This study suggests vitamins from nutrient-rich food may decrease DR risk. Photo: Getty Images.

Carrots, with their ready supply of vitamin A, have long been touted as the food of choice for general eye health, but for patients with diabetic retinopathy (DR), it’s a little more complex, according to a recent study on the associations of circulating micronutrients and DR risk.

“Diabetes mellitus (DM) is predominantly a metabolically-driven pathogenesis,” wrote the study authors. “Appropriate nutritional and dietary advice form an essential part of DM management. Micronutrients, otherwise known as vitamins and minerals, also play an important role in the maintenance of metabolic homeostasis. While the number of people taking daily micronutrient supplements is rapidly rising, micronutrient supplementation hasn’t been adopted in general DM management methods due to the paucity of evidence on its benefits and potential adverse effects.”

The researchers noted that some studies have reported that micronutrients are protective against DM development and its complications by modulating insulin sensitivity and maintaining pancreatic β-cell function. Since these nutrients can be consumed as part of a well-balanced diet or with supplements, the researchers said further research on the real-world effects of micronutrients on DR may help guide clinical practice and patient behavior.

The cross-sectional study included 517 patients with diabetes (aged 40 and older) in the 2005-2006 National Health and Nutrition Examination Survey. The researchers assessed micronutrient levels (vitamins A, C, D, E and carotenoids). They converted serum vitamin D to liquid chromatography-tandem, mass spectrometry-equivalent results and measured the other micronutrients with high-performance liquid chromatography. DR was diagnosed by non-mydriatic fundus photographs. Additionally, the researchers performed a meta-analysis of relevant studies published between January 1, 1990, and December 31, 2020.

They identified DR in 159 of 517 patients (25.17%). Serum vitamin C alone was found to be associated with a lower risk of DR after adjusting for multiple confounders. In the meta-analysis, 35 studies were included comparing a total of 1,056 patients with DR and 920 controls (pooled weighted mean differences of vitamins C, D and E were -11.01, -3.06 and -3.03, respectively). The researchers didn’t identify any associations between DR and circulating vitamin A or carotenoids.

Previously published studies have consistently reported an inverse association between circulating vitamin C and DR, with one study suggesting that vitamin C depletion and oxidative stress in the retina may be common among DR patients because vitamin C levels in the vitreous, aqueous humor and serum were all found to be lower in patients with proliferative DR vs. controls after pars plana vitrectomy. One potential mechanism suggested in a previous study was that vitamin C scavenges reactive oxygen species, prevents the breakdown of nitric oxide and decreases lipid oxidation.

In the present cross-sectional study, the authors found no association between serum vitamin D and DR. They noted that this aligned with previous observational studies, though four meta-analyses including this one found positive associations between vitamin D deficiency and DR in diabetic patients. Potential mechanisms may include angiogenesis prevention, inflammation mitigation in the retina and systemic effects on insulin secretion and function. The authors suggested that these inconsistent vitamin D and DR findings may be due to lack of adjustment for DM severity or different HbA1c levels.

However, the authors wrote that their subgroup analyses “failed to demonstrate this finding.” They suggested another possible explanation: “the risk of DR increases only when serum vitamin D level reduces to a certain threshold, although a comparable rate of vitamin D deficiency was detected among participants with and without DR in the current analysis.” They wrote that a number of factors such as ethnic differences in vitamin D metabolism or serum measurement methods may explain the inconsistent findings.

“Although increasing evidence suggests serum vitamin D may be a potential biomarker of DR, further investigations are needed to confirm the findings and reveal any dose-response relationship,” they wrote.

This study and others noted significantly lower vitamin E levels in DR patients. “Beyond its antioxidant effect, vitamin E could normalize the retinal blood flow by inhibiting the hyperglycemia-induced activation of the PKC pathway, reducing the production of VEGF and intercellular cell adhesion molecule-1. However, we noticed that the majority of studies reporting a protective effect of vitamin E on DR were conducted in one country (India) and that the sample size for each study was limited, thus whether vitamin E can be used as a biomarker for DR in different ethnic populations remains inconclusive.”

The association between circulating vitamin A and DR was also controversial, perhaps owing to ethnic differences, DM types and patient behaviors. However, given its essential role in the systemic and visual pathway, the researchers said further investigation into its effect on DR pathogenesis will be meaningful.

As for the effects of lutein and zeaxanthin on DR progression, the meta-analysis found that previous studies were inconclusive, consistently finding insignificant differences in serum levels of combined lutein/zeaxanthin between DR patients and controls. Both lutein and zeaxanthin are present in the macular pigment, and because measuring macular pigment optical density is direct and noninvasive, the study authors recommended exploring it as a possible DR biomarker.

“This study demonstrated a significant inverse association between circulating vitamin C level and DR using a [US] population-based dataset,” the authors wrote. “Our comprehensive meta-analysis also suggested a lower circulating level of vitamins D and E in patients with DR than those without.” They recommended that the general diabetic population consume foods rich in vitamins C, D and E to prevent DR risk but cautioned that prospective studies and randomized controlled trials are needed before these recommendations can be formally adopted in long-term DM management strategies. “There’s still insufficient evidence to recommend routine supplementation of multiple micronutrients, such as multi-vitamin tablets, for DR management,” they explained.

Xiong R, Yuan Y, Zhu Z, et al. Micronutrients and diabetic retinopathy: evidence from the National Health and Nutrition Examination Survey and a meta-analysis. Am J Ophthalmol. January 13, 2022. [Epub ahead of print].