Inflammatory footprints: Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as novel biomarkers for diabetic peripheral neuropathy

INTRODUCTION

Diabetic peripheral neuropathy (DPN) is one of the most prevalent and debilitating complications of diabetes mellitus, affecting between 6% and 51% of patients with both type 1 and type 2 diabetes.^[1] It is characterized by progressive damage to peripheral nerves, leading to sensory and motor dysfunction that significantly impacts quality of life and increases morbidity.^[2] Approximately 50% of people with diabetes will develop a foot ulcer during their lifetime.^[1] The pathogenesis of DPN is multifactorial, involving complex interactions between metabolic, vascular, and inflammatory mechanisms triggered by chronic hyperglycemia.^[3]

Early detection and management of diabetic neuropathy are crucial for preventing its progression and improving patient outcomes. However, current diagnostic methods for DPN often rely on clinical examinations and specialized tests that may not be readily available in all healthcare settings or may detect the condition only after substantial nerve damage has occurred.^[4] This has spurred interest in identifying simple, cost-effective biomarkers that could aid in early detection and risk stratification.

In recent years, there has been growing attention toward hematological indices as potential indicators of various inflammatory and metabolic conditions.^[5] Complete blood count (CBC) is one of the most commonly performed laboratory tests and provides valuable information about the immune system status. Two derived parameters from CBC – the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) – have emerged as potential markers of systemic inflammation in various diseases, including diabetes and its complications.^[3,5,6]

The NLR, calculated by dividing the absolute neutrophil count by the absolute lymphocyte count, reflects the balance between neutrophil-mediated acute inflammatory responses and lymphocyte-mediated adaptive immune regulation.^[5,6] While lymphocytes encompass both pro-inflammatory (Th1, Th17) and anti-inflammatory (Th2, Treg) subsets, a relative lymphopenia in the context of elevated neutrophils suggests a shift toward acute inflammatory processes and reduced regulatory immune capacity. This imbalance may reflect the chronic low-grade inflammatory state characteristic of diabetic complications.^[7,8] Similarly, PLR is determined by dividing the platelet count by the lymphocyte count and may indicate increased platelet activation and inflammatory processes.^[5,6,9] Both ratios represent the balance between different immune pathways and have been proposed as markers of inflammation in various conditions.

The relationship between inflammation, oxidative stress, and the development of diabetic complications, including neuropathy, is well-established. Chronic hyperglycemia leads to increased production of reactive oxygen species (ROS), advanced glycation end products, and inflammatory cytokines, which contribute to nerve damage and impaired regeneration.^[10] Given this inflammatory basis, NLR and PLR might serve as surrogate markers for the underlying pathophysiological processes in diabetic neuropathy.

Several studies have investigated the association between these hematological ratios and diabetic complications, with some suggesting that elevated NLR and PLR values may be associated with the presence and severity of diabetic neuropathy.^[11-20] However, the exact relationship and potential utility of these markers in clinical practice, particularly in comparison with traditional inflammatory markers, require further elucidation.

This study aims to evaluate the potential of NLR and PLR as diagnostic and prognostic indicators for DPN in patients with type 2 diabetes. We hypothesize that these inflammatory markers are elevated in patients with DPN compared to those without, and that they correlate with the severity of neuropathy. In addition, we explore the potential mechanisms underlying this association and discuss the clinical implications for diabetes management.

MATERIAL AND METHODS

RESULTS

Inflammatory marker comparisons

NLR

The NLR values were significantly higher in the DPN-positive group compared to the DPN-negative group (3.42 ± 1.15 vs. 2.18 ± 0.87, P < 0.001), as shown in Table 2 and Figure 1. This difference remained statistically significant after adjusting for potential confounding factors such as age, gender, diabetes duration, and HbA1c levels.

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Figure 1:

Comparison of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio values between patients with diabetic peripheral neuropathy (DPN positive) and without DPN negative. Error bars represent standard deviation.

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Table 2: Comparison of hematological parameters between groups.

Parameter	DPN- positive (n=171)	DPN- negative (n=135)	P-value
White blood cell count (×103/μL)	7.92±1.64	7.45±1.46	0.02
Neutrophil count (×103/μL)	4.86±1.28	3.85±0.96	<0.001
Lymphocyte count (×103/μL)	1.48±0.42	1.82±0.38	<0.001
Platelet count (×103/μL)	248.5±62.4	245.8±58.7	0.73
Neutrophil-to-lymphocyte ratio	3.42±1.15	2.18±0.87	<0.001
Platelet-to-lymphocyte ratio	172.6±45.3	138.4±36.7	<0.001
Hemoglobin (g/dL)	13.2±1.8	13.8±1.5	0.01
Hematocrit (%)	39.6±4.7	41.2±4.1	0.008

DPN: Diabetic peripheral neuropathy

PLR

Similarly, PLR values were significantly elevated in patients with diabetic neuropathy compared to those without (172.6 ± 45.3 vs. 138.4 ± 36.7, P < 0.001), as shown in Table 2 and Figure 1. This difference also remained significant after multivariate adjustment.

ROC curve analysis

ROC curve analysis was performed to evaluate the diagnostic performance of NLR and PLR in identifying patients with diabetic neuropathy [Figure 2]. The area under the curve (AUC) for NLR was 0.763 (95% confidence interval [CI]: 0.712–0.814, P < 0.001), and for PLR was 0.682 (95% CI: 0.625–0.739, P < 0.001). The optimal cutoff value for NLR was determined to be 2.56, with a sensitivity of 75.4% and specificity of 68.9%. For PLR, the optimal cutoff value was 155.3, with a sensitivity of 64.3% and specificity of 62.2%.

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Figure 2:

Receiver operating characteristic curve analysis for neutrophilto-lymphocyte ratio and platelet-to-lymphocyte ratio in predicting diabetic peripheral neuropathy. NLR: Neutrophil-to-lymphocyte ratio, PLR: Platelet-to-lymphocyte ratio, AUC: Area under curve.

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DISCUSSION

Our study demonstrates that NLR and PLR are significantly elevated in patients with DPN compared to those without neuropathy. With NLR values of 3.42 ± 1.15 in DPN-positive patients versus 2.18 ± 0.87 in DPN-negative patients (P < 0.001) and PLR values of 172.6 ± 45.3 versus 138.4 ± 36.7 (P < 0.001), our findings align with the growing body of evidence linking inflammation to the pathogenesis of diabetic neuropathy.^[6,9]

When comparing our results with previous studies, we found substantial consistency in the direction of the relationship, though the absolute values and magnitude of differences vary across studies [Table 5]. Xu et al. (2017) reported NLR values of 2.58 ± 0.5 in DPN-positive patients versus 2.18 ± 0.61 in DPN-negative patients, which shows a similar pattern to our findings but with lower absolute values.^[12] Similarly, Abou Raya et al. (2020) found NLR values of 2.44 ± 1.11 in DPN-positive patients compared to 1.92 ± 0.89 in DPN-negative patients.^[17] In contrast, Senyigit (2018) reported substantially higher NLR values (4.17 ± 3.85 vs. 2.32 ± 1.29), while Demirdal and Sen (2018) observed even higher values (9.8 ± 11.5), possibly reflecting differences in study populations or methodologies.^[15,16]

For PLR, our values (172.6 ± 45.3 in DPN-positive patients) are comparable to those reported by Zhang et al. (2021) for diabetic foot ulcer patients (171.19 ± 60.73) but considerably lower than the values reported by Demirdal and Sen (2018) of 285.58 ± 207.4.^[16,18] The observed variability across studies might be attributed to differences in patient characteristics, neuropathy severity, diabetes duration, and comorbidities. While platelets can be elevated in various conditions including iron deficiency anemia,^[22] our study excluded patients with clinical evidence of anemia (hemoglobin <12 g/dL in women, <13.5 g/dL in men) or those on hematinics to minimize confounding effects.

The correlation analysis revealed a gradient of associations between these inflammatory markers and clinical parameters. NLR demonstrated the strongest correlation with DPN severity score (r = 0.624), followed by substantial correlations with vibration perception threshold (r = 0.528) and MNSI score (r = 0.542), moderate correlations with HbA1c (r = 0.385) and diabetes duration (r = 0.365), and weaker correlation with age (r = 0.246). PLR showed a similar pattern but with generally lower correlation coefficients. The negative correlation observed with nerve conduction velocity further supports the relationship between these inflammatory markers and functional nerve impairment. This gradient of correlations supports the hypothesis that these ratios reflect the underlying inflammatory processes in DPN pathophysiology. The significant correlations between both NLR and PLR with HbA1c levels suggest an interrelationship between glycemic control, inflammatory status, and neuropathy development, consistent with findings by Lou et al. (2024) regarding the combined predictive value of HbA1c and NLR.^[23]

Regarding diagnostic performance, our ROC curve analysis yielded an AUC of 0.763 for NLR and 0.682 for PLR, with optimal cutoff values of 2.56 (sensitivity 75.4% and specificity 68.9%) and 155.3 (sensitivity 64.3% and specificity 62.2%), respectively. These results compare favorably with Liu et al. (2017), who reported a sensitivity of 63% and specificity of 72% for NLR in type 1 diabetes patients.^[11] Xu et al. (2017) found a higher sensitivity (81%) but lower specificity (48%) for NLR, while Ranjith et al. (2018) reported 88% sensitivity and 57% specificity at a lower cutoff value of 2.26.^[12,14] Interestingly, Chen et al. (2021) observed lower diagnostic performance for NLR (sensitivity 38% and specificity 79%) but comparable values for PLR (sensitivity 55.4% and specificity 70.4%).^[19] These findings suggest that particularly NLR could serve as a useful screening tool for identifying patients at risk of developing DPN. Patients with values above these thresholds might benefit from more intensive screening for neuropathy, even in the absence of overt symptoms, potentially enabling earlier intervention to prevent disease progression.

Several potential mechanisms may explain the association between elevated NLR, PLR, and diabetic neuropathy. Diabetes is characterized by a state of chronic low-grade inflammation, which plays a crucial role in the development and progression of diabetic complications, including neuropathy.^[3] Elevated NLR and PLR reflect this systemic inflammatory state, with an imbalance favoring pro-inflammatory processes over regulatory mechanisms.^[3,24,25]

Chronic hyperglycemia in diabetes leads to increased oxidative stress, which is a key factor in the pathogenesis of diabetic neuropathy. Neutrophils are a major source of ROS, and an elevated neutrophil count (reflected in a higher NLR) may indicate increased oxidative stress. This oxidative environment can damage nerve fibers and contribute to neuropathy.^[3,10]

Both NLR and PLR have also been associated with endothelial dysfunction and microvascular complications in diabetes. Impaired microvascular function can lead to reduced blood flow to peripheral nerves, contributing to the development of neuropathy. The relationship between these hematological ratios and vascular function may partly explain their association with diabetic neuropathy.^[3,26]

Elevated PLR may reflect increased platelet activation, which has been implicated in the pathogenesis of diabetic complications. Activated platelets can release pro-inflammatory mediators and growth factors that may contribute to nerve damage and impaired regeneration in diabetic neuropathy. Furthermore, platelets can interact with neutrophils and other immune cells, amplifying inflammatory responses and exacerbating tissue damage.^[3,25,27]

The findings of this study have several potential clinical implications. NLR and PLR could serve as simple, cost-effective tools for early screening and risk stratification of diabetic patients. These ratios can be easily calculated from routine CBC tests, which are commonly performed in clinical practice. Patients with elevated ratios may be identified for more intensive monitoring and earlier intervention to prevent or delay the onset of neuropathy.

CONCLUSION

Our study shows that NLR and PLR are significantly elevated in DPN patients compared to those without neuropathy. These hematological markers correlate with neuropathy severity and remain independent predictors after adjusting for confounding factors. These findings align with diabetic neuropathy’s pathophysiology involving chronic inflammation, oxidative stress, immune dysregulation, and microvascular dysfunction. NLR and PLR likely reflect these processes, serving as surrogate markers for inflammatory and vascular components. These accessible, cost-effective tools could improve timely identification of at-risk patients when integrated into routine diabetes care. However, longitudinal studies and standardization are needed to establish their full clinical utility. By identifying simple biomarkers for early detection and risk stratification, we can potentially improve neuropathy management and patients’ quality of life.