levels of total cholesterol, at 167.41, 199.66, and 202.81 mg/dL.
Among healthy controls, levels of nitric oxide catabolites averaged 12.31 pmol/mL. But in patients with mild, moderate, or severe retinopathy, the levels were 25.32 pmol/mL, 36.56 pmol/and 45.62 pmol/mL (P<0.0001), suggesting the presence of nitrosative stress, according to the researchers.
Aside from these pro-oxidant factors, abnormalities also were seen in patients' antioxidant profiles that correlated with worsening control of metabolic processes.
Compared with uric acid values of 22.41 mEq/mL (representing total antioxidant capacity) in healthy individuals, levels decreased to 16.05 mEq/mL, 12.90 mEq/mL, and 7.98 mEq/mL in patients with mild, moderate, and severe retinopathy.
"Uric acid has antioxidant activity by participating in the detoxification of lipid hydroperoxides into nontoxic alcohols," they wrote.
Catalase and glutathione peroxidase activity also increased with worsening retinopathy. For erythrocyte catalase activity, levels were 142.12, 136.45, and 139.40 U/mg protein in the mild, moderate, and severe groups (P<0.0001), while levels of glutathione peroxidase activity were 100.21, 95.32, and 117.13 U/min/mg protein (P<0.0001).
"It is possible that the greater catalase and [glutathione peroxidase] activity in nonproliferative [diabetic retinopathy] could be due to a compensatory response to the oxidative stress caused by a persistent metabolic disorder," the researchers suggested.
They then looked at mitochondrial function, measuring the fluidity of platelet mitochondrial membranes, and found that the fluorescence ratio of excimer to monomer was low in patients with all levels of retinopathy (P<0.0001).
"The decrease in fluidity compared with the control group could be related to the effect that the fluidity of the membrane has on membrane potential induced by the increase in HbA1c, dyslipidemia, oxidative stress, or their combination," the researchers explained.
Alterations in mitochondrial membranes have also been observed in Alzheimer's disease.
The research team also detected increases in the hydrolytic activity of mitochondrial ATP, which "could mean lower ATP synthesis with excessive production of cellular catabolism."
These findings could have implications for monitoring and treatment, they noted. For instance, periodic measurement of levels of products of lipid peroxidation could provide an early signal of incipient retinopathy, and the administration of antioxidants might help counteract oxidative stress.
"We believe that understanding the distinct molecular mechanisms responsible for mitochondrial damage could help identify management alternatives to postpone or prevent the [diabetic retinopathy] that threatens the vision of people who suffer from [diabetes mellitus]," they concluded.
Primary source: Journal of Diabetes
Source reference: Rodriguez-Carrizalez A, et al "Oxidants, antioxidants, and mitochondrial function in non-proliferative diabetic retinopathy" J Diabetes 2013; DOI: 10.1111/1753-0407.12076.