Exploring the link: Hemogram-derived markers in type 2 diabetes mellitus and its complications

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia and insulin resistance, often leading to severe complications. Hemogram markers have attracted great attention from researchers for their established role in inflammatory conditions. In this respect, T2DM and its microvascular complications are characterized by high inflammatory burden. Hence, recent studies in the literature have reported an association between T2DM and hemogram-derived markers. Emerging evidence highlights the utility of hemogram-derived markers, including the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, red cell distribution width, and mean platelet volume, as potential predictors of T2DM onset and progression. These markers, readily available from routine hemogram tests, offer valuable insights into the systemic inflammation and vascular changes associated with T2DM and its complications, such as cardiovascular disease, nephropathy, and retinopathy. This review synthesizes current research on the association between hemogram-derived markers and T2DM, emphasizing their prognostic value in predicting disease severity and complications. We also explore the underlying pathophysiological mechanisms linking these markers to inflammation and metabolic dysfunction. The findings suggest that hemogram-derived markers could serve as cost-effective, non-invasive tools for risk stratification and early intervention in T2DM management. Future research should focus on standardizing reference ranges and validating these markers in diverse populations to enhance their clinical utility.

Key Words: Type 2 diabetes mellitus; Inflammation; Hemogram markers; Microvascular complications; Macrovascular complications

Core Tip: Type 2 diabetes mellitus (T2DM) is a chronic condition marked by high blood glucose and insulin resistance, often accompanied by severe complications and systemic inflammation. Recent research highlights hemogram-derived markers, such as the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, red cell distribution width, and mean platelet volume, as valuable tools for predicting the onset, progression, and complications of T2DM. These markers, accessible through routine blood tests, provide insights into inflammation and vascular changes linked to T2DM including cardiovascular disease, nephropathy, and retinopathy.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a prevalent chronic disease characterized by insulin resistance (IR) and chronic hyperglycemia. It significantly increases the risk of complications such as cardiovascular disease (CVD), diabetic retinopathy (DR), kidney disease, and diabetic neuropathy (DN). Inflammation has been identified as a key contributor to the development of T2DM and its associated complications, linking metabolic imbalance with vascular damage and tissue dysfunction[1]. A study indicated that of a total of half a billion people with diabetes, 9 of 10 of them have T2DM[2].

Markers derived from hemograms, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), and red cell distribution width (RDW), have gained attention for their ability to indicate systemic inflammation. The relationships between inflammatory conditions and the NLR[3], PLR[4], MPV[5], and RDW[6] are well established. These markers are readily available through routine blood tests, cost-effective, and non-invasive, making them valuable tools in the follow-up of disease progression and predicting complications in T2DM.

This review explored the potential role of these hemogram-derived markers in the context of T2DM, examining their relationship with disease severity, inflammation, and the development of diabetic complications. By integrating current research, the aim was to provide insights into their clinical utility and their potential to enhance patient management in T2DM.

REVIEW AND DISCUSSION

Role of the NLR in T2DM and its complications

T2DM is linked to a higher risk of various complications, such as CVD, diabetic kidney damage (DKD), DR, and DN, all of which substantially influence morbidity and mortality[7]. Growing evidence suggests that chronic low-grade inflammation plays a central role in the onset and progression of T2DM and its associated complications[8,9]. The NLR, a simple marker derived from routine blood tests, has attracted attention as a potential indicator of systemic inflammation. Elevated NLR has been reported in a range of inflammatory conditions including autoimmune disorders[10], inflammatory bowel disease[11], infectious diseases[12], metabolic syndrome[13], and obesity[14]. Like T2DM, these are characterized by a substantial inflammatory burden.

The NLR is calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Neutrophils, key components of the innate immune system, typically increase in response to inflammation, infection, or tissue damage, whereas lymphocytes, part of the adaptive immune system, play a role in regulating inflammatory responses. In T2DM, chronic inflammation and immune system dysfunction can lead to alterations in both neutrophil and lymphocyte counts.

Inflammatory pathways, particularly those involving cytokines like tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), play a pivotal role in the development of IR[15]. Neutrophils contribute to the inflammatory cascade by releasing pro-inflammatory cytokines, generating oxidative stress, and secreting proteolytic enzymes. These actions are central to promoting endothelial dysfunction, exacerbating IR, and inducing pancreatic β-cell apoptosis[16]. At the same time, lymphocyte activation might amplify inflammation by releasing cytokines, further disrupting glucose homeostasis and contributing to the progression of diabetic complications[17]. The imbalance, characterized by an increased neutrophil count and a relative depletion of lymphocytes, in T2DM underscores the severity of the inflammatory process, with a higher NLR serving as an indicator of a more pronounced inflammatory state.

The NLR has garnered attention as a potential biomarker for assessing the inflammatory burden in T2DM and its complications. Research indicates that elevated NLR is associated with poor glycemic control[18], increased levels of inflammatory markers[18], and common comorbidities such as hypertension[19] and dyslipidemia[19]. Moreover, elevated NLR has also been linked to DKD[3] and increased IR, underscoring its role as a marker of metabolic dysfunction. A Spanish study reported that higher NLR values were associated with IR in obese population[20]. Similarly, a study by Zhang and Liu[21] found a correlation between NLR and IR, as measured by the homeostasis model assessment (HOMA) of IR. Elevated NLR levels have also been associated with adverse outcomes in patients with T2DM, including increased risks of CV events, hospitalizations, and mortality. A study from China analyzing data from 1454 subjects found that elevated NLR was an independent risk factor for CV events and overall mortality in individuals with T2DM[22]. Subsequently, a meta-analysis, involving 407512 subjects, confirmed that the NLR serves as a prognostic marker for mortality in patients with T2DM[23]. These findings highlight the significant role of NLR in the management and prognosis of T2DM.

CVD is the leading cause of death in patients with T2DM. Chronic inflammation plays a central role in the development of atherosclerosis and CV complications in patients with diabetes[24]. Elevated NLR has been consistently associated with an increased risk of coronary artery disease, myocardial infarction, and other CV events in patients with T2DM. A recent study followed 8835 subjects for a median 2.4 years and reported that a high NLR in patients with T2DM was associated with poor clinical outcome in coronary events[19]. Additionally, authors studied 3780 patients with diabetes or prediabetes with coronary artery disease and found that high NLR levels were linked to CV mortality in that population[25].

The inflammatory environment in T2DM, reflected by a high NLR, might contribute to endothelial dysfunction, plaque formation, and vascular remodeling, which are key factors in the pathogenesis of CVD[26]. Thus, NLR may serve as a simple, cost-effective tool to predict the risk of CV events in this high-risk population.

DKD, also known as diabetic nephropathy, is a common and serious complication of T2DM, characterized by progressive and eventual renal failure. Chronic inflammation plays a critical role in the development and progression of DKD, with immune cell infiltration and the release of inflammatory mediators driving glomerular injury and fibrosis[27]. Elevated NLR has been associated with an increased risk of developing DKD in patients with T2DM, and higher NLR levels correlate with worsening kidney function. A 2021 study demonstrated that increased NLR was linked to the presence of DKD in patients with T2DM[28]. Similarly, a cross-sectional study of 4813 adults with diabetesindicated that elevated NLR increased the risk of DKD by 2.5 times[29]. These findings were supported by a Japanese study, which showed that the NLR could be a useful marker for declining in renal function in subjects with diabetes[30]. Thus, the NLR is recommended as a predictor of early-stage , and may be valuable for monitoring renal function in patients with T2DM.

DR is an important cause of blindness in adults and is closely associated with the duration and severity of hyperglycemia. Inflammation, oxidative stress, and vascular dysfunction are central to the development of DR[31]. Elevated NLR has been associated with an increased risk of DR in patients with T2DM, with some studies suggesting that the NLR could serve as an early indicator of retinal changes in diabetes mellitus. The authors conducted a follow-up study on 857 patients with diabetes, of whom 140 patients later developed DR. Elevated baseline NLR levels were associated with a higher risk of incident DR[32]. A confirmatory study by Dascalu et al[33] reported that the NLR was an independent risk factor of DR in patients with T2DM. In addition, a Scottish study on 23531 patients with diabetes reported that the NLR was a significant predictor of DR[34]. The relationship between the NLR and retinal damage may reflect systemic inflammation that contributes to microvascular injury in the retina, similar to its role in other diabetic complications.

DN is another common complication of T2DM, often resulting in pain, sensory loss, and functional impairment. The role of inflammation in the development of DN is well established, with immune-mediated damage to peripheral nerves contributing to the pathophysiology[35]. Studies have shown that elevated NLR is associated with the presence and severity of DN, suggesting that the NLR may reflect the extent of nerve injury and inflammatory involvement in patients with T2DM. One study revealed patients with diabeteswith DN had higher NLR levels than those without DN[36]. A recent meta-analysis confirmed these findings showing that patients with DN consistently exhibited higher NLR levels than those without the condition[37].

Role of the PLR in T2DM and in its complications

The PLR is a straightforward and easily calculated biomarker obtained from routine hemogram tests. In recent years, it has gained attention as a potential marker of systemic inflammation and a valuable tool for assessing the risk and severity of T2DM and its complications. The PLR represents the ratio of the absolute platelet count to the absolute lymphocyte count in the bloodstream. Platelets play a critical role in hemostasis and thrombosis and actively contribute to the inflammatory response by releasing various pro-inflammatory cytokines, growth factors, and chemokines. These substances promote endothelial dysfunction, IR, and atherosclerosis[15]. By contrast, lymphocytes are central to the adaptive immune response, and their depletion or dysfunction can result in a dysregulated immune system, contributing to chronic inflammation[38]. In T2DM, elevated platelet count and altered lymphocyte function are both observed as part of the inflammatory process, leading to an increased PLR in patients with this condition. Higher PLR levels have been reported in patients with T2DM compared to healthy controls[39]. Moreover, the PLR was correlated with glycated hemoglobin (HbA1c) level in that study[39]. In addition, Liu et al[40] reported that the PLR was an independent predictor of gestational diabetes in their study on 120 subjects. These data suggest its potential benefits in the follow-up of patients with gestational or T2DM.

Inflammatory pathways leading to IR and β-cell dysfunction are mediated by various pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and C-reactive protein (CRP). These cytokines activate platelets, promoting aggregation and driving vascular inflammation. Both processes play a key role in the progression of diabetic complications, particularly CVD[41]. The imbalance characterized by elevated platelet counts and relatively reduced lymphocyte counts is believed to indicate the extent of inflammation and oxidative stress in T2DM. This makes the PLR a convenient marker for evaluating the inflammatory burden in T2DM and related conditions.

PLR has been found to be significantly associated inflammation in T2DM. Elevated PLR is often seen in patients with poor glycemic control and advanced stages of the disease, suggesting its potential as a marker for disease severity. In 2019, authors compared the PLR levels in patients with T2DM and healthy subjects and revealed that subjects with diabeteshad increased PLR compared to the controls[39]. Higher PLR has been linked to IR, a hallmark of T2DM, and some studies have suggested that the PLR may serve as a predictor of metabolic syndrome, which frequently accompanies T2DM. For instance, a study reported that the PLR is correlated with the components of metabolic syndrome[39]. Moreover, a recent study noted that a high PLR could be an indicator of IR[21]. Due to its easy accessibility, the PLR is a valuable tool in clinical practice for evaluating the inflammatory status of patients with T2DM and monitoring the risk of developing complications.

PLR and CVD in T2DM

Chronic inflammation and platelet activation are key factors in the development of atherosclerosis and thrombosis, both of which contribute to CV events. An elevated PLR has been consistently linked to a higher risk of CVD, including myocardial infarction, stroke, and peripheral artery disease, particularly in patients with T2DM. A 2021 meta-analysis reported that the PLR can predict prognosis in patients with myocardial infarction[42]. In another study, authors studied the role of the PLR in ischemic stroke subjects and found that it was an independent predictor of outcome in this population[43]. Additionally, Selvaggio et al[44] reported the PLR as a reliable marker of peripheral artery disease. A high PLR indicates increased platelet activation and inflammation, both of which play a role in endothelial dysfunction, plaque formation, and vascular damage[45]. Elevated PLR serves as an independent predictor of adverse CV events, making it a useful biomarker for evaluating CV risk in patients with diabetes.

The initiation and progression of DKD are closely linked to inflammation, oxidative stress, and vascular injury, all of which contribute to glomerular damage and fibrosis[46]. Studies have associated elevated PLR with both the presence and severity of DKD in patients with T2DM, suggesting its potential as a predictor of early and declining renal function. For example, Duan et al[47] studied 167 biopsy-proven subjects with DKD and revealed that the PLR was associated with proteinuria and the disease outcome. Considering the significant role of inflammation in the pathophysiology of DKD, PLR may serve as a valuable biomarker for identifying individuals at increased risk of renal complications and tracking the progression of kidney disease in patients with T2DM.

The development of DR is linked to vascular changes, inflammation, and oxidative stress in subjects with diabetes. Chronic low-grade inflammation plays a key role in the pathogenesis of DR[48], and platelet activation has been implicated in retinal microvascular injury[49]. Elevated PLR has been associated with an increased risk of DR, with higher PLR values indicating more severe retinopathy. A previous study compared the PLR levels of the subjects with DR to those with non-DR and found that they were increased in patients with DR compared to those in non-DR group[50]. Thus, the PLR may be useful for distinguishing between patients with DR and non-DR and assessing the risk of progression to advanced stages of retinopathy, facilitating earlier intervention.

The interaction between DN and inflammation is well established in patients with T2DM. Serum levels of inflammation markers are reportedly increased in subjects with DN[51]. Accordingly, as an inflammation marker, the PLR has been associated with the presence and severity of DN, which suggests that increased platelet activation and reduced lymphocyte counts may reflect the underlying inflammatory processes involved in nerve damage. A study by Chen et al [36] confirmed that patients with diabetic polyneuropathy had higher PLR levels than the diabetic subjects without DN. Therefore, we conclude that high PLR may indicate diabetic peripheral neuropathy, which is helpful in identifying patients at risk of this debilitating complication.

Role of MPV in T2DM and in its complications

As the prevalence of T2DM continues to rise globally, so too does the burden of its associated complications, including CVD, diabetic nephropathy, DR, and DN. These complications contribute significantly to morbidity and mortality among individuals with T2DM. MPV, a simple marker of platelet size, has emerged as a potential biomarker for assessing platelet activation and systemic inflammation[52]. A recent study suggested MPV in association with platelet adhesion in T2DM[53]. Moreover, MPV has been linked with inflammation and liver cirrhosis in patients with chronic hepatitis B[54]. Similar to T2DM, this chronic condition is also characterized with inflammatory burden.

MPV refers to the average size of platelets in circulation, with larger platelets generally considered more reactive and prothrombotic[55]. Platelets play an essential role in hemostasis, but are also involved in inflammation, contributing to the development of atherosclerosis, thrombosis, and vascular dysfunction. In T2DM, platelets are often hyperactivated due to the underlying inflammatory state and metabolic dysregulation, which leads to an increase in MPV levels[56].

The elevated MPV in T2DM is linked to several mechanisms, including oxidative stress, IR, and inflammatory cytokine release. Pro-inflammatory cytokines such as TNF-α and IL-6, which are elevated in T2DM, contribute to platelet activation and the release of pro-inflammatory mediators. Larger platelets have been shown to release more pro-inflammatory cytokines, which further exacerbate endothelial dysfunction and promote the development of diabetic complications[57]. The increase in MPV thus reflects both the degree of platelet activation and the overall inflammatory burden in T2DM.

It is obvious that MPV is a simple and inexpensive biomarker that can be easily measured through routine blood tests. Research has shown that higher MPV is associated with poor glycemic control and IR, both of which are hallmarks of T2DM[58]. Elevated MPV levels are also correlated with markers of systemic inflammation, such as CRP, suggesting that MPV may serve as a surrogate marker for inflammation in T2DM. Furthermore, elevated MPV has been associated with higher risks of adverse clinical outcomes, including an increased likelihood of developing diabetic complications. A study from Egypt reported that MPV was significantly higher in patients with T2DM with microvascular complications than the diabetics without those complications[59]. In addition, a Japanese study revealed that elevated MPV was also associated with macrovascular complications of T2DM[60].

In clinical practice, MPV can be used to assess the degree of platelet activation in patients with diabetes, offering insights into the patient's inflammatory status and potential risk for developing complications. Wu et al[61] found a correlation between MPV and HbA1c, supporting its role in glycemic monitoring. As a cost-effective and easily accessible marker, MPV holds promise as a useful tool for managing and monitoring T2DM, particularly in identifying individuals at higher risk of poor outcomes.

The association between MPV and CVD is well established as the association between MPV and T2DM. Platelet activation plays a central role in the pathogenesis of atherosclerosis and thrombosis[62]. In a recent work, Cassano et al[63] compared MPV levels among new-onset patients with T2DM, subjects with prediabetes, and controls with normal glycemia and reported that MPV was increased in subjects with diabetes and prediabetescompared to the controls. Moreover, the same study also revealed that MPV was correlated with arterial stiffness and subclinical myocardial damage[63]. Increased MPV has been consistently associated with elevated risk of CVD in patients with T2DM. Larger platelets are more thrombogenic, containing more pro-coagulant and pro-inflammatory substances, and they promote vascular injury, atherosclerotic plaque formation, and thrombus development. Elevated MPV is associated with poor endothelial function, a key factor in the development of atherosclerosis.

Several studies have identified high MPV as a predictor of adverse CV events, including myocardial infarction, stroke, and peripheral arterial disease in individuals with T2DM. A study from China showed that MPV was an independent risk factor of acute myocardial infarction[64]. Another study reported that MPV was associated with stroke risk[65]. Increased MPV has been recognized as a risk factor for peripheral artery disease according to a study by Li et al[66]. Elevated MPV levels have also been linked to the presence of coronary artery disease, suggesting that MPV can serve as a marker for subclinical CVD and a predictor of future CV events. Monitoring MPV levels may be useful in identifying patients with T2DM at high risk for CV complications and in guiding therapeutic interventions.

DKD is a common and severe complication of T2DM. It is characterized by progressive KD and eventual renal failure. Platelet activation and inflammation are key contributors to the development and progression of DKD. Elevated MPV has been shown to be associated with the presence and severity of diabetic nephropathy. One study demonstrated the utility of MPV in monitoring patients with DKD[67]. In patients with T2DM, larger platelets are more likely to promote microvascular injury in the kidneys, contributing to glomerular damage and fibrosis.

Studies have found that higher MPV levels are correlated with increased urinary albumin excretion, an early marker of KD in DKD. Sengupta et al[67] reported that MPV was increased in advanced stages of diabetic nephropathy compared to the early stages of the disease. Furthermore, increased MPV is associated with declining renal function, indicating its utility as an early marker of kidney dysfunction in patients with T2DM[68]. Monitoring MPV levels in patients with T2DM may help identify those at higher risk for developing nephropathy and could provide valuable insights into the progression of kidney disease.

DR is also associated with chronic inflammatory burden[69]. Platelet activation is thought to play a significant role in the development of DR, as activated platelets can contribute to retinal microvascular injury and thrombosis[70]. Elevated MPV has been associated with an increased risk of DR in patients with T2DM, with higher MPV values correlating with the severity of retinal damage. Authors have reported that elevated levels of MPV are associated with development and severity of DR in patients with T2DM[71].

As a reflection of systemic inflammation and endothelial dysfunction, two central processes in DR pathogenesis, elevated MPV may provide a valuable, non-invasive means of monitoring retinal health in patients with diabetes. Its ease of measurement makes MPV a practical tool for screening and tracking DR progression, potentially enabling earlier intervention to prevent vision loss.

DN is also characterized by a high burden of inflammation[35]. Inflammation and microvascular injury play a central role in the development of DN, and platelet activation is thought to contribute to these processes. Elevated MPV has been associated with the presence and severity of DN. A significant association between MPV and diabetic peripheral neuropathy was reported in a recent study[72]. Larger platelets, which are more reactive, may exacerbate nerve injury by promoting microvascular damage and inflammation.

Several studies have demonstrated that increased MPV correlates with the severity of neuropathic symptoms in patients with T2DM. Increased MPV was linked to the more serious neuropathic symptoms in patients with diabetesin a study by Nimmala et al[73]. Monitoring MPV levels may provide insights into the inflammatory processes that contribute to nerve damage and help identify individuals at a higher risk of neuropathy. By tracking MPV, clinicians may be able to identify those who require more intensive management to prevent the progression of neuropathy.

Role of RDW in T2DM and its complications

Among the biomarkers that reflect such systemic inflammation and vascular dysfunction, RDW measures the variation in the size of red blood cells (RBCs)[74]. Beyond its role as a marker of erythrocyte indices, it has been also linked to a variety of diseases, including T2DM, and serves as an indicator of underlying inflammatory and oxidative stress[75,76]. Elevated RDW levels are thought to reflect a dysregulated response to oxidative stress, inflammation, and changes in erythropoiesis. In T2DM, chronic hyperglycemia and IR lead to increased oxidative stress and inflammation, which in turn can alter RBC morphology and function, contributing to an increase in RDW[77]. The mechanisms linking RDW to T2DM involve various factors. The inflammatory environment in T2DM leads to the release of cytokines such as IL-6, TNF-α, and CRP, which can disrupt erythropoiesis and RBC turnover. Additionally, oxidative stress, which is prevalent in T2DM, can contribute to hemoglobin glycosylation and RBC damage, resulting in an increased RDW. Furthermore, the metabolic dysfunction in T2DM can lead to deficiencies in important nutrients such as iron, vitamin B₁₂, and folic acid, all of which can further influence RBC production and lead to increased RDW.

An important feature of RDW as a disease marker that is inexpensive and readily available nature. It can be measured as part of a routine complete blood count test. In T2DM, elevated RDW has been linked to poor glycemic control. A 2021 study revealed that poorly controlled patients with diabeteshad elevated levels of RDW compared to the well-controlled subjects with diabetes,and RDW was correlated with HbA1c[78]. Conversely, another study reported higher RDW in patients with T2DM compared to healthy controls but found no significant difference between well-controlled and poorly controlled subgroups[79]. This discrepancy may be attributed to a relatively small sample size (n = 220) or the single-center design of the study. RDW has also been linked to IR in the literature. A study that analyzed data from more than 2000 subjects showed that RDW was correlated with an IR index, HOMA-beta[80]. In addition, an increased risk of developing diabetic complications is associated with RDW levels. Furthermore, increased RDW has been proposed as a risk factor for DR[81]. Moreover, DKDreportedly increases with elevated levels of RDW[82]. RDW may also reflect the degree of metabolic dysregulation in T2DM since literature suggested positive correlation between higher RDW levels and poor blood glucose control. Interestingly, a significant negative correlation between RDW and HbA1c was reported in subjects with diabetes; however, a positive correlation among them was notable in the non-diabetic population[83]. This finding was supported by a study by Zhang et al[84], which found a negative correlation between HbA1c levels and RDW in a diabetic cohort. Furthermore, RDW has also been shown to correlate with other inflammatory markers, such as CRP, suggesting that RDW may serve as a reflection of the systemic inflammatory state in T2DM. Zhao et al[81] reported a significant correlation between RDW and CRP in patients with diabeteswith DR. As an indicator of both inflammation and oxidative stress, RDW could be a valuable tool for monitoring disease progression and guiding treatment decisions in patients with T2DM.

Elevated RDW levels have been associated with a higher risk of adverse CV outcomes in individuals with T2DM. These include including myocardial infarction, stroke, and peripheral artery disease. Higher RDW values reflect increased erythrocyte turnover and a pro-inflammatory state, which may contribute to endothelial injury and the progression of atherosclerosis[85]. RDW has been linked with an increased risk of CVDs in patients with diabetes[86]. The association between RDW and CVDs in T2DM is further supported by its correlation with B-type natriuretic factor[87]. Therefore, RDW may serve as a valuable biomarker for identifying patients with T2DM at high risk of CV events and for assessing the efficacy of therapeutic interventions.

Several studies have highlighted the relationship between RDW and DKD, a common and serious microvascular complication of T2DM. The pathogenesis of DKD involves chronic hyperglycemia, increased oxidative stress, inflammation, and microvascular damage[88]. RDW is also associated with inflammation, oxidative stress and hyperglycemia. A study by Tonelli et al[89] revealed that elevation in RDW was associated with end-stage renal disease in the general population. In addition, higher levels of RDW in subjects with diabetes have been reported, particularly in those with poorly controlled disease[90]. RDW has been shown to be elevated in patients with DKD and correlates with markers of kidney dysfunction, such as albuminuria and glomerular filtration rate (GFR). RDW is correlated with GFR and albuminuria in patients with DKD[91]. Moreover, RDW has been proposed as an independent risk factor of diabetic chronic kidney disease[92]. In addition to CVD, elevated RDW has also been linked to risk of kidney dysfunction in subjects with diabetes[93]. High RDW values are associated with both diabetic chronic kidney disease[94] and acute kidney injury[95]. By contrast, a prospective cohort study by Engström et al[96], which followed 26709 non-diabetic individuals over 14 years, found that higher baseline RDW was associated with a lower incidence of DM[96]. Elevated RDW levels may reflect the ongoing inflammatory process in the kidneys and the increased oxidative stress that accompanies diabetic nephropathy. Given the association between RDW and inflammation, it is thought that RDW may serve as an early indicator of in patients with T2DM, providing valuable information about the need for early intervention to prevent the progression of nephropathy.

The RDW has been studied in DR, another microvascular complication of diabetes mellitus. Chronic hyperglycemia and associated inflammatory processes play a significant role in the development of DR. As mentioned before, RDW is also associated with inflammation and correlated with plasma glucose levels. Elevated RDW has been reported in subjects with DR compared to those without[97]. Moreover, RDW has been identified as a potential marker for the presence and severity of DR[81]. Studies have shown that elevated RDW levels are associated with more severe stages of DR, and RDW may reflect the inflammatory and microvascular changes occurring in the retina[98]. Another study reported that RDW was associated with the presence of DR and positively correlated with HbA1c in patients with diabetes[99]. Increased RDW could serve as a valuable tool for identifying patients at risk of developing DR or for monitoring disease progression.

While the association between RDW and DN is well documented, no significant relationship has been observed between RDW and DN in studies[100,101]. DN is associated with inflammatory burden[35]. RDW is also associated with inflammation; however, no association was reported between RDW and neuropathy in patients with T2DM. Yet, diabetic foot ulcer, a complication of DN has been reported to be related with elevated levels of RDW[76]. This association is thought to reflect the underlying inflammatory and microvascular damage that contributes to nerve injury in T2DM.

Elevated RDW levels have been linked to an increased risk of CV events, kidney disease, and retinopathy. RDW is a simple, cost-effective, and widely available biomarker that can provide valuable insights into the inflammatory and oxidative stress burden in patients with T2DM. Regular monitoring of RDW levels may help clinicians identify individuals at higher risk for complications and allow for earlier intervention to prevent or mitigate the effects of these complications. Moreover, RDW may be useful for assessing the effectiveness of treatment regimens aimed at controlling inflammation, improving glycemic control, and reducing the risk of complications in patients with T2DM. As a tool for monitoring disease progression and guiding therapeutic decisions, RDW could play a significant role in improving the long-term outcomes for individuals with T2DM.

Clinical utility of these hemogram markers in daily practice

In light of the available data, it is appropriate to state that the NLR, PLR, MPV, and RDW are associated with both T2DM and its chronic complications. Figure 1 illustrates the associations between these markers and T2DM, as well as chronic diabetescomplications. It is also important to consider the implications of these associations in clinical practice. As inflammatory markers, the NLR, PLR, MPV, and RDW have been linked to T2DM and various diabetes-related complications, making them potentially useful clinical tools for risk stratification, prognosis, and disease monitoring. Chronic low-grade inflammation plays a central role in the pathogenesis of T2DM, contributing to IR, β-cell dysfunction, and vascular complications. Neutrophils, lymphocytes, erythrocytes, and platelets contribute to oxidative stress and tissue damage, and elevated levels of these markers reflect the inflammatory burden in T2DM. The predictive value of these markers for CVD, nephropathy, DR, and DN underscores their potential role in clinical settings. However, although they are simple and cost-effective biomarkers, they should be used in conjunction with other diagnostic and prognostic tools to ensure comprehensive patient management. Furthermore, the clinical application of these markers remains largely investigational. Most available evidence regarding their association with T2DM is derived from retrospective cohort studies. Prospective clinical trials are necessary to provide more robust evidence supporting their use in routine clinical practice.

Figure 1 Association between the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, mean platelet volume, red cell distribution width, and type 2 diabetes mellitus and diabetic chronic complications. MPV: Mean platelet volume; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; RDW: Red cell distribution width.

CONCLUSION

Hemogram-derived inflammatory markers could be useful in diagnosis and follow up of the patients with T2DM and its complications. Their cost effectiveness and accessibility make them valuable supplementary diagnostic and prognostic tools in the diabetic population. However, most studies that have reported their association with DM and diabetic complications are cross-sectional, which limit causal interference.