Diabetes mellitus is a health issue affecting 529 million patients worldwide (1). Alarmingly, up to one-third of these individuals are at risk of developing the diabetic foot ulcer (DFU) at some point in their lives. Furthermore, research indicates that over 15% of DFU eventually lead to lower extremity amputation (2). Various factors contribute to the increased likelihood of DFU development among individuals with diabetes, including prolonged diabetes duration, poor glycemic control, Charcot deformity, diabetic peripheral neuropathy, peripheral arterial disease (PAD), and a history of ulcers or amputation (3–6). The quality of life for DFU patients can be significantly improved through early identification, rapid treatment, and continued foot care.

The presence of inflammation significantly influences the development and progression of DFU (7–9). Clinicians commonly utilize laboratory markers such as white blood cell (WBC) count, C-reactive protein (CRP) level, and erythrocyte sedimentation rate to monitor levels of inflammation (10, 11). There has been a steady increase in research showing that certain inflammatory biomarkers, including CRP, procalcitonin (PTC), malondialdehyde and tumor necrosis factor-alpha, are associated with an elevated risk of DFU over time (9, 12–15). However, despite the close association of inflammatory markers with the diagnosis and prognosis of DFU, there currently lacks a specific inflammatory indicator.

The monocyte-to-lymphocyte ratio (MLR) has emerged as a novel and promising inflammatory marker, obtained by dividing the absolute monocyte and lymphocyte counts in blood samples (16). It has been widely studied in various inflammation-related disorders, such as cancer, tuberculosis and cardiovascular diseases, and has proven to be a reliable biomarker of systemic inflammation (17–19). Elevated MLR has been associated with poor prognosis and accelerated disease progression in several disorders, including acute kidney injury and hematoma after cerebral contusion (20, 21). Recently, some studies have shown that the MLR is associated with the occurrence and progression of diabetes complications, including diabetic nephropathy, diabetic retinopathy (DR), and PAD (7, 22–24).It is reasonable to assume that MLR may play a significant role in the onset and progression of DFU, given the mounting body of research emphasizing its importance in diabetes complications (7, 22–24). However, it is currently unclear whether there is a relationship between MLR and the occurrence and progression of DFU.

In order to comprehensively elucidate this interaction, more research is required to determine the precise connection between MLR and DFU. This study aimed to evaluate MLR’s clinical and predictive value in diabetic patients with DFU. We aimed to clarify the possible function of MLR as a prognostic marker for DFU by assessing MLR levels in a sample of patients and examining their clinical outcomes. This knowledge may have significant effects on early identification, care, and general management of DFU in patients with diabetes.

The NHANES database’s data were used to perform the current investigation. An in-depth examination of this database enabled us to examine the connection between the prevalence of DFU and MLR. To our knowledge, our study is the first to show that the incidence of DFU increases with MLR. Specifically, every 0.1 unit increase in MLR was associated with a 20% increase in the presence of DFU. Moreover, our findings revealed a notable link between MLR and DFU. Thus, the MLR may be a useful biomarker for predicting DFU. We considered additional possible variables that could cloud the association between MLR and DFU and discovered that even after controlling for these variables, MLR continued to be strongly correlated with the occurrence of DFU. These findings demonstrate the potential diagnostic value of MLR for identifying patients who are more likely to develop DFU. Early detection and treatment of patients with a high MLR may help delay or even stop the development of DFU, improve patient outcomes, and lessen the burden of crippling diabetic complications.

The onset of diabetes and its associated problems are mostly influenced by pathophysiological circumstances, including inflammation, endothelial dysfunction, ferroptosis and procoagulant imbalance (26–28). These pathophysiological processes interact with metabolic and inflammatory problems in patients with diabetes, causing tissue damage and ultimately leading to consequences, such as PAD, retinopathy, neuropathy, and nephropathy (28).According to several studies, changes in inflammatory biomarkers has been confirmed to be closely related to the occurrence and progression of diabetic complications (7, 22–24). These biomarkers may provide new insights for the early detection and treatment of diabetes and its consequences (27–30).

Systemic inflammation affects neutrophils, lymphocytes, monocytes, and platelets by the fat metabolism, oxidative stress, damaging islet cells and depletion of nutrient (30). During systemic inflammation, neutrophil and monocyte counts are typically high, whereas lymphocyte count may decrease. The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and MLR are indicators of these immune cells. Numerous studies have demonstrated that these markers can predict the presence of systemic inflammation and may be helpful in the diagnosis of various disorders (8, 20, 21, 31). Recently, some studies have shown that the high MLR is associated with the occurrence and progression of diabetes complications, including diabetic nephropathy, DR, and PAD (7, 22–24, 32).

Although inflammation and diabetes or diabetic complications are closely related, limited research has been conducted on the utility of these biomarkers in DFU. Aydın and colleagues confirmed that the systemic immune inflammation index is closely associated with the amputation rate of DFU patients and can be used as a predictive indicator for amputation along with other inflammatory markers (9). Moreover, Umapathy et al. (13) demonstrated that PCT can serve as a valuable indicator for diagnosing type 2 diabetes patients with infected diabetic foot ulcers (with a positive predictive value of 100% and a negative predictive value of 12%). In our study, patients with DFU had a significant high MLR and incidence of DFU increases with MLR. This is similar to the research on MLR in other diabetes complications (7, 22–24). For example, Yue et al. (22) demonstrated that MLR is a risk factor for DR and may be related to the pathophysiology and clinical aspects of DR. Gao et al. (32) explored the association between MLR, the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio and the risk of non-healing ulceration in patients with type 2 diabetes. They found that after adjusting for confounding variables, MLR and NLR were significantly higher in type 2 diabetes patients with non-healing ulceration. In fact, aberrant glucose metabolism in diabetes leads to altered immunological function of leukocytes (30, 33). This may have an impact on lymphocyte levels, which modulate inflammation. Furthermore, hyperglycemia in individuals with diabetes may increase reactive oxygen species, which can harm lymphocyte DNA by oxidative oxidation and potentially diminish their levels (34). Because of increased lymphocyte death, systemic inflammation frequently leads to reduced lymphocyte levels (35, 36).

This study has several limitations. First, because our study was cross-sectional and relied on data from the NHANES database, we could not prove a causal connection. We were able to establish a connection between MLR and the occurrence of DFU; however, we were unable to establish whether MLR caused DFU or whether DFU caused changes in MLR. Further investigation is required to overcome this limitation, ideally in the form of a prospective study that can offer better proof of causal association. Second, as people may not correctly recall or self-report their diabetes history, self-reported recollections, which was the source of part of the diabetes data, raises the possibility of recall and self-report biases.

This study investigated the relationship between the MLR and DFU incidence. After considering additional variables that may have an impact on the findings, the MLR exhibited a substantial increase in patients with diabetes who had DFU. MLR, obtained from a standard blood test, is a practical and affordable biomarker. Its potential utility during follow-up appointments for diabetes patients is where its significance resides. Further research is required to completely comprehend the underlying mechanism between MLR and DFU.

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

The studies involving humans were approved by Ethics Committee of Affiliated Hospital of Zunyi Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

ZL: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal Analysis, Data curation. YJ: Writing – review & editing, Writing – original draft, Methodology, Investigation, Data curation. ZW: Writing – review & editing, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition.