KEY FIGURE

Highlights

• Neutrophil heterogeneity links innate immunity to diabetic microvascular injury.

• Neutrophil-derived inflammatory signatures serve as biomarkers for risk stratification.

• Neutrophil heterogeneity offers novel insights into diabetic microvascular complications.

INTRODUCTION

Diabetes is a chronic metabolic disorder characterized by persistent hyperglycemia, insulin resistance, and systemic low-grade inflammation [1,2]. Among its long-term complications, diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DN) remain major causes of morbidity and mortality [3-5]. Although these complications have traditionally been attributed to hyperglycemia-driven metabolic and hemodynamic changes, increasing evidence indicates that innate immune dysregulation also plays an important role in their development and progression [2,6-8].

Neutrophils, the most abundant circulating leukocytes, are increasingly recognized as key contributors to diabetes-associated inflammation. In diabetes, hyperglycemia and insulin resistance impair neutrophil chemotaxis and phagocytosis while enhancing degranulation, reactive oxygen species (ROS) production, and neutrophil extracellular trap (NET) formation (NETosis) [1,9-12]. These alterations promote persistent inflammation, endothelial dysfunction, and tissue injury, and are further amplified through interactions with macrophages, dendritic cells, and lymphocytes [6,13-15].

As summarized in Fig. 1, chronic hyperglycemia disrupts neutrophil recruitment, adhesion, and migration, and reduces chemotactic accuracy and phagocytic capacity [1,9,16-18]. Neutrophils also exhibit dysregulated degranulation and excessive ROS and NET production, which exacerbate oxidative stress, vascular injury, and tissue damage, ultimately contributing to microvascular complications [2,7,10,12,19-21].

In parallel, neutrophil-associated inflammatory biomarkers—such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-neutrophil ratio (PNR), and systemic immune-inflammation index (SII), neutrophil percentage-to-albumin ratio (NPAR)—have gained increasing attention as accessible and cost-effective indicators of systemic inflammation and diabetic disease severity [22-26]. This review summarizes neutrophil-mediated inflammatory mechanisms and highlights the clinical relevance of related biomarkers for early diagnosis, monitoring, and therapeutic stratification in diabetic microvascular complications. It also outlines diabetes-induced alterations in key neutrophil functions, including recruitment, phagocytosis, degranulation, ROS production, and NET formation, contributing to chronic inflammation and vascular damage [2,11,21].

NEUTROPHILS AND INFLAMMATORY MECHANISMS IN DIABETES

Neutrophil recruitment and migration in diabetes

Neutrophil recruitment is a key component of innate immunity, involving migration from the circulation to sites of infection or tissue damage in response to chemotactic signals, including chemokines and damage-associated molecular patterns [1].

In diabetes, this process is significantly impaired. Chronic hyperglycemia disrupts neutrophil chemotaxis, leading to reduced migration and impaired infection resolution [27]. Mechanistically, hyperglycemia induces Toll-like receptor 2 (TLR2) signaling, promoting C-X-C motif chemokine receptor 2 (CXCR2) internalization, while acute-phase proteins upregulate G protein-coupled receptor kinase 2 (GRK2), further desensitizing chemokine receptors [28].

Experimental studies demonstrate that high glucose and advanced glycation end products (AGEs) impair neutrophil migration, with additional alterations in adhesion-related functions reported under diabetic conditions [16,29]. Endothelial dysfunction further disrupts adhesion and transmigration, contributing to persistent inflammation and tissue injury [9,17].

Neutrophil phagocytosis and pathogen recognition

Neutrophil phagocytosis is significantly impaired in diabetes due to multiple interconnected mechanisms. Chronic hyperglycemia induces excessive ROS production, disrupting actin polymerization and cytoskeletal rearrangement essential for phagocytosis [30]. AGEs further impair phagosome formation via receptor for advanced glycation end products (RAGE) signaling, while insulin resistance disrupts phosphatidylinositol-3-kinase (PI3K)-Akt signaling, a key pathway regulating neutrophil activation and phagocytosis. In addition, hyperglycemia downregulates Fcγ receptor expression, reducing pathogen recognition and uptake [18,30]. Neutrophils from type 2 diabetes mellitus (T2DM) patients also exhibit altered resolution receptor profiles, with increased E-series resolvin 1 (ERV-1) and decreased leukotriene B4 receptor 1 (BLT1) expression [31], and endoplasmic reticulum (ER) stress further disrupts intracellular signaling. Collectively, these abnormalities impair pathogen clearance and contribute to increased susceptibility to infection in diabetic individuals [32].

Neutrophil degranulation and antimicrobial release

Neutrophil degranulation is essential for antimicrobial defense through the release of enzymes such as myeloperoxidase (MPO) and neutrophil elastase (NE) [30]. In diabetes, chronic hyperglycemia disrupts calcium homeostasis, impairing granule mobilization and fusion with the plasma membrane. Additionally, insulin resistance affects PI3K-Akt and protein kinase C (PKC) signaling, both crucial for granule exocytosis [10]. Elevated levels of neutrophil-derived enzymes, including chitotriosidase, acidic mammalian chitinase, and chitinase-3-like protein 1 (YKL-40), reflect dysregulated granule release in diabetic patients [19]. In addition, AGEs and ER stress impair vesicle trafficking and protein processing. These defects collectively reduce antimicrobial enzyme release and weaken innate immune responses, increasing infection susceptibility [10].

ROS production in diabetic environment

ROS plays a crucial role in diabetes pathophysiology, contributing to oxidative stress and chronic inflammation. ROS generation in diabetes occurs both intracellularly and extracellularly, driven by hyperglycemia and metabolic dysregulation.

Intracellular ROS production

Intracellular ROS generation is primarily driven by mitochondrial dysfunction and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation. Hyperglycemia increases mitochondrial electron transport chain activity, leading to superoxide (O₂−) production, which is converted to hydrogen peroxide (H₂O₂) and contributes to oxidative damage [2,33]. NOX enzymes, particularly NOX2 and NOX4, are upregulated and further amplify ROS generation [20]. In addition, ER stress and AGE-related pathways enhance ROS production and impair antioxidant defense mechanisms [20,34].

Extracellular ROS production

Extracellular ROS is generated through immune activation and vascular dysfunction. Neutrophil-derived microparticles amplify inflammatory signaling [35], while endothelial NOX activation and mitochondrial dysfunction reduce nitric oxide bioavailability and promote endothelial dysfunction [36]. Diabetic platelets further contribute to ROS-mediated vascular injury [13], and circulating AGEs sustain ROS production through RAGE signaling [20]. These processes create a self-amplifying cycle of oxidative stress and vascular damage in diabetes.

NETs formation in diabetes

NETs are DNA-based structures released during NETosis that contribute to inflammation and tissue injury [7]. NETosis occurs through distinct pathways, including suicidal, vital, and mitochondrial mechanisms [21,37].

Hyperglycemia significantly enhances neutrophil activation, increasing ROS production and promoting NET formation [38]. Increased NET production has been consistently observed in diabetes and correlates with disease severity [11]. Mechanistically, NOX-mediated ROS generation plays a central role in NET formation.

Inflammatory signaling pathways, including IL-6/signal transducer and activator of transcription 3 (STAT3) activation and recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), further amplify NET production through NOX2-dependent mechanisms [6]. Clinically, elevated circulating NET markers, such as MPO-DNA complexes, elastase, and cell-free DNA, are observed in T2DM patients and are associated with increased inflammatory cytokines including interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) [12,39]. Persistent NET formation contributes to chronic inflammation and progression of diabetic complications [40].

Neutrophil-derived inflammatory cytokines

Neutrophils regulate immune responses through the release of pro- and anti-inflammatory cytokines. Pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, and IL-8 promote leukocyte recruitment, vascular permeability, and immune activation [8,41-43], whereas anti-inflammatory cytokines including IL-10 and TGF-β contribute to immune regulation and tissue repair [44,45]. Dysregulation of this balance in diabetes promotes persistent inflammation and tissue injury.

Neutrophil interactions with immune cells

Neutrophils interact with multiple immune cells and play a central role in amplifying inflammatory responses in diabetes [15,46]. They promote pro-inflammatory M1 macrophage polarization while inhibiting M2 transition, thereby sustaining inflammation and insulin resistance [46,47].

Neutrophil-derived MPO, NE, and LL-37 impair dendritic cell maturation and antigen presentation, weakening T cell priming and adaptive immunity [15]. In addition, neutrophils modulate T cell function by promoting Th17 differentiation and inducing regulatory T cell apoptosis, while dysregulating B cell activation through B cell–activating factor (BAFF), a proliferation-inducing ligand (APRIL), and IL-21 signaling [15,46,47]. Recent studies show that targeting upstream regulators of neutrophil function, such as mast cell stabilization with cromolyn sodium, reduces neutrophil recruitment and activation in diabetic tissue [48].

These interactions create a persistent inflammatory state that promotes tissue damage, metabolic dysfunction, and disease progression, ultimately contributing to diabetic complications.

Single-cell and spatial transcriptomic profiling of neutrophils in diabetes

High-dimensional transcriptomic studies have begun to characterize immune programs associated with neutrophil dysfunction in diabetes, although direct resolution of neutrophil states remains limited. Single-cell and spatial analyses have identified NET-related pathways, C-X-C motif chemokine ligand 8 (CXCL8)–CXCR2 signaling, and inflammatory neutrophil polarization across diabetic tissues [49,50]. In diabetic wound models, these approaches have revealed microenvironmental programs linked to impaired healing, although analyses have largely focused on non-neutrophil compartments [51-53]. Bulk and spatial transcriptomic studies further demonstrate altered immune recruitment networks and compartment-specific transcriptional changes [54,55]. Despite these advances, neutrophil heterogeneity in diabetes remains incompletely defined due to granulocyte under-capture, peripheral blood mononuclear cells (PBMCs)-biased workflows, and analytical focus on non-neutrophil populations. Future studies using granulocyte-preserving and spatially resolved approaches are required to define neutrophil-specific programs and their roles in diabetic complications.

NEUTROPHIL-RELATED INFLAMMATORY BIOMARKERS IN DIABETES

Neutrophil count in target organ

In type 1 diabetes mellitus (T1DM), neutrophils have been shown to induce the condition through islet infiltration, with studies showing that blocking neutrophil activities inhibits both insulitis and diabetic development [56]. Similar immune cell infiltration patterns occur in T2DM, with macrophages being the most abundant infiltrating cell type, followed by neutrophils [57,58]. Experimental models further demonstrate immune cell accumulation within pancreatic islets, supporting the role of local inflammation in diabetes pathogenesis [58]. However, direct assessment of tissue neutrophils is limited by invasiveness and cost, leading to increased interest in circulating neutrophil-based biomarkers as more practical alternatives.

Circulating neutrophil count

Circulating neutrophil count is a simple and accessible marker associated with glycemic status and metabolic dysfunction. Multiple studies have demonstrated positive correlations between neutrophil count and glycated hemoglobin (HbA1c), fasting glucose, and insulin resistance (Table 1) [59,60]. Neutrophil counts are consistently higher in poorly controlled T2DM compared with well-controlled disease, supporting their association with metabolic severity [61,62]. Differences across diabetes subtypes have also been reported. While T2DM patients generally exhibit elevated neutrophil counts, meta-analyses indicate no significant difference in T1DM compared with controls [63,64]. Some studies further report lower neutrophil counts in T1DM, with negative correlations to pancreatic autoantibodies [22]. These findings suggest that neutrophil-related inflammatory responses differ between autoimmune and metabolic forms of diabetes, reflecting distinct underlying mechanisms.

Neutrophil-to-lymphocyte ratio

The NLR is a widely used marker of systemic inflammation, calculated as the ratio of absolute neutrophil to lymphocyte counts [65-68]. It reflects combined neutrophilia and lymphopenia and is considered more stable than individual leukocyte parameters [69]. Elevated NLR is consistently associated with the presence of T2DM and correlates with glycemic parameters such as HbA1c (Table 1) [23,68,70]. In T1DM, lower NLR values have been associated with reduced insulin requirements, suggesting potential relevance across diabetes types [71]. Elevated NLR is also associated with poor glycemic control and reduced quality of life in T2DM, supporting its role as a complementary marker to HbA1c [65,68,72-74]. However, NLR is a non-specific marker influenced by various inflammatory conditions, and most evidence is derived from cross-sectional studies, limiting its predictive value. Additionally, elevated NLR may reflect overall health status rather than diabetes-specific pathology.

Platelet-to-neutrophil ratio

The PNR, calculated as platelet count divided by neutrophil count, has been explored as a potential biomarker in prediabetes and T2DM. PNR is significantly lower in T2DM compared to prediabetic and healthy individuals and shows a negative correlation with HbA1c levels (Table 1) [23,75]. In contrast, PLR decreases from normal glucose tolerance to prediabetes and newly diagnosed diabetes, but increases in established diabetes [76]. Consistently, Klisic et al. [23] and Essawi et al. [75] reported reduced PNR in T2DM compared with prediabetes and non-diabetic controls (Table 1). However, these findings are based on limited cross-sectional studies, and standardized cutoff values remain lacking; thus, PNR should be considered an exploratory marker that complements, rather than replaces, established indices such as NLR and absolute neutrophil counts.

Neutrophil percentage‐to‐albumin ratio

The NPAR has emerged as a potential marker reflecting systemic inflammation and metabolic risk. Elevated NPAR has been associated with the presence of diabetes and increased risks of all-cause and cardiovascular mortality in large cohort studies (Table 1) [77,78]. These findings suggest that NPAR may capture inflammatory burden and identify high-risk phenotypes in diabetes. However, available evidence remains limited, and its incremental predictive value and optimal cutoff thresholds have yet to be established.

Systemic immune-inflammation index

The SII, calculated as platelet×neutrophil/lymphocyte, reflects the balance between innate immune activation and adaptive immune suppression [79,80]. Elevated SII levels have been consistently observed in T2DM and are positively associated with HbA1c and fasting glucose levels (Table 1) [80]. SII may provide an integrated measure of systemic inflammatory burden and has shown potential as a biomarker for metabolic dysregulation [81]. However, current evidence is largely based on cross-sectional studies, and further research is needed to establish standardized cutoff values and confirm its clinical utility.

NEUTROPHIL-DRIVEN INFLAMMATION IN DIABETIC MICROVASCULAR COMPLICATIONS

Neutrophil activation and recruitment

In DKD, neutrophils infiltrate damaged tubular regions and contribute to disease progression through enhanced chemotaxis, adhesion, and oxidative stress. Activation by IL-33 and glycoxidized albumin promotes MPO release and NET formation, amplifying inflammation and renal injury [3]. IL-33 expression is increased in diabetic tubules and correlates with declining renal function, highlighting its role as a key NET-associated mediator [82].

In DR, neutrophil recruitment is driven by inflammatory chemokines such as CXCL1, which increases vascular permeability and leukocyte infiltration [83]. Hyperglycemia further disrupts the blood-retinal barrier, facilitating neutrophil adhesion and leukostasis, thereby contributing to retinal microvascular damage [11,83].

NETs in microvascular complications

Excessive NET formation is a common feature of diabetic microvascular complications, with deposition observed in the kidney and retina [11,82]. IL-33 has been identified as a central regulator of NET-associated pathways, promoting inflammation through the IL-33–suppression of tumorigenicity 2 (ST2) axis and correlating with disease progression in DKD [82]. In DR, therapeutic interventions such as anti-vascular endothelial growth factor (VEGF) treatment have been shown to reduce NET formation, supporting their pathological role in microvascular injury [11].

Neutrophil elastase

NE, a serine protease released during neutrophil degranulation, plays a key role in diabetic microvascular complications. Elevated NE activity has been observed in diabetic conditions, contributing to inflammation and tissue injury [84,85]. In DR, NE disrupts endothelial integrity by activating inflammatory pathways (e.g., nuclear factor kappa B, protease-activated receptor 2 [PAR2]) and degrading vascular endothelial cadherin (VE-cadherin), leading to increased vascular permeability [84,86]. Experimental studies demonstrate that genetic deletion or pharmacological inhibition of NE reduces oxidative stress, leukostasis, and capillary degeneration, highlighting its therapeutic potential [84]. NE expression is also regulated by IL-17, further linking it to inflammatory signaling in diabetes [86].

Neutrophil-derived extracellular vesicles

Neutrophil-derived extracellular vesicles (EVs) contribute to inflammatory signaling and vascular injury in diabetes. Under diabetic conditions, neutrophil EV production is increased and promotes endothelial inflammation and cytotoxicity, leading to enhanced vascular damage compared with EVs from non-diabetic conditions [87,88].

NEUTROPHIL-RELATED BIOMARKERS FOR PREDICTING MICROVASCULAR COMPLICATIONS

Diabetic kidney disease

A major challenge in DKD is the lack of early symptoms, with significant renal impairment often detected only at advanced stages. Current diagnostic approaches rely on albuminuria and estimated glomerular filtration rate (eGFR), which have limited sensitivity for detecting early renal injury and may not reflect direct tissue damage [85,89-93]. In addition, renal injury can occur even in the absence of microalbuminuria. These limitations have prompted increasing interest in neutrophil-related inflammatory biomarkers.

Neutrophil counts in the kidney of diabetic patients

Although systemic neutrophil activation is well documented in DKD, prominent neutrophil infiltration in renal tissue is limited, and neutrophils are not considered a dominant feature of DKD pathology compared to macrophages and T lymphocytes [85]. However, systemic neutrophil activation may contribute to renal injury through the release of ROS, proteolytic enzymes, and pro-inflammatory cytokines, promoting oxidative stress and endothelial dysfunction [87]. Experimental studies also suggest that NETs, although rarely detected in renal histology, may contribute to microvascular and glomerular injury in diabetes [3].

Circulating neutrophil count

Several studies have evaluated circulating neutrophil count as a biomarker for DKD. In a large National Health and Nutrition Examination Survey (NHANES) cohort, higher neutrophil counts were independently associated with increased risks of all-cause and cardiovascular mortality, even after adjustment for conventional risk factors such as eGFR and urinary albumin-to-creatinine ratio (uACR) (Table 2) [94]. Patients in the highest neutrophil quartile showed significantly worse outcomes, underscoring the prognostic value of systemic neutrophil activation. Similar findings have been reported in autoimmune diabetes. In T1DM, higher circulating neutrophil counts correlate with albuminuria and reduced eGFR, indicating a relationship with renal involvement [95]. Collectively, these findings support circulating neutrophil count as an accessible biomarker reflecting systemic inflammation and increased risk of DKD progression.

Neutrophil-to-lymphocyte ratio

Multiple studies have shown that NLR is significantly elevated in T2DM patients with DKD compared to those without nephropathy, reflecting increased systemic inflammatory burden (Table 2) [24,96-99]. Elevated baseline NLR has been associated with renal function decline independent of conventional risk factors, and correlates with leukocyte profile changes characterized by neutrophilia and lymphopenia [24,100]. Several studies have proposed threshold values of NLR that are associated with higher risk of progressive albuminuria and renal impairment [4,98,101]. Fluid balance alterations may partially contribute to this association [102].

Similar findings have been observed across diabetes subtypes. In T1DM and latent autoimmune diabetes in adults, higher NLR levels are associated with albuminuria and early kidney involvement, suggesting that NLR may serve as a pandiabetic marker for DKD [95,103,104]. In addition, cross-sectional studies have demonstrated independent associations between NLR and DKD presence in diabetic populations [99].

Neutrophil percentage-to-albumin ratio

In NHANES-based studies, higher NPAR levels were significantly associated with the presence of DKD and independently predicted increased risks of all-cause and cardiovascular mortality (Table 2) [105,106]. These findings suggest that NPAR reflects inflammation-related renal dysfunction and adverse outcomes, supporting its potential as a biomarker for early kidney involvement and risk stratification in diabetes.

Systemic immune-inflammation index

Recent studies have identified SII as a promising biomarker for DKD. Elevated SII levels are associated with DKD prevalence and renal dysfunction, including albuminuria and reduced eGFR, and have been shown to be independent of conventional risk factors (Table 2) [107-109]. Mechanistically, SII reflects neutrophil-driven inflammation and immune dysregulation, with increased neutrophil activity contributing to renal injury [107,108]. While SII may improve risk stratification and early detection of DKD, current evidence is largely based on observational studies, and standardized cutoff values remain to be established [109,110]. Emerging evidence also supports its role in T1DM, where SII predicts early kidney damage, suggesting its potential as a universal biomarker across diabetes types [111].

Diabetic retinopathy

DR is a major microvascular complication leading to progressive vision impairment and blindness. Despite advances in management, early detection remains critical [112]. Inflammation plays a central role in DR pathogenesis, and neutrophil-related inflammatory biomarkers may offer potential for early diagnosis, risk stratification, and targeted intervention [5,113,114].

Target organ neutrophil infiltration in diabetic retinopathy

Experimental evidence supports a pathogenic role for neutrophils in DR. Binet et al. [5] demonstrated that NETs target senescent retinal vasculature, promoting inflammatory vascular remodeling. Although most clinical studies focus on circulating markers, hyperglycemia-induced NETosis has been consistently linked to T2DM and its complications, suggesting that local neutrophil activation contributes to DR progression [12,21].

Circulating neutrophil count

Several studies have evaluated circulating neutrophil count as a biomarker of systemic inflammation in DR. A large cross-sectional study demonstrated that neutrophil counts are significantly elevated in patients with DR and correlate with disease severity (Table 2) [115]. Mechanistically, hyperglycemia induces neutrophil activation and NET formation via NOX pathways, contributing to retinal vascular damage [11]. In addition, systemic NET formation may further amplify inflammation and promote DR progression [116]. Collectively, circulating neutrophil count represents a readily accessible marker reflecting systemic inflammation and microvascular injury in DR.

Neutrophil-to-lymphocyte ratio

NLR has emerged as a robust systemic inflammatory biomarker in DR. A meta-analysis showed that NLR levels are significantly elevated in patients with DR compared to diabetic controls, with values increasing according to disease severity [25,117,118]. Elevated NLR has also been identified as an independent risk factor for proliferative DR, reflecting neutrophil-driven vascular inflammation, endothelial dysfunction, and oxidative stress (Table 2) [65,119,120]. Additionally, higher NLR levels are associated with diabetic macular edema severity [121]. Overall, NLR may serve as a practical biomarker for risk stratification and progression assessment in DR.

Neutrophil percentage-to-albumin ratio

NPAR has recently emerged as a potential biomarker reflecting systemic inflammatory burden in diabetic microvascular complications [122]. In DR, elevated NPAR levels are significantly associated with disease presence and increased retinopathy risk, independent of glycemic control and cardiovascular risk factors (Table 2) [26]. These findings suggest that NPAR may capture subclinical inflammation contributing to retinal microvascular damage and could serve as an accessible biomarker for early detection and progression monitoring in DR.

Platelet-to-neutrophil ratio

PNR has been investigated as a potential inflammatory marker in DR [123,124]. Lower PNR values have been associated with proliferative DR and identified as independent predictors of diabetic macular edema, reflecting enhanced neutrophil-driven inflammation and microvascular injury [124,125]. Although evidence remains limited, decreased PNR may serve as a surrogate marker of systemic inflammation in DR (Table 2).

Systemic immune-inflammation index

The SII, integrating platelet, neutrophil, and lymphocyte counts, reflects the balance between innate immune activation and adaptive immune suppression and has emerged as a promising biomarker in DR [119]. Elevated SII levels are significantly associated with DR presence and severity, and may improve predictive performance when combined with indices such as the triglyceride-glucose index (TyG) (Table 2) [119,126,127]. Beyond T2DM, SII has also shown relevance in T1DM, where it correlates with choroidal thickness as an early marker of retinal microvascular change [128], suggesting its potential to capture subclinical inflammation before overt DR. In addition, SII has been associated with DR across disease stages in T2DM cohorts [129]. Overall, SII reflects systemic inflammatory burden and may serve as an accessible biomarker for early detection and risk stratification in DR.

Diabetic neuropathy

DN affects approximately 50% of diabetic patients but remains challenging to diagnose early with conventional methods [94, 130]. Inflammation contributes to DN pathogenesis through release of cytokines, proteolytic enzymes, and ROS that damage Schwann cells and peripheral nerves [125]. Experimental studies show that neutrophil infiltration can precede functional deficits, supporting the potential of neutrophil-derived parameters as diagnostic and prognostic biomarkers for early detection and monitoring of DN [131].

Target organ neutrophil infiltration in diabetic peripheral neuropathy

In diabetic peripheral neuropathy (DPN), systemic neutrophil activation is well documented, whereas direct evidence of local infiltration in peripheral nerves remains limited. Experimental studies show that hyperglycemia induces neutrophil infiltration and NET formation in the spinal cord and peripheral nerves, contributing to microvascular dysfunction and neural injury [11,131]. However, clinical studies have primarily focused on systemic markers such as NLR and circulating neutrophil count, which correlate with DPN presence and severity but do not confirm local accumulation [132]. Thus, while systemic neutrophil dysregulation likely contributes to DPN pathophysiology, the role of local tissue infiltration requires further investigation.

Circulating neutrophil

Systemic neutrophil activation is increasingly recognized as a contributor to DPN development and progression. Higher neutrophil-related inflammatory indices have been associated with DPN severity, and circulating neutrophil count correlates with both the presence and severity of neuropathy in T2DM patients [132,133]. These findings support circulating neutrophil count as an accessible biomarker for identifying patients at higher risk of DPN, reflecting systemic inflammatory dysregulation contributing to microvascular and neuronal injury.

Neutrophil-to-lymphocyte ratio

Multiple studies have demonstrated that NLR is significantly elevated in patients with DN and is independently associated with disease presence and severity (Table 2) [68,70]. Higher NLR levels correlate with reduced nerve conduction velocity, reflecting more severe neuropathy [68]. NLR is a stable inflammatory marker with established diagnostic cutoff values and has shown good sensitivity and specificity for DPN [68-70]. Type-specific differences have also been reported, with NLR showing stronger predictive performance in T2DM, whereas PLR may be more relevant in T1DM [65,75,134]. Importantly, prospective studies indicate that elevated baseline NLR predicts future DPN development, supporting its utility for early risk stratification [65,134].

Systemic immune-inflammation index

SII reflects systemic inflammatory dysregulation contributing to nerve injury in DPN. Elevated SII levels are independently associated with DPN, supporting a link between systemic inflammation and neural damage (Table 2) [135]. Mechanistically, increased neutrophil activity and platelet-mediated vascular dysfunction contribute to endothelial damage, microvascular ischemia, and neuronal impairment. Although SII shows potential as an early biomarker for DPN detection and risk stratification, further large-scale prospective studies are required to establish standardized cutoff values and confirm its clinical utility.

THERAPEUTIC MODULATION OF NEUTROPHIL-DRIVEN INFLAMMATION IN DIABETES

Neutrophil dysfunction in diabetes has been explored through both direct targeting of neutrophil effector pathways and indirect modulation by antidiabetic agents. Existing evidence, summarized in Tables 3 and 4, remains limited but highlights emerging therapeutic strategies targeting neutrophil-driven inflammation.

Direct modulation of neutrophil-intrinsic effector pathways

Direct therapeutic approaches have primarily focused on NET formation and neutrophil-derived protease activity. NETosis, largely mediated by peptidylarginine deiminase 4 (PAD4)-dependent chromatin decondensation, plays a central role in diabetic inflammation. Experimental studies demonstrate that inhibition of NET formation (e.g., PAD4 or elastase, neutrophil expressed [ELANE] deficiency) improves vascular dysfunction, reduces thromboxane production, and attenuates endothelial injury in T1DM [136]. In DKD, NETosis correlates with albuminuria and promotes NLRP3 inflammasome activation, while PAD4 inhibition reduces renal injury [137]. In diabetic wounds, excessive NET formation delays healing, whereas NET inhibition accelerates tissue repair and improves angiogenesis [138,139]. Emerging regulators of NETosis further support its therapeutic relevance. Gonadotropin-releasing hormone signaling promotes NET formation and delays wound healing, while its antagonism improves tissue repair [140]. Milk fat globule–epidermal growth factor VIII (MFG-E8) suppresses the NET–NLRP3 axis, enhancing angiogenesis and wound closure [141]. In DR, NE contributes to vascular leakage and leukostasis, and its inhibition preserves endothelial integrity and reduces microvascular damage [84,86].

Neutrophil-related effects of currently used antidiabetic agents

Neutrophil-related inflammatory changes have been reported with commonly used antidiabetic agents, although these effects are generally interpreted within broader metabolic and inflammatory regulation rather than direct neutrophil targeting (Table 4).

Metformin suppresses NETosis via inhibition of PKC–NOX signaling and reduces circulating NET components, with additional anti-inflammatory effects observed across models [142-145]. SGLT2 inhibitors are associated with reduced inflammatory indices, including NLR, and exhibit anti-inflammatory and cardioprotective effects, although neutrophil-specific contributions remain unclear [146-148]. Glucagon-like peptide-1 receptor agonists (e.g., liraglutide) reduce NET formation via sirtuin 1 (SIRT1)-mediated pathways in preclinical models [149]. Thiazolidinediones decrease neutrophil-driven inflammation and normalize circulating leukocyte profiles while attenuating systemic inflammatory responses [150,151].

Despite these findings, evidence remains limited. Human interventional data are scarce, and neutrophil-related effects are difficult to distinguish from systemic metabolic changes. Mechanistic understanding is incomplete, particularly regarding neutrophil subsets and tissue- or stage-specific roles. Further studies are needed to clarify neutrophil-specific therapeutic mechanisms without compromising host defense.

CONCLUSIONS

Neutrophils are increasingly recognized as key mediators in diabetic microvascular complications. Dysregulated functions—including impaired chemotaxis, defective pathogen clearance, and excessive ROS and NET formation—drive chronic inflammation, tissue injury, and vascular dysfunction. Neutrophil-related biomarkers such as NLR and SII show potential as accessible tools for early detection and risk stratification, although further validation in large and diverse populations is required.

A deeper understanding of neutrophil biology, including temporal dynamics and functional heterogeneity, will advance mechanistic insight and support the development of neutrophil-specific biomarkers and targeted therapies. Emerging strategies targeting NETosis and neutrophil-derived pathways, together with multi-omics approaches, may further enable precision medicine in diabetic microvascular disease. Interdisciplinary efforts will be essential to translate these findings into clinical practice.

NOTES

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

FUNDING

This research was financially supported by the National Research Foundation of Korea (NRF) (grant number RS-2021-NR061617). This work was supported by the NRF grant funded by the Korea government (MSIT) (grant number RS-2024-00406568). This work is also supported by the Korea Health Technology R&D Project through the KHIDI, founded by the Ministry of Health and Welfare (grant number RS-2020-KH088690 and RS-2025- 24536373). We also thank the use of the Histopathology Core Facility of the Regional Medica Research Capability Enhancement Project, Biomedical Research Institute, Chungnam National University Hospital, for providing data analysis support.

ACKNOWLEDGMENTS

None

Fig. 1.

Neutrophil functional alterations in hyperglycemic conditions. In blood vessels (top), hyperglycemia and advanced glycation end products (AGEs) disrupt neutrophil adhesion cascade, affecting rolling, firm adhesion, and transmigration. In tissues (bottom), diabetes compromises neutrophil chemotaxis, phagocytosis, degranulation, and promotes excessive neutrophil extracellular trap formation (NETosis) and inflammatory cytokine production. These dysfunctions drive pathological immune cell interactions and reactive oxygen species (ROS) generation, creating a cycle that worsens tissue damage and microvascular complications. Glc, glucose; P-selectin, P-selectin; PSGL-1, P-selectin glycoprotein ligand-1; ICAM-1, intercellular adhesion molecule 1; DC, dendritic cell; IL, interleukin; NE, neutrophil elastase; MPO, myeloperoxidase; LL-37, cathelicidin antimicrobial peptide; TNF-α, tumor necrosis factor alpha; NADPH, nicotinamide adenine dinucleotide phosphate; STAT3, signal transducer and activator of transcription 3; ER, endoplasmic reticulum; PI3K, phosphatidylinositol-3-kinase.

REFERENCES

• 1. Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol 2011;12:1035-44.ArticlePubMedPMCPDF
• 2. Darenskaya MA, Kolesnikova LI, Kolesnikov SI. Oxidative stress: pathogenetic role in diabetes mellitus and its complications and therapeutic approaches to correction. Bull Exp Biol Med 2021;171:179-89.ArticlePubMedPMCPDF
• 3. Michelis R, Kristal B, Zeitun T, Shapiro G, Fridman Y, Geron R, et al. Albumin oxidation leads to neutrophil activation in vitro and inaccurate measurement of serum albumin in patients with diabetic nephropathy. Free Radic Biol Med 2013;60:49-55.ArticlePubMed
• 4. Azab B, Daoud J, Naeem FB, Nasr R, Ross J, Ghimire P, et al. Neutrophil-to-lymphocyte ratio as a predictor of worsening renal function in diabetic patients (3-year follow-up study). Ren Fail 2012;34:571-6.ArticlePubMed
• 5. Binet F, Cagnone G, Crespo-Garcia S, Hata M, Neault M, Dejda A, et al. Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy. Science 2020;369:eaay5356.ArticlePubMed
• 6. Xue C, Chen K, Gao Z, Bao T, Dong L, Zhao L, et al. Common mechanisms underlying diabetic vascular complications: focus on the interaction of metabolic disorders, immuno-inflammation, and endothelial dysfunction. Cell Commun Signal 2023;21:298.ArticlePubMedPMCPDF
• 7. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol 2018;18:134-47.ArticlePubMedPDF
• 8. Herrero-Cervera A, Soehnlein O, Kenne E. Neutrophils in chronic inflammatory diseases. Cell Mol Immunol 2022;19:177-91.ArticlePubMedPMCPDF
• 9. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013;13:159-75.ArticlePubMedPDF
• 10. Thimmappa PY, Nair AS, D’silva S, Aravind A, Mallya S, Soman SP, et al. Neutrophils display distinct post-translational modifications in response to varied pathological stimuli. Int Immunopharmacol 2024;132:111950.ArticlePubMed
• 11. Wang L, Zhou X, Yin Y, Mai Y, Wang D, Zhang X. Hyperglycemia induces neutrophil extracellular traps formation through an NADPH oxidase-dependent pathway in diabetic retinopathy. Front Immunol 2018;9:3076.ArticlePubMed
• 12. Menegazzo L, Ciciliot S, Poncina N, Mazzucato M, Persano M, Bonora B, et al. NETosis is induced by high glucose and associated with type 2 diabetes. Acta Diabetol 2015;52:497-503.ArticlePubMedPDF
• 13. Gauer JS, Ajjan RA, Ariens RA. Platelet-neutrophil interaction and thromboinflammation in diabetes: considerations for novel therapeutic approaches. J Am Heart Assoc 2022;11:e027071.ArticlePubMedPMC
• 14. Mordecai EA, Cohen JM, Evans MV, Gudapati P, Johnson LR, Lippi CA, et al. Detecting the impact of temperature on transmission of Zika, dengue, and chikungunya using mechanistic models. PLoS Negl Trop Dis 2017;11:e0005568.ArticlePubMedPMC
• 15. Shrestha S, Hong CW. Extracellular mechanisms of neutrophils in immune cell crosstalk. Immune Netw 2023;23:e38.ArticlePubMedPMCPDF
• 16. Taverner K, Murad Y, Yasunaga AB, Furrer C, Little J, Li IT. The effect of type-2 diabetes conditions on neutrophil rolling adhesion. BMC Res Notes 2022;15:355.ArticlePubMedPMCPDF
• 17. Pezhman L, Tahrani A, Chimen M. Dysregulation of leukocyte trafficking in type 2 diabetes: mechanisms and potential therapeutic avenues. Front Cell Dev Biol 2021;9:624184.ArticlePubMedPMC
• 18. Monach PA, Nigrovic PA, Chen M, Hock H, Lee DM, Benoist C, et al. Neutrophils in a mouse model of autoantibody-mediated arthritis: critical producers of Fc receptor gamma, the receptor for C5a, and lymphocyte function-associated antigen 1. Arthritis Rheum 2010;62:753-64.PubMedPMC
• 19. Zurawska-Plaksej E, Lugowska A, Hetmanczyk K, Knapik-Kordecka M, Piwowar A. Neutrophils as a source of chitinases and chitinase-like proteins in type 2 diabetes. PLoS One 2015;10:e0141730.ArticlePubMedPMC
• 20. Vermot A, Petit-Hartlein I, Smith SM, Fieschi F. NADPH oxidases (NOX): an overview from discovery, molecular mechanisms to physiology and pathology. Antioxidants (Basel) 2021;10:890.ArticlePubMedPMC
• 21. Zhu Y, Xia X, He Q, Xiao QA, Wang D, Huang M, et al. Diabetes-associated neutrophil NETosis: pathogenesis and interventional target of diabetic complications. Front Endocrinol (Lausanne) 2023;14:1202463.ArticlePubMedPMC
• 22. Huang J, Xiao Y, Zheng P, Zhou W, Wang Y, Huang G, et al. Distinct neutrophil counts and functions in newly diagnosed type 1 diabetes, latent autoimmune diabetes in adults, and type 2 diabetes. Diabetes Metab Res Rev 2019;35:e3064.ArticlePubMedPDF
• 23. Klisic A, Scepanovic A, Kotur-Stevuljevic J, Ninic A. Novel leukocyte and thrombocyte indexes in patients with prediabetes and type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci 2022;26:2775-81.PubMed
• 24. Akase T, Kawamoto R, Ninomiya D, Kikuchi A, Kumagi T. Neutrophil-to-lymphocyte ratio is a predictor of renal dysfunction in Japanese patients with type 2 diabetes. Diabetes Metab Syndr 2020;14:481-7.ArticlePubMed
• 25. Luo WJ, Zhang WF. The relationship of blood cell-associated inflammatory indices and diabetic retinopathy: a meta-analysis and systematic review. Int J Ophthalmol 2019;12:312-23.PubMedPMC
• 26. He X, Dai F, Zhang X, Pan J. The neutrophil percentage-to-albumin ratio is related to the occurrence of diabetic retinopathy. J Clin Lab Anal 2022;36:e24334.ArticlePubMedPMCPDF
• 27. Gazzaz ZJ. Diabetes and COVID-19. Open Life Sci 2021;16:297-302.ArticlePubMedPMC
• 28. Sorriento D, Rusciano MR, Visco V, Fiordelisi A, Cerasuolo FA, Poggio P, et al. The metabolic role of GRK2 in insulin resistance and associated conditions. Cells 2021;10:167.ArticlePubMedPMC
• 29. Yang K, Yang X, Gao C, Hua C, Hong C, Zhu L. A novel microfluidic device for the neutrophil functional phenotype analysis: effects of glucose and its derivatives AGEs. Micromachines (Basel) 2021;12:944.ArticlePubMedPMC
• 30. Guo G, Liu Z, Yu J, You Y, Li M, Wang B, et al. Neutrophil function conversion driven by immune switchpoint regulator against diabetes-related biofilm infections. Adv Mater 2024;36:e2310320.ArticlePubMed
• 31. Freire MO, Dalli J, Serhan CN, Van Dyke TE. Neutrophil resolvin E1 receptor expression and function in type 2 diabetes. J Immunol 2017;198:718-28.ArticlePubMedPDF
• 32. Vig S, Lambooij JM, Dekkers MC, Otto F, Carlotti F, Guigas B, et al. ER stress promotes mitochondrial DNA mediated type-1 interferon response in beta-cells and interleukin-8 driven neutrophil chemotaxis. Front Endocrinol (Lausanne) 2022;13:991632.ArticlePubMedPMC
• 33. Kotova DA, Ivanova AD, Pochechuev MS, Kelmanson IV, Khramova YV, Tiaglik A, et al. Hyperglycemia exacerbates ischemic stroke not through increased generation of hydrogen peroxide. Free Radic Biol Med 2023;208:153-64.ArticlePubMed
• 34. Prasad M K, Mohandas S, Ramkumar KM. Role of ER stress inhibitors in the management of diabetes. Eur J Pharmacol 2022;922:174893.ArticlePubMed
• 35. Thom SR, Bhopale VM, Arya AK, Ruhela D, Bhat AR, Mitra N, et al. Blood-borne microparticles are an inflammatory stimulus in type 2 diabetes mellitus. Immunohorizons 2023;7:71-80.ArticlePubMedPMCPDF
• 36. Kang Q, Yang C. Oxidative stress and diabetic retinopathy: molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol 2020;37:101799.ArticlePubMedPMC
• 37. Tan C, Aziz M, Wang P. The vitals of NETs. J Leukoc Biol 2021;110:797-808.ArticlePubMedPDF
• 38. Mikhalchik EV, Lipatova VA, Basyreva LY, Panasenko OM, Gusev SA, Sergienko VI. Hyperglycemia and some aspects of leukocyte activation in vitro. Bull Exp Biol Med 2021;170:748-51.ArticlePubMedPDF
• 39. Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, et al. Neutrophil extracellular traps in COVID-19. JCI Insight 2020;5:e138999.ArticlePubMedPMC
• 40. Zhang H, Wang Y, Qu M, Li W, Wu D, Cata JP, et al. Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis. Clin Transl Med 2023;13:e1170.ArticlePubMedPMCPDF
• 41. Hou Y, Li X, Yang Y, Shi H, Wang S, Gao M. Serum cytokines and neutrophil-to-lymphocyte ratio as predictive biomarkers of benefit from PD-1 inhibitors in gastric cancer. Front Immunol 2023;14:1274431.ArticlePubMedPMC
• 42. Slaats J, Ten Oever J, van de Veerdonk FL, Netea MG. IL-1β/IL-6/CRP and IL-18/ferritin: distinct inflammatory programs in infections. PLoS Pathog 2016;12:e1005973.ArticlePubMedPMC
• 43. Poveda E, Blanco F, Garcia-Gasco P, Alcolea A, Briz V, Soriano V. Successful rescue therapy with darunabir (TMC114) in HIV-infected patients who have failed several ritonavir-boosted protease inhibitors. AIDS 2006;20:1558-60.ArticlePubMed
• 44. Gideon HP, Phuah J, Junecko BA, Mattila JT. Neutrophils express pro- and anti-inflammatory cytokines in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques. Mucosal Immunol 2019;12:1370-81.ArticlePubMedPMCPDF
• 45. Xing J, Zhang J, Wang J. The immune regulatory role of adenosine in the tumor microenvironment. Int J Mol Sci 2023;24:14928.ArticlePubMedPMC
• 46. Lee H, Kim MJ, Lee IK, Hong CW, Jeon JH. Impact of hyperglycemia on immune cell function: a comprehensive review. Diabetol Int 2024;15:745-60.ArticlePubMedPMCPDF
• 47. Shofler D, Rai V, Mansager S, Cramer K, Agrawal DK. Impact of resolvin mediators in the immunopathology of diabetes and wound healing. Expert Rev Clin Immunol 2021;17:681-90.ArticlePubMed
• 48. Kesserwan S, Mao L, Sharafieh R, Kreutzer DL, Klueh U. A pharmacological approach assessing the role of mast cells in insulin infusion site inflammation. Drug Deliv Transl Res 2022;12:1711-8.ArticlePubMedPDF
• 49. Xiao M, Xu Z, Zhu X, Chen J, Wang R, Wang Y, et al. Immunological profiling in type 2 diabetes mellitus and type 2 diabetic kidney disease: insights from single-cell LacNAc sequencing. Front Endocrinol (Lausanne) 2025;16:1550925.ArticlePubMedPMC
• 50. Alghamdi B, Liu M, Huang X, Debnath R, Afzali H, Troka M, et al. Single-cell RNA profiling identifies immune cell population shifts in diabetes associated mucosal inflammation. Mucosal Immunol 2025;18:1082-97.ArticlePubMedPMC
• 51. Theocharidis G, Thomas BE, Sarkar D, Mumme HL, Pilcher WJ, Dwivedi B, et al. Single cell transcriptomic landscape of diabetic foot ulcers. Nat Commun 2022;13:181.ArticlePubMedPMCPDF
• 52. Ma J, Song R, Liu C, Cao G, Zhang G, Wu Z, et al. Single-cell RNA-Seq analysis of diabetic wound macrophages in STZ-induced mice. J Cell Commun Signal 2023;17:103-20.ArticlePubMedPDF
• 53. Li Y, Ju S, Li X, Li W, Zhou S, Wang G, et al. Characterization of the microenvironment of diabetic foot ulcers and potential drug identification based on scRNA-seq. Front Endocrinol (Lausanne) 2022;13:997880.ArticlePubMed
• 54. Sawaya AP, Stone RC, Brooks SR, Pastar I, Jozic I, Hasneen K, et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nat Commun 2020;11:4678.ArticlePubMedPMCPDF
• 55. Marshall JL, Noel T, Wang QS, Chen H, Murray E, Subramanian A, et al. High-resolution Slide-seqV2 spatial transcriptomics enables discovery of disease-specific cell neighborhoods and pathways. iScience 2022;25:104097.ArticlePubMedPMC
• 56. Diana J, Simoni Y, Furio L, Beaudoin L, Agerberth B, Barrat F, et al. Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat Med 2013;19:65-73.ArticlePubMedPDF
• 57. Lundberg M, Seiron P, Ingvast S, Korsgren O, Skog O. Insulitis in human diabetes: a histological evaluation of donor pancreases. Diabetologia 2017;60:346-53.ArticlePubMedPDF
• 58. Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 2007;56:2356-70.ArticlePubMedPDF
• 59. Al-Dewachi AB, Al-Dewachi SO. Association between hematological indices and blood glucose level among patients with type 2 diabetes. Ir J Med Sci 2024;193:2307-12.ArticlePubMedPDF
• 60. Vozarova B, Weyer C, Lindsay RS, Pratley RE, Bogardus C, Tataranni PA. High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 2002;51:455-61.ArticlePubMedPDF
• 61. Sefil F, Ulutas KT, Dokuyucu R, Sumbul AT, Yengil E, Yagiz AE, et al. Investigation of neutrophil lymphocyte ratio and blood glucose regulation in patients with type 2 diabetes mellitus. J Int Med Res 2014;42:581-8.ArticlePubMedPDF
• 62. Hussain M, Babar MZ, Akhtar L, Hussain MS. Neutrophil lymphocyte ratio (NLR): a well assessment tool of glycemic control in type 2 diabetic patients. Pak J Med Sci 2017;33:1366-70.ArticlePubMedPMCPDF
• 63. Bambo GM, Asmelash D, Alemayehu E, Gedefie A, Duguma T, Kebede SS. Changes in selected hematological parameters in patients with type 1 and type 2 diabetes: a systematic review and meta-analysis. Front Med (Lausanne) 2024;11:1294290.ArticlePubMedPMC
• 64. Aukrust SG, Holte KB, Opstad TB, Seljeflot I, Berg TJ, Helseth R. NETosis in long-term type 1 diabetes mellitus and its link to coronary artery disease. Front Immunol 2021;12:799539.ArticlePubMed
• 65. Adane T, Melku M, Worku YB, Fasil A, Aynalem M, Kelem A, et al. The association between neutrophil-to-lymphocyte ratio and glycemic control in type 2 diabetes mellitus: a systematic review and meta-analysis. J Diabetes Res 2023;2023:3117396.ArticlePubMedPMCPDF
• 66. Gasparyan AY, Ayvazyan L, Mukanova U, Yessirkepov M, Kitas GD. The platelet-to-lymphocyte ratio as an inflammatory marker in rheumatic diseases. Ann Lab Med 2019;39:345-57.ArticlePubMedPMCPDF
• 67. Yamamoto T, Kawada K, Obama K. Inflammation-related biomarkers for the prediction of prognosis in colorectal cancer patients. Int J Mol Sci 2021;22:8002.ArticlePubMedPMC
• 68. Duman TT, Aktas G, Atak BM, Kocak MZ, Erkus E, Savli H. Neutrophil to lymphocyte ratio as an indicative of diabetic control level in type 2 diabetes mellitus. Afr Health Sci 2019;19:1602-6.ArticlePubMedPMC
• 69. Balta S, Kurtoglu E, Kucuk U, Demirkol S, Ozturk C. Neutrophil-lymphocyte ratio as an important assessment tool. Expert Rev Cardiovasc Ther 2014;12:537-8.ArticlePubMed
• 70. Chen HL, Wu C, Cao L, Wang R, Zhang TY, He Z. The association between the neutrophil-to-lymphocyte ratio and type 2 diabetes mellitus: a cross-sectional study. BMC Endocr Disord 2024;24:107.ArticlePubMedPMCPDF
• 71. Erbas IM, Hajikhanova A, Besci O, Acinikli KY, Demir K, Bober E, et al. Initial neutrophil/lymphocyte and lymphocyte/monocyte ratios can predict future insulin need in newly diagnosed type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2022;35:593-602.ArticlePubMed
• 72. Akin S, Aydin Z, Yilmaz G, Aliustaoglu M, Keskin O. Evaluation of the relationship between glycaemic regulation parameters and neutrophil-to-lymphocyte ratio in type 2 diabetic patients. Diabetes 2019;7:91-6.Article
• 73. Dayama N, Yadav SK, Saxena P, Sharma A, Kashnia R, Sharda K. A study of relationships between the HbA1c level and inflammatory markers, neutrophil-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio in controlled and uncontrolled type 2 diabetes mellitus. J Assoc Physicians India 2024;72:24-6.Article
• 74. Rias YA, Kurniasari MD, Traynor V, Niu SF, Wiratama BS, Chang CW, et al. Synergistic effect of low neutrophil-lymphocyte ratio with physical activity on quality of life in type 2 diabetes mellitus: a community-based study. Biol Res Nurs 2020;22:378-87.ArticlePubMedPDF
• 75. Essawi K, Dobie G, Shaabi MF, Hakami W, Saboor M, Madkhali AM, et al. Comparative analysis of red blood cells, white blood cells, platelet count, and indices in type 2 diabetes mellitus patients and normal controls: association and clinical implications. Diabetes Metab Syndr Obes 2023;16:3123-32.ArticlePubMedPMCPDF
• 76. Mertoglu C, Gunay M. Neutrophil-Lymphocyte ratio and platelet-lymphocyte ratio as useful predictive markers of prediabetes and diabetes mellitus. Diabetes Metab Syndr 2017;11 Suppl 1:S127-31.ArticlePubMed
• 77. Wang L, Liu L, Liu X, Yang L. The association between neutrophil percentage-to-albumin ratio (NPAR) and depression among US adults: a cross-sectional study. Sci Rep 2024;14:21880.ArticlePubMedPMCPDF
• 78. Jing Y, Tian B, Deng W, Ren Z, Xu X, Zhang D, et al. The neutrophil percentage-to-albumin ratio as a biomarker for all-cause and diabetes-cause mortality among diabetes patients: evidence from the NHANES 1988-2018. J Clin Lab Anal 2024;38:e25110.PubMedPMC
• 79. Ye C, Yuan L, Wu K, Shen B, Zhu C. Association between systemic immune-inflammation index and chronic obstructive pulmonary disease: a population-based study. BMC Pulm Med 2023;23:295.ArticlePubMedPMCPDF
• 80. Lewis A, Wilma Delphine Silvia CR, Chakraborty A, Devi L, Prasad H, Madhuvan HS. Assessment of systemic immuneinflammatory (SII) index and systemic inflammatory response index (SIRI) in type 2 diabetes mellitus: a cross-sectional study. Eur J Cardiovasc Med 2025;15:669-73.
• 81. Nie Y, Zhou H, Wang J, Kan H. Association between systemic immune-inflammation index and diabetes: a population-based study from the NHANES. Front Endocrinol (Lausanne) 2023;14:1245199.ArticlePubMedPMC
• 82. Ye Y, Huang A, Huang X, Jin Q, Gu H, Liu L, et al. IL-33, a neutrophil extracellular trap-related gene involved in the progression of diabetic kidney disease. Inflamm Res 2025;74:15.ArticlePubMedPDF
• 83. Monickaraj F, Acosta G, Cabrera AP, Das A. Transcriptomic profiling reveals chemokine CXCL1 as a mediator for neutrophil recruitment associated with blood-retinal barrier alteration in diabetic retinopathy. Diabetes 2023;72:781-94.ArticlePubMedPMCPDF
• 84. Lessieur EM, Liu H, Saadane A, Du Y, Tang J, Kiser J, et al. Neutrophil-derived proteases contribute to the pathogenesis of early diabetic retinopathy. Invest Ophthalmol Vis Sci 2021;62:7.Article
• 85. Satirapoj B. Tubulointerstitial biomarkers for diabetic nephropathy. J Diabetes Res 2018;2018:2852398.ArticlePubMedPMCPDF
• 86. Liu H, Lessieur EM, Saadane A, Lindstrom SI, Taylor PR, Kern TS. Neutrophil elastase contributes to the pathological vascular permeability characteristic of diabetic retinopathy. Diabetologia 2019;62:2365-74.ArticlePubMedPMCPDF
• 87. Gomez I, Ward B, Souilhol C, Recarti C, Ariaans M, Johnston J, et al. Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium. Nat Commun 2020;11:214.ArticlePubMedPMCPDF
• 88. Lessieur EM, Gao F, Du Y, Jiyacharoen J, Kiser J, Kern TS. Neutrophil-derived extracellular vesicles from diabetic mice promote retinal endothelial cell cytotoxicity. Invest Ophthalmol Vis Sci 2023;64:1844.
• 89. Concepcion M, Quiroz J, Suarez J, Paz J, Roseboom P, Ildefonso S, et al. Novel biomarkers for the diagnosis of diabetic nephropathy. Caspian J Intern Med 2024;15:382-91.PubMedPMC
• 90. Liu H, Feng J, Tang L. Early renal structural changes and potential biomarkers in diabetic nephropathy. Front Physiol 2022;13:1020443.ArticlePubMedPMC
• 91. Loughman A, Staudacher HM, Rocks T, Ruusunen A, Marx W, O Apos Neil A, et al. Diet and mental health. Mod Trends Psychiatry 2021;32:100-12.ArticlePubMed
• 92. Pasala S, Carmody JB. How to use… serum creatinine, cystatin C and GFR. Arch Dis Child Educ Pract Ed 2017;102:37-43.ArticlePubMed
• 93. Liu KZ, Tian G, Ko AC, Geissler M, Brassard D, Veres T. Detection of renal biomarkers in chronic kidney disease using microfluidics: progress, challenges and opportunities. Biomed Microdevices 2020;22:29.ArticlePubMedPDF
• 94. Xie R, Bishai DM, Lui DT, Lee PC, Yap DY. Higher circulating neutrophil counts is associated with increased risk of all-cause mortality and cardiovascular disease in patients with diabetic kidney disease. Biomedicines 2024;12:1907.ArticlePubMedPMC
• 95. Yu Y, Lin Q, Ye D, Wang Y, He B, Li Y, et al. Neutrophil count as a reliable marker for diabetic kidney disease in autoimmune diabetes. BMC Endocr Disord 2020;20:158.ArticlePubMedPMCPDF
• 96. Huang W, Huang J, Liu Q, Lin F, He Z, Zeng Z, et al. Neutrophil-lymphocyte ratio is a reliable predictive marker for early-stage diabetic nephropathy. Clin Endocrinol (Oxf) 2015;82:229-33.ArticlePubMed
• 97. Kawamoto R, Ninomiya D, Kikuchi A, Akase T, Kasai Y, Kusunoki T, et al. Association of neutrophil-to-lymphocyte ratio with early renal dysfunction and albuminuria among diabetic patients. Int Urol Nephrol 2019;51:483-90.ArticlePubMedPDF
• 98. Akbas EM, Demirtas L, Ozcicek A, Timuroglu A, Bakirci EM, Hamur H, et al. Association of epicardial adipose tissue, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio with diabetic nephropathy. Int J Clin Exp Med 2014;7:1794-801.PubMedPMC
• 99. Wan H, Wang Y, Fang S, Chen Y, Zhang W, Xia F, et al. Associations between the neutrophil-to-lymphocyte ratio and diabetic complications in adults with diabetes: a cross-sectional study. J Diabetes Res 2020;2020:6219545.ArticlePubMedPMCPDF
• 100. Nakhjavani M, Aghajani Nargesi A, Salabati M, Mahmoudzadeh R, Morteza A, Heidari B, et al. Changes in leukocyte subpopulations with decline in glomerular filtration rate in patients with type 2 diabetes. Acta Med Iran 2015;53:425-31.PubMed
• 101. DiGangi C. Neutrophil-lymphocyte ratio: predicting cardiovascular and renal complications in patients with diabetes. J Am Assoc Nurse Pract 2016;28:410-4.PubMed
• 102. Moh MC, Low S, Shao YM, Subramaniam T, Sum CF, Lim SC. Association between neutrophil/lymphocyte ratio and kidney impairment in type 2 diabetes mellitus: a role of extracellular water/total body water ratio. Diabetes Res Clin Pract 2023;199:110634.ArticlePubMed
• 103. Yildirim AT, Bayar NTI, Yigit Y, Ersoy B. The role of biomarkers of innate and adaptive immunity in the early detection of diabetic nephropathy in children and adolescents with type 1 diabetes mellitus. J Diabetes Complications 2025;39:109090.ArticlePubMed
• 104. Xiang Z, Liu W, Fu S, Hu J, Yang Y. Clinical value of lymphocyte count in autoimmune diabetic nephropathy. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2023;48:1639-49.PubMedPMC
• 105. Li H, Xu Y, Fan S, Wang Z, Chen H, Zhang L, et al. Association between neutrophil-percentage-to-albumin ratio and diabetic kidney disease in type 2 diabetes mellitus patients: a cross-sectional study from NHANES 2009-2018. Front Endocrinol (Lausanne) 2025;16:1552772.ArticlePubMedPMC
• 106. Tan J, Du J, Liu J, Zhao W, Liu Y. Prognostic effect of neutrophil percentage-to-albumin ratio (NPAR) on all-cause and cardiovascular mortality in diabetic kidney disease (DKD): NHANES 1999-2018. Diabetol Metab Syndr 2025;17:105.ArticlePubMedPMCPDF
• 107. Guo W, Song Y, Sun Y, Du H, Cai Y, You Q, et al. Systemic immune-inflammation index is associated with diabetic kidney disease in type 2 diabetes mellitus patients: evidence from NHANES 2011-2018. Front Endocrinol (Lausanne) 2022;13:1071465.ArticlePubMedPMC
• 108. Yan P, Yang Y, Zhang X, Zhang Y, Li J, Wu Z, et al. Association of systemic immune-inflammation index with diabetic kidney disease in patients with type 2 diabetes: a cross-sectional study in Chinese population. Front Endocrinol (Lausanne) 2023;14:1307692.ArticlePubMed
• 109. Zhang X, Fang Y, Weng M, Chen C, Xu Y, Wan J. Systemic immune-inflammation index as an independent risk factor for diabetic nephropathy: a retrospective, single-center study. PeerJ 2024;12:e18493.ArticlePubMedPMCPDF
• 110. Duman TT, Ozkul FN, Balci B. Could systemic inflammatory index predict diabetic kidney injury in type 2 diabetes mellitus? Diagnostics (Basel) 2023;13:2063.ArticlePubMedPMC
• 111. Cao LF, Xu QB, Yang L. Systemic immune indicators for predicting renal damage in newly diagnosed type 1 diabetic children. World J Diabetes 2025;16:104482.ArticlePubMedPMC
• 112. Tan TE, Wong TY. Diabetic retinopathy: looking forward to 2030. Front Endocrinol (Lausanne) 2022;13:1077669.ArticlePubMed
• 113. Kastelan S, Oreskovic I, Biscan F, Kastelan H, Gverovic Antunica A. Inflammatory and angiogenic biomarkers in diabetic retinopathy. Biochem Med (Zagreb) 2020;30:030502.PubMedPMC
• 114. Ninomiya H, Katakami N, Osonoi T, Saitou M, Yamamoto Y, Takahara M, et al. Association between new onset diabetic retinopathy and monocyte chemoattractant protein-1 (MCP-1) polymorphism in Japanese type 2 diabetes. Diabetes Res Clin Pract 2015;108:e35-7.ArticlePubMed
• 115. Woo SJ, Ahn SJ, Ahn J, Park KH, Lee K. Elevated systemic neutrophil count in diabetic retinopathy and diabetes: a hospital-based cross-sectional study of 30,793 Korean subjects. Invest Ophthalmol Vis Sci 2011;52:7697-703.ArticlePubMed
• 116. Floyd JL, Prasad R, Dupont MD, Adu-Rutledge Y, Anshumali S, Paul S, et al. Intestinal neutrophil extracellular traps promote gut barrier damage exacerbating endotoxaemia, systemic inflammation and progression of diabetic retinopathy in type 2 diabetes. Diabetologia 2025;68:866-89.ArticlePubMedPMCPDF
• 117. Deng R, Zhu S, Fan B, Chen X, Lv H, Dai Y. Exploring the correlations between six serological inflammatory markers and different stages of type 2 diabetic retinopathy. Sci Rep 2025;15:1567.ArticlePubMedPMCPDF
• 118. Huang L, Li L, Wang M, Zhang D, Song Y. Correlation between ultrawide-field fluorescence contrast results and white blood cell indexes in diabetic retinopathy. BMC Ophthalmol 2022;22:231.ArticlePubMedPMCPDF
• 119. Gao Y, Lu RX, Tang Y, Yang XY, Meng H, Zhao CL, et al. Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio in patients with type 2 diabetes at different stages of diabetic retinopathy. Int J Ophthalmol 2024;17:877-82.PubMedPMC
• 120. Li J, Wang X, Jia W, Wang K, Wang W, Diao W, et al. Association of the systemic immuno-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio with diabetic microvascular complications. Front Endocrinol (Lausanne) 2024;15:1367376.ArticlePubMedPMC
• 121. Ozata Gundogdu K, Dogan E, Celik E, Alagoz G. Serum inflammatory marker levels in serous macular detachment secondary to diabetic macular edema. Eur J Ophthalmol 2022;32:3637-43.ArticlePubMedPDF
• 122. Li X, Gu Z, Gao J. Elevated neutrophil percentage-to-albumin ratio predicts increased all-cause and cardiovascular mortality among individuals with diabetes. Sci Rep 2024;14:27870.ArticlePubMedPMCPDF
• 123. Ali MH, Draman N, Mohamed WM, Yaakub A, Embong Z. Predictors of proliferative diabetic retinopathy among patients with type 2 diabetes mellitus in Malaysia as detected by fundus photography. J Taibah Univ Med Sci 2016;11:353-8.Article
• 124. Sun H, Li Y, Liu S, Pan C, Li D, Zhou X. The diagnostic value of platelet-to-neutrophil ratio in diabetic macular edema. BMC Ophthalmol 2025;25:167.ArticlePubMedPMCPDF
• 125. Zhao L, Hu H, Zhang L, Liu Z, Huang Y, Liu Q, et al. Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions. MedComm (2020) 2024;5:e516.ArticlePubMedPMC
• 126. Li J, Li Y, Qi Q, Chen N, Zhang Y. Predictive value of triglyceride glucose index and systemic inflammation index for diabetic retinopathy in type-2 diabetes. Pak J Med Sci 2025;41:1072-7.ArticlePubMedPMCPDF
• 127. Wang S, Pan X, Jia B, Chen S. Exploring the correlation between the systemic immune inflammation index (SII), systemic inflammatory response index (SIRI), and type 2 diabetic retinopathy. Diabetes Metab Syndr Obes 2023;16:3827-36.ArticlePubMedPMCPDF
• 128. Kahraman HG, Guven YZ, Akay F, Uzum Y, Aysin M. New marker for the detection of pre-retinopathy in patients with type 1 diabetes mellitus: systemic immuno-inflammation index. BMC Ophthalmol 2025;25:296.ArticlePubMedPMCPDF
• 129. Dascalu AM, Serban D, Tanasescu D, Vancea G, Cristea BM, Stana D, et al. The value of white cell inflammatory biomarkers as potential predictors for diabetic retinopathy in type 2 diabetes mellitus (T2DM). Biomedicines 2023;11:2106.ArticlePubMedPMC
• 130. Yorek M, Malik RA, Calcutt NA, Vinik A, Yagihashi S. Diabetic neuropathy: new insights to early diagnosis and treatments. J Diabetes Res 2018;2018:5378439.ArticlePubMedPMCPDF
• 131. Newton VL, Guck JD, Cotter MA, Cameron NE, Gardiner NJ. Neutrophils infiltrate the spinal cord parenchyma of rats with experimental diabetic neuropathy. J Diabetes Res 2017;2017:4729284.ArticlePubMedPMCPDF
• 132. Rezaei Shahrabi A, Arsenault G, Nabipoorashrafi SA, Lucke-Wold B, Yaghoobpoor S, Meidani FZ, et al. Relationship between neutrophil to lymphocyte ratio and diabetic peripheral neuropathy: a systematic review and meta-analysis. Eur J Med Res 2023;28:523.PubMedPMC
• 133. Cheng Y, Cao W, Zhang J, Wang J, Liu X, Wu Q, et al. Determinants of diabetic peripheral neuropathy and their clinical significance: a retrospective cohort study. Front Endocrinol (Lausanne) 2022;13:934020.ArticlePubMedPMC
• 134. Xu T, Weng Z, Pei C, Yu S, Chen Y, Guo W, et al. The relationship between neutrophil-to-lymphocyte ratio and diabetic peripheral neuropathy in type 2 diabetes mellitus. Medicine (Baltimore) 2017;96:e8289.ArticlePubMedPMC
• 135. Li J, Zhang X, Zhang Y, Dan X, Wu X, Yang Y, et al. Increased systemic immune-inflammation index was associated with type 2 diabetic peripheral neuropathy: a cross-sectional study in the Chinese population. J Inflamm Res 2023;16:6039-53.ArticlePubMedPMCPDF
• 136. Liu C, Yalavarthi S, Tambralli A, Zeng L, Rysenga CE, Alizadeh N, et al. Inhibition of neutrophil extracellular trap formation alleviates vascular dysfunction in type 1 diabetic mice. Sci Adv 2023;9:eadj1019.ArticlePubMedPMC
• 137. Gupta A, Singh K, Fatima S, Ambreen S, Zimmermann S, Younis R, et al. Neutrophil extracellular traps promote NLRP3 inflammasome activation and glomerular endothelial dysfunction in diabetic kidney disease. Nutrients 2022;14:2965.ArticlePubMedPMC
• 138. Fadini GP, Menegazzo L, Rigato M, Scattolini V, Poncina N, Bruttocao A, et al. NETosis delays diabetic wound healing in mice and humans. Diabetes 2016;65:1061-71.ArticlePubMedPDF
• 139. Yang S, Wang S, Chen L, Wang Z, Chen J, Ni Q, et al. Neutrophil extracellular traps delay diabetic wound healing by inducing endothelial-to-mesenchymal transition via the Hippo pathway. Int J Biol Sci 2023;19:347-61.ArticlePubMedPMC
• 140. Lee YS, Kang SU, Lee MH, Kim HJ, Han CH, Won HR, et al. GnRH impairs diabetic wound healing through enhanced NETosis. Cell Mol Immunol 2020;17:856-64.ArticlePubMedPDF
• 141. Huang W, Jiao J, Liu J, Huang M, Hu Y, Ran W, et al. MFG-E8 accelerates wound healing in diabetes by regulating “NLRP3 inflammasome-neutrophil extracellular traps” axis. Cell Death Discov 2020;6:84.ArticlePubMedPMCPDF
• 142. Menegazzo L, Scattolini V, Cappellari R, Bonora BM, Albiero M, Bortolozzi M, et al. The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo. Acta Diabetol 2018;55:593-601.ArticlePubMedPDF
• 143. Carestia A, Frechtel G, Cerrone G, Linari MA, Gonzalez CD, Casais P, et al. NETosis before and after hyperglycemic control in type 2 diabetes mellitus patients. PLoS One 2016;11:e0168647.ArticlePubMedPMC
• 144. Zhu W, Xu D, Mei J, Lu B, Wang Q, Zhu C, et al. Metformin reverses impaired osteogenesis due to hyperglycemia-induced neutrophil extracellular traps formation. Bone 2023;176:116889.ArticlePubMed
• 145. Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res 2016;119:652-65.ArticlePubMedPMC
• 146. Sen Uzeli U, Dogan M. The effects of dapagliflozin on monocyte-HDL ratio and neutrophil-lymphocyte ratio among patients with type-2 diabetes mellitus. Eur Rev Med Pharmacol Sci 2023;27:10577-82.PubMed
• 147. Topsakal S, Ozmen O, Asci H, Gulal A, Ozcan KN, Aydin B. Dapagliflozin prevents reproductive damage caused by acute systemic inflammation through antioxidant, anti-inflammatory, and antiapoptotic mechanisms. Basic Clin Pharmacol Toxicol 2024;135:561-74.ArticlePubMed
• 148. Paolisso P, Bergamaschi L, Santulli G, Gallinoro E, Cesaro A, Gragnano F, et al. Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry. Cardiovasc Diabetol 2022;21:77.ArticlePubMedPMCPDF
• 149. Zhong S, Huang L, Lin T, Li Y, Deng B, Kong D, et al. The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide regulates sirtuin-1-mediated neutrophil extracellular traps to improve diabetes-induced bone metabolism imbalance. Iran J Pharm Res 2024;23:e148139.ArticlePubMedPMCPDF
• 150. van Wijk JP, Cabezas MC, Coll B, Joven J, Rabelink TJ, de Koning EJ. Effects of rosiglitazone on postprandial leukocytes and cytokines in type 2 diabetes. Atherosclerosis 2006;186:152-9.ArticlePubMed
• 151. Kim MS, Yamamoto Y, Kim K, Kamei N, Shimada T, Liu L, et al. Regulation of diet-induced adipose tissue and systemic inflammation by salicylates and pioglitazone. PLoS One 2013;8:e82847.ArticlePubMedPMC

Figure & Data

References

Citations

Citations to this article as recorded by  

About this article

Kim J, Jung D, Kang DH, Kim H, Park JO, Heo JY, Lee SE, Kim HJ, Lee JH, Kang YE, Ku BJ. Neutrophil-Linked Inflammatory Mechanisms and Biomarkers in Diabetic Microvascular Complications. Diabetes Metab J. 2026;50(3):450-471.

Received: Oct 16, 2025; Accepted: Mar 27, 2026

DOI: https://doi.org/10.4093/dmj.2025.1034.

Download citation ↓