Diabetic retinopathy (DR) is one of the most prevalent and severe microvascular complications of diabetes, characterized by pathological alterations in the retinal vasculature triggered by persistent hyperglycemia. This condition leads to endothelial damage, increased vascular permeability, microhemorrhage, and neovascularization, potentially resulting in visual impairment (1, 2). Current treatments for DR include laser photocoagulation, intravitreal injections of anti-VEGF agents, and surgical procedures, such as vitrectomy (3). However, the multifactorial nature of DR, which involves hyperglycemia-induced metabolic disturbances, low-grade inflammation, and complex lipid dysregulation, poses significant challenges. Therefore, developing robust strategies for prevention, early detection, and timely intervention remains imperative (4–6).

Globally, approximately the 30–40% of individuals with diabetes develop DR, creating substantial clinical, economic, and psychological burden. With diabetes prevalence rising worldwide, identifying accessible and integrative biomarkers that reflect underlying metabolic and inflammatory processes is crucial for improving risk stratification and guiding targeted interventions (7–9).

In recent years, the advanced lung cancer inflammation index (ALI), originally introduced as a prognostic indicator in patients with advanced lung cancer, has gained attention in various diseases. ALI integrates metrics such as body mass index, albumin levels, and neutrophil-to-lymphocyte ratio, combining nutritional status and systemic inflammatory burden into a single measure. Although initially established in oncology, research suggests that ALI may have predictive value in metabolic and vascular conditions (10–12). However, its role in diabetic microvascular complications, including DR, remains underexplored.

Drawing on data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018, the present cross-sectional study investigated the association between ALI and DR prevalence among US adults with diabetes. This is the first comprehensive effort to evaluate this integrated inflammation-nutrition index in the context of DR risk. Confirming this relationship could facilitate new approaches for risk profiling and interventions tailored to the inflammatory and nutritional dimensions of DR pathogenesis (13). To our knowledge, this is the first large-scale epidemiological study to investigate the relationship between ALI and DR in a nationally representative sample. By repurposing ALI—originally developed for oncology—as a potential biomarker for diabetic microvascular complications, we introduce a novel perspective that integrates inflammatory and nutritional dimensions into DR risk assessment. The findings of this study will not only offer novel insights into the systemic nature of DR pathogenesis but also guide future longitudinal and interventional research aimed at improving clinical outcomes for individuals with diabetes through targeted anti-inflammatory and nutritional interventions.

This study utilized a nationally representative sample of American adults with diabetes to explore the relationship between the advanced lung cancer inflammation index (ALI) and the prevalence of diabetic retinopathy (DR). ALI integrates body mass index (BMI), albumin levels, and neutrophil-to-lymphocyte ratio (NLR), thus reflecting systemic inflammatory, nutritional, and metabolic states. Our analysis revealed a significant L-shaped, non-linear association between ALI and DR prevalence. These observations suggest an association between systemic inflammatory-nutritional states and retinal microvascular status. Furthermore, racial differences moderated this association, underscoring the interplay between genetic, cultural, and socioeconomic factors in DR pathogenesis. These findings expand the applicability of ALI beyond oncology, highlighting its utility in systemic diseases and underscoring the need for a holistic approach for DR risk assessment (4, 16).

Reframing DR within the broader context of systemic health, this study challenges the traditional focus on hyperglycemia-induced microvascular damage (17). While chronic hyperglycemia disrupts endothelial function, induces oxidative stress, and increases vascular permeability (18, 19), our findings suggest that inflammatory and nutritional imbalances are equally pivotal. Additionally, glycoxidation of protein by reactive carbonyl compounds like methylglyoxal has been shown to disturb structural integrity and increase immunogenicity of important serum proteins like IgG, thereby contributing to inflammation and immune dysregulation in T2DM (20). The L-shaped association we observed underscores this complexity: lower ALI values may represent inadequate nutrition and increased inflammation, impairing repair mechanisms of retinal vasculature (21), while higher ALI values likely signify a more favorable metabolic environment with better nutritional status and lower inflammatory burden (22, 23). These observations align with emerging research on the role of inflammation in DR pathogenesis, where pro-inflammatory cytokines like TNF-α and IL-1β exacerbate vascular leakage and pathological angiogenesis (7). A comparison with existing literature further corroborates the clinical relevance of ALI (24). Previous studies have linked ALI to outcomes in coronary heart disease, chronic kidney disease, and diabetic nephropathy, suggesting shared pathophysiological pathways rooted in systemic inflammation and metabolic dysregulation. By demonstrating the association between ALI and DR, our study broadens its clinical scope, establishing it as a systemic health indicator rather than an organ-specific biomarker. Leveraging NHANES data ensures external validity and reduces selection bias, while our advanced statistical methods enable rigorous examination of non-linearities and effect modifiers. These methodological strengths underscore our findings: ALI appears to correlate with DR risk based on underlying systemic health. This perspective aligns with integrated care paradigms that emphasize the interplay between systemic and localized disease processes (25–27).

The potential mechanisms linking ALI to diabetic retinopathy are multifaceted. Chronic hyperglycemia triggers a cascade of deleterious changes in the retina, but the three components of ALI collectively reflect additional dimensions of systemic health that may influence retinal microvascular integrity. BMI correlates with metabolic states—high BMI indicates insulin resistance (28), while low BMI may signal malnutrition; albumin reflects nutritional and inflammatory status—low albumin implies chronic inflammation and catabolic stress (29); and NLR serves as a marker of systemic inflammation—elevated NLR indicates neutrophil predominance and lymphocyte suppression (30). By combining these factors, ALI transcends isolated biomarkers to provide a comprehensive measure of the patient’s physiological milieu (31). Poor nutritional status, as reflected by low albumin levels, compromises tissue repair mechanisms and antioxidant defenses, rendering the retina more vulnerable to metabolic insults (11). Furthermore, an abnormal body mass index, whether too low or excessively high, modulates insulin sensitivity, lipid profiles, and adipokine secretion, potentially amplifying microvascular damage (32) The neutrophil-to-lymphocyte ratio emphasizes the chronic inflammatory milieu that may accelerate these processes through increased oxidative stress, endothelial dysfunction, and vascular permeability. This systemic environment likely influences the delicate balance between damage and repair in retinal tissues, with lower ALI reflecting conditions that favor microvascular deterioration. Research suggests that inflammatory cells infiltrate the retina early in DR, where pro-inflammatory cytokines exacerbate vascular leakage and promote neovascularization (9). Thus, ALI emerges as a sentinel that reflects the systemic environment from which DR evolves. Rather than focusing exclusively on advanced retinal changes, ALI may potentially serve as an early indicator of systemic disturbances that precede clinically detectable retinopathy, though longitudinal studies are needed to confirm this temporal relationship.

The potential clinical implications of incorporating ALI into research on diabetes management warrant consideration, though our cross-sectional findings cannot establish causality. Current DR screening protocols primarily focus on glycemic control, diabetes duration, and periodic retinal examination. Evaluating whether complementing these approaches with ALI measurements provides clinically meaningful insights into patients’ systemic environment would require prospective clinical trials. If such studies confirm our findings, several potential applications might emerge. Patients with diabetes who exhibit lower ALI levels might benefit from more frequent retinal screening, even in the absence of other risk factors. Targeted nutritional interventions to improve serum albumin levels and anti-inflammatory strategies to reduce NLR could represent novel approaches to DR prevention, though these require prospective evaluation (33). In resource-limited settings where advanced imaging is inaccessible, ALI’s simplicity and cost-effectiveness could theoretically make it a practical complementary tool for risk stratification, though implementation would require validation studies. As healthcare paradigms shift toward precision medicine and prevention-focused strategies, integrative biomarkers like ALI align with these trends. Beyond individual care, the adoption of ALI has potential broader implications for public health research addressing diabetes complications. Replication of our findings across diverse populations could encourage further investigation into nutritional and inflammatory pathways in DR pathogenesis. On a population level, ALI distributions could identify at-risk subgroups, potentially guiding targeted research into community initiatives such as culturally sensitive dietary programs and exercise campaigns (26, 34–36). This research direction, focusing on upstream factors rather than downstream complications, may ultimately contribute to improved patient outcomes and more efficient use of healthcare resources. However, we emphasize that these potential applications require confirmation through longitudinal and interventional studies before any clinical implementation can be recommended.

Before concluding, it is important to acknowledge several limitations of this study. The cross-sectional design precludes definitive conclusions about causality, as the temporal relationship between ALI elevation and DR development remains undetermined—whether high ALI predisposes individuals to DR or if early DR alters systemic parameters reflected in ALI components. Prospective longitudinal studies are needed to establish these temporal sequences and evaluate if ALI modification reduces DR risk. A notable limitation is our use of self-reported DR data rather than clinical verification, potentially underestimating DR prevalence, especially in milder cases. While pragmatic for large-scale surveys like NHANES, incorporating retinal imaging or standardized ophthalmoscopy would substantially enhance diagnostic accuracy in future studies. The absence of comprehensive glycemic control assessment, particularly HbA1c measurements, represents a significant methodological limitation that introduces interpretative complexity to our findings. Additionally, while ALI integrates key inflammatory and metabolic indicators, its current formulation omits critical variables including glycemic control, blood pressure measurements, and angiogenic factors such as VEGF. Refining ALI or combining it with complementary markers could significantly improve its clinical utility (37). Important unmeasured confounders—genetic factors, dietary patterns, and psychosocial stressors—likely contribute to unexplained variability despite our adjustment efforts. Furthermore, our study did not differentiate between non-proliferative and proliferative DR stages. Future research should explore whether the relationship between ALI and DR varies by retinopathy severity, which could facilitate more targeted preventive strategies. The study’s strengths lie in its large, diverse NHANES sample, enhancing external validity. However, the relatively modest number of DR cases limits statistical power for subgroup analyses and may obscure important interactions. Future pooled analyses across multiple datasets could provide more precise population-specific ALI thresholds and clarify their role in DR pathophysiology (38).

In conclusion, this cross-sectional study identifies a significant inverse association between ALI and DR prevalence, suggesting potential utility of ALI as a risk stratification tool. While our findings suggest ALI could be relevant to DR pathophysiology, prospective studies are necessary before recommending its integration into routine clinical practice.