Diabetes mellitus (DM) is a slowly progressive metabolic illness characterized by long-standing hyperglycemia that can cause various complications (1). Diabetic retinopathy (DR) is one of the most prevalent complications and a leading cause of blindness among working-age adults, seriously affecting patient quality of life and increased financial burden (2, 3). The early detection and prevention of DR are crucial to avoid blindness.

There is accumulating evidence that chronic low-grade inflammation has a particular influence on the development of DM and metabolic syndrome (4). Chronic inflammation is a hallmark of type 2 DM (T2DM), possibly due to insulin resistance and impaired glucose metabolism (5).

DR is a progressive microvascular and neurodegenerative disease that occurs gradually with years of poor glycemic control (6). Although clinical signs, such as acellular capillaries, retinal nonperfusion, and ischemia appear later, early changes involve persistent low-grade leukocyte activation triggered by metabolic dysregulation (7). This activation disrupts the retinal neurovascular unit and its cellular components (7).

The neutrophil-to-lymphocyte ratio (NLR), which is the synthesis of two distinct but complementary immune pathways of the innate and adaptive cellular immune responses, has been studied extensively as an inflammatory marker in many malignant and benign diseases (8). Western studies have reported that an elevated NLR is independently linked to increased cardiovascular death and all-cause mortality in patients with diabetes, as well as a higher risk for diabetic kidney disease (9, 10). However, the relationship between the NLR and DR remains unclear, with only a limited number of cross-sectional studies exploring this relationship (11, 12). As such, the present cohort study aimed to evaluate whether the presence of DR is correlated with NLR in Chinese patients.

A total of 857 (560 male, 297 female) subjects were included in the final analysis. Over a median 3-year follow-up period, 140 patients developed DR. Baseline characteristics stratified according to incident DR are summarized in Table 1 . The median NLR was 2.21 in patients who developed the retinopathy outcome (i.e., DR), compared with 1.86 in the patients not developing retinopathy (i.e., NDR) (P<0.001). The 25th, 50th, and 75th NLR percentiles were 1.46, 1.90, and 2.45, respectively. Briefly, subjects with incident DR had a notably higher mean age (52.4 vs. 47.3 years; P<0.001), a longer diabetes course (median 89.5 vs. 42 months; P<0.001), higher levels of HbA1c (median 7.75% vs. 7.3%; P=0.001), FBG (median 8.60 vs. 7.63 mmol/L; P=0.046), NLR and lower levels of fasting insulin (median 8.26 vs. 9.85 mU/L; P=0.015), TGs (median 1.27 vs. 1.49 mmol/L; P=0.048), uric acid (mean 316.10 vs. 336.51μmol/L; P=0.010), and eGFR (mean 104.79 vs. 107.72 mL/min/1. 73m²; P=0.043) than those without incident DR.

The multivariable-adjusted (age, sex, diabetes course, smoking history, drinking history, BMI, SBP, TG, HbA1c, FBG, fasting insulin, uric acid, eGFR, and UACR) hazard ratios (HRs) for incident DR across ascending NLR quartiles (≤1.46 [reference], 1.47–1.90, 1.91–2.45 and > 2.45) were 1.000, 1.327 (95% confidence interval [CI] 0.754–2.334), 1.555 (95% CI 0.913–2.648) and 2.217 (95% CI 1.348–3.649), respectively (P=0.011) ( Table 2 ). For each 1-SD increase in NLR, the risk for DR increased by 29.2% (HR 1.292 [95% CI 1.112–1.501]; P=0.001) after adjusting for confounders ( Table 3 ). Age, diabetes course, and HbA1c level were also independently associated with incident DR ( Table 3 ).

The present cohort study identified a positive correlation between NLR, a composite metric for chronic inflammation, and the incidence of DR in patients with T2DM. Each 1-SD increase in the NLR corresponded to a 29% increased risk for developing DR.

Chronic low-grade inflammation and endothelial dysfunction are well-established contributors to insulin resistance, T2DM, and other microvascular and macrovascular complications (12). Inflammatory responses triggered by hyperglycemia play a key role in vascular dysfunction. Hyperglycemia induces the production of reactive oxygen species and upregulates the expression of pro-inflammatory and pro-coagulant factors, which promote adhesion between white blood cells and endothelial cells (22). The accumulation of leukocytes in capillaries disrupts the normal structure between the retinal endothelial cells and pericytes, leading to a damaged blood-retinal barrier. Excessive accumulation of leukocytes can cause vascular blockage and leakage, which in turn exacerbate damage to the blood-retinal barrier (23). Overall, the emergence of inflammatory mediators and disturbances in the balance between angiogenesis-related factors promote the development of DR (24). This results in increased retinal vascular permeability, neurodegeneration, damage to the blood-reticulum barrier, and neovascularization, ultimately leading to diabetic macular edema and proliferative DR (24). NLR reflects both cellular immune activation and systemic inflammatory response, acting as an indicator of the balance between two key immune system components: neutrophils, active non-specific inflammatory cells, lymphocytes, and protective or regulatory cells (8). The NLR has emerged as a promising marker in this context.

Our results are consistent with those of most previous studies that have explored the relationship between the inflammatory index and diabetic complications. This aligns with a case-control study from Turkey (25), where NLR levels were higher in patients with diabetes and DR than in those without DR. While some studies, such as those from northern China (26), reported higher NLR in patients with DR, and the investigators did not find NLR to be an independent risk factor. Moreover, another cross-sectional study from Turkey that analyzed 114 patients with T2DM reported that NLR was not independently associated with DR (27). Potential explanations for these variations include the larger sample size, differences in subject characteristics, and variations in lifestyle factors.

Several studies have supported the link between NLR and diabetic microvascular complications. A cross-sectional study observed a positive association between a higher NLR and the occurrence of both nephropathy and retinopathy in an Indian population (12). Additionally, an elevated NLR was correlated with diabetic nephropathy in other studies (10, 28) and even served as an independent predictor of kidney function decline in individuals with DM (29). DR and nephropathy share common underlying mechanisms and often co-occur (30). Given this shared etiology and the association between NLR and both complications, NLR may emerge as a valuable predictor and prognostic marker for both DR and nephropathy.

The present study had several limitations, the first of which was its retrospective cohort design, which precluded the determination of a causal relationship between the biomarkers and outcomes. Second, we did not analyze correlations stratified according to DR severity (i.e., non-proliferative and proliferative DR), because only 1 participant developed proliferative DR. Third, lifestyle, socioeconomic, and pharmacological interventions were not considered in this study. Additionally, the relatively short follow-up period limited our ability to fully assess the long-term impact of NLR on DR progression. Future studies with larger cohorts and extended follow-up periods are essential to validate our findings and explore these associations more thoroughly.

In summary, results of the present study indicate that the incidence of DR is associated with a higher NLR. These findings may provide instructive options for clinical practice. According to statistics, there are an estimated 141 million patients with diabetes in China, and the number of patients with DR has exceeded 19 million (31, 32). With an aging population and a high incidence of DM, dealing with visual impairment and blindness is a huge challenge. Screening for DR offers a preferable solution to decrease preventable blindness and the medical economic burden. According to these guidelines, routine screening every to 1–2 years is recommended. Based on the results of our study, we recommend that patients with diabetes and higher NLR should undergo a shorter period of regular screening for DR (e.g., 6 months). Eye examination by fundus photography using a non-mydriatic fundus camera costs < $2 in our hospital, and early detection of DR could save thousands from medical expenditures for the treatment of DR.

In conclusion, results of the present study indicated that, among patients with T2DM, a higher NLR was associated with an increased risk for incident DR. Given the advantages of NLR in terms of stability and accessibility, this result further supports that NLR could be a valuable clinical measure. Future studies with various populations and designs are necessary to further explore the potential value of the NLR in predicting diabetes-related outcomes.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Research Ethics Committee of Ruijin Hospital (2017 No. 42) and the First Affiliated Hospital of Ningbo University (2019-R057). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

YT: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Software, Supervision, Writing – original draft, Writing – review & editing. LL: Funding acquisition, Writing – review & editing. JL: Funding acquisition, Writing – review & editing.