In recent years, a growing body of epidemiological evidence has suggested oxidative stress may play a key role in the pathogenesis of diabetic retinopathy. While previous experimental studies have implicated oxidative damage in the development and progression of diabetic retinopathy [4], evidence from human observational studies directly linking oxidative biomarkers to clinically relevant outcomes has been limited [8, 15]. To address this knowledge gap, we conducted a population-based longitudinal cohort study of 5,251 U.S. adults, investigating the association between an integrated oxidative balance score (OBS) and risk as well as severity of diabetic retinopathy.
While previous studies have provided insights into oxidative stress and diabetic retinopathy, there are key differences between our study and prior literature.Firstly, most earlier observational studies focused exclusively on participants with existing diabetes or diabetic retinopathy [15–17]. In contrast, our study included both diabetic and non-diabetic individuals from the general population. The nationally representative sampling enhances generalizability of the findings. Secondly, the majority of preceding studies utilized only one or several circulating biomarkers such as 8-OHdG and isoprostanes to reflect oxidative stress status [18, 19]. However, our study employed an integrated oxidative balance score incorporating both pro- and anti-oxidants from dietary, lifestyle and metabolic factors. This provides a more comprehensive assessment of redox homeostasis.Thirdly, few prior studies examined hard clinical outcomes such as incident diabetic retinopathy or progression to vision loss [16]. We investigated the relationship between oxidative balance score and risk as well as severity of diabetic retinopathy over long-term follow-up. The prospective design and standardized outcome ascertainment are major strengths.
Oxidative stress exerts multifaceted effects in the complex pathogenesis of diabetic retinopathy. Under hyperglycemic conditions, mitochondrial overproduction of superoxide and downstream reactive oxygen species (ROS) is a central mechanism triggering oxidative injury to retinal capillary cells [4, 20]. Excessive ROS leads to activation of major biochemical pathways implicated in diabetic retinopathy, including increased polyol flux through aldose reductase, augmented advanced glycation end-product (AGE) formation, protein kinase C activation, and hexosamine pathway flux [21–23]. ROS also stimulate inflammation by upregulating release of adhesion molecules, cytokines and vascular endothelial growth factor (VEGF). This results in breakdown of the blood-retinal barrier, leukostasis and pathological angiogenesis [24–26]. Additionally, oxidative stress causes apoptotic death of retinal endothelial cells and pericytes through DNA damage and altered gene expression [27, 28].
Antioxidant nutrients and compounds may mitigate the multifaceted effects of oxidative stress through various mechanisms. Vitamin C, vitamin E, carotenoids and polyphenols can directly neutralize ROS and prevent downstream oxidative reactions [29, 30]. Other antioxidants like taurine and lipoic acid help regenerate depleted antioxidants such as glutathione. Certain antioxidants also activate the Nrf2-KEAP1 signaling pathway to induce endogenous antioxidant enzymes [31, 32]. These combined effects on redox homeostasis likely underlie the observed protective associations between higher antioxidant exposure and risk as well as severity of diabetic retinopathy.
Among patients with existing diabetic retinopathy, we found those with higher OBS had substantially lower long-term mortality risk. Several mechanistic pathways may underlie this observed association between oxidative balance and risk of death. Firstly, oxidative stress leads to retinal capillary cell apoptosis and breakdown of the blood-retinal barrier, resulting in progression of diabetic retinopathy and severe vision loss [33, 34]. Visual impairment is an established predictor of higher mortality, which may partly mediate the link between lower antioxidant status and increased mortality [35]. Secondly, optimal oxidative balance protects against micro- and macrovascular complications of diabetes through shared endpoints of endothelial dysfunction, low-grade inflammation and accelerated atherosclerosis [4, 21]. Diabetic nephropathy, cardiovascular disease, stroke and related complications that are more prevalent in those with poorer antioxidant status could contribute to higher mortality [36, 37].Finally, beyond diabetes, higher overall antioxidant exposure has been associated with lower risks of cancer, lung disease, infection, dementia and frailty – all of which can directly impact survival [38–40]. The cumulative effects of enhanced antioxidant capacity on this multitude of age-related conditions likely contributes to improved prognosis.
The application prospects of antioxidant interventions may encompass the following aspects: Lifestyle factors such as diet, smoking and exercise strongly influence oxidative balance, suggesting potential for lifestyle interventions to enhance antioxidant status and mitigate development and progression of diabetic retinopathy [8, 41, 42]. Epidemiological studies indicate higher intake of antioxidant-rich foods like fruits, vegetables, whole grains, nuts and fish are associated with lower incidence of diabetic retinopathy, whereas cigarette smoking increases risk [6, 7, 43]. Clinical trials also demonstrate antioxidant supplementation improves redox status in diabetic patients [41, 44]. However, direct evidence on the effects of lifestyle changes and antioxidant supplements on hard clinical outcomes like diabetic retinopathy remains limited [45, 46]. Further rigorously designed lifestyle and supplementation intervention studies are warranted to determine whether enhancing antioxidant exposure can effectively help prevent onset and progression of diabetic retinopathy.
This prospective cohort study providesinitial evidence linking higher cumulative antioxidant exposure assessed through OBS to lower risk and severity of diabetic retinopathy in U.S. adults. Our study highlights the potential role of oxidative stress in contributing to human diabetic retinopathy based on a composite measure of oxidative balance, rather than individual biomarkers. This underscores the importance of overall redox homeostasis beyond isolated antioxidant levels. The nationwide sampling and long-term follow-up for clinical outcomes are also major strengths. However, the observational design limits causal inference. Specific antioxidants driving the observed associations could not be determined given the composite exposure measure. Additional randomized controlled trials are warranted to establish whether interventions targeting oxidative balance could impact diabetic retinopathy pathogenesis and progression.