As the gold standard for evaluating long-term glycemic control, HbA1c offers a reliable measure of average blood glucose levels over 2–3 months. Accumulating evidence has indicated that elevated HbA1c levels (above the normal range) are associated with both the onset and progression of diabetic neuropathy (7–10). Zhang et al. (11) also have found a positive correlation between elevated HbA1c levels and the severity of DPN. In a retrospective cohort study involving 1,091pariticipants, Cheng et al. (12) further found that an HbA1c level of ≥7.7% could serve as a predictive threshold for neuropathic pain, and patients with HbA1c ≥7.7% exhibited a 3.15-fold higher risk of developing DPN compared to those with lower HbA1c levels(Table 1). In addition, evidence suggests that maintaining HbA1c within the range of 6.5%-7.0% may be optimal for preventing the progression of DPN in patients with T2DM (13) (Table 1).

C-peptide, a polypeptide co-secreted with insulin by pancreatic β-cells, serves as a critical biomarker for evaluating β-cell secretory function. Beyond its role in glucose homeostasis, accumulating evidence has found the pleiotropic effects of C-peptide, including anti-inflammatory, immunomodulation, and neuroprotective properties, which are increasingly recognized as playing a crucial role in modulating diabetic complications (14).

Clinical studies have consistently indicated significantly lower serum C-peptide levels in patients with DPN compared to non-DPN controls (15), and fasting C-peptide levels were found to be negatively correlated with the incidence DPN (16–18). In a cross-sectional study of 816 T2DM patients, Fu et al. (18) found higher ratio of fasting C-peptide to diabetes duration ratio (FCP/DD) ratio provided independently protection against DPN, exhibiting superior value to either FCP or diabetes duration (Table 1), suggesting the potential utility of FCP/DD as a composite predictive biomarker for DPN. Similarly, Cao et al. (19) found that 2-hour postprandial C-peptide (2h-CP) could be an independent predictor of DPN (Table 1). In a retrospective cohort study involving 1,278 patients with diabetes, Lian et al. (20) applied machine learning (XGBoost) to develop a DPN prediction model and identified the postprandial-to-fasting C-peptide ratio (C2/C0) as a protective factor for DPN through SHAP analysis (Table 1). Therefore, circulating C-peptide levels or their derived ratios might serve as potential DPN predictors.

However, evidence regarding the association between C-peptide levels and painful diabetic peripheral neuropathy (PDPN) remains inconsistent and controversial. Li et al. (21) reported a U-shaped relationship between serum C-peptide concentrations and PDPN risk: the prevalence of PDPN was elevated when serum C-peptide levels ranged from 1.2 to 2.8 ng/mL, whereas concentrations below 0.8 ng/mL or above 3.5 ng/mL appeared protective, which correlated with a reduced risk of PDPN (Table 1). In contrast, in multicenter cross-sectional study conducted by Christensen et al. (22) found a linear positive correlation between C-peptide and DPN, but no statistically significant association was observed between C-peptide concentrations and PDPN (Table 1). These conflicting results may be due to the differences in study design, patient characteristics and diagnostic criteria for PDPN. Furthermore, the potential U-shaped relationship between C-peptide and neuropathy risk suggests that conventional linear statistical models may be insufficient to capture its complex biological effects.

The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) is a well-validated parameter for peripheral insulin sensitivity derived from fasting glucose and insulin concentrations. Elevated HOMA-IR reflects impaired tissue insulin sensitivity when elevated, which is a key pathophysiological mechanism of microvascular complications. Both HOMA-IR and HOMA2-IR are used to assess insulin resistance, but HOMA2-IR is considered to be the more accurate than HOMA-IR of the two. Using the updated HOMA2-IR algorithm, Liu et al. (23) found that patients with diabetic cardiac autonomic neuropathy (CAN) exhibited significantly increased insulin resistance in compared to non-CAN controls., and the severity of autonomic dysfunction was positively correlated with HOMA2-IR values and the HOMA2-IR threshold of >1.735 was associated with higher risk of CAN(Table 1). This suggests its potential role in the clinical risk stratification of patients with DM and targeted therapeutic intervention in patients at high risk of CAN.

Therefore, the integration of HbA1c levels, C-peptide-derived indices, and HOMA2-IR into routine assessments would enable the early risk stratification of DPN and personalised intervention. Future research should clarify the contradictory role of C-peptide in PDPN and validate composite prediction models combining these metabolic markers.

Emerging evidence has indicated the potential role of hepatic dysfunction in the pathogenesis of diabetic neuropathy. Multiple serum hepatic parameters have been shown to exhibit significant correlations with diabetic neuropathy, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB) (Figure). Yan et al. (24) found that the AST/ALT ratio (ARR) was significantly elevated in T2DM patients with DPN in comparison to those without DPN (Figure), suggesting ARR has the potential to serve as a novel and promising biomarker for the risk stratification of DPN in T2DM patients.

Serum ALB, a key marker of hepatic synthetic function, has been found to exhibit a significant inverse correlation with the prevalence and severity of DPN (25, 26) (Figure). Lower serum ALB levels have been associated with reduced nerve conduction velocity and increased severity of DPN (25), and hypoalbuminemia (serum ALB <35 g/L) has been associated with approximately 2.8-fold increased risk of DPN compared to normal levels (≥35 g/L) (25). Additionally, patients in the lowest quartile of serum ALB exhibited significantly lower nerve conduction velocity and higher vibration perception thresholds compared to those in the highest quartile (26), suggesting that maintenance of adequate serum albumin levels may represent a potential therapeutic target for neuropathy prevention in diabetic populations.

Evidence has indicated that both the presence of hepatic steatosis and the severity of hepatic fibrosis are associated with diabetic neuropathy in patients. As posited by Huang et al. (27) found that among 520 T2DM patients, DPN prevalence was significantly higher in those with hepatic steatosis and fibrosis, with liver fibrosis remaining independently associated with DPN after multivariate adjustment(Figure). Similarly, Kim et al. (28) evaluated the predictive value of non-invasive hepatic fibrosis markers in a cohort of T2DM subjects, and found that a FIB-4 index≥1.3 could serve as an independent risk predictor for DPN. Silibinin, an adjuvant therapeutic agent for liver diseases, has been shown to alleviate the symptoms of DPN largely by reducing oxidative stress and exerting anti-inflammatory effects (29).

Previous studies have established a close relationship between renal dysfunction and DPN. Lai et al. (30) has the investigated the relationship between the urinary albumin-to-creatinine ratio (UACR) and the risk of developing DPN, and found that UACR≥98.6 mg/g was a critical threshold for increased DPN risk (Figure). In a 6-year prospective study, Wang et al. (31) found that in T2DM patients, lower baseline eGFR was independently associated with the incident DPN, whereas elevated serum Cr predicted DPN development exclusively in patients aged <65 years, indicating age-dependent predictive values of renal function markers for DPN. Notably, Zhang et al. (32) found that, in a cohort of 221 DPN patients with preserved renal function (eGFR ≥60 mL/min/1.73m²), eGFR was positively correlated with DPN risk in T2DM patients (Figure). This counterintuitive association may reflect a neurohemodynamic compensatory regulatory mechanism activated during the early renal hyperfiltration phase, a characteristic feature of diabetic kidney disease (DKD) even in patients with seemingly normal eGFR. Given the intricate relationship between renal function and DPN, conducting subgroup analyses stratified by distinct renal function stages is imperative to elucidate these associations.

In a meta-analysis encompassing 39 studies, Cai et al. (33) has found that, patients with DPN had significantly higher serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels, as well as lower high-density lipoprotein cholesterol (HDL-C) levels, compared to diabetic patients without DPN(Figure). However, inconsistent evidence found by Chang et al. (34) has indicated that, DPN patients showed significantly lower serum total cholesterol (TC) and LDL-C levels compared to non-DPN controls (Figure). This paradoxical association may be attributable to impaired cholesterol availability for axonal regeneration following diabetic nerve injury. Excessively low cholesterol levels may impede the reparative processes necessary for damaged nerves. As Jende et al. (35) also found that, severely reduced serum TC levels were not only positively correlated with neuropathy severity but also associated with a progressive decline in both nerve conduction velocity and action potential amplitude. The discrepancies in conclusions across studies are likely attributable to two factors: the stage of the disease and variations in measurement. The presence of atherogenic dyslipidaemia has been observed in patients with early-stage DPN. By contrast, the advanced stage exhibit altered lipid profiles, partly because less cholesterol is required for axonal repair. Moreover, discrepancies in the specific lipid parameters measured in different studies have been associated with inconsistent results. The relationship between lipid profiles and DPN remains incompletely elucidated and warrants further investigation.

Recent studies regarding the correlation between dysregulated UA metabolism and DPN remain controversial. It has been established that UA exerts a concentration-dependent dual effect: at physiological concentrations, it functions as an antioxidant by scavenging free radicals and protecting neuronal cells, whereas at high concentrations, it acts as a pro-oxidant, promoting damage to both microvascular and neural cells (36).

Wang et al. (16) found that elevated serum UA levels within the normal physiological range were associated with a reduced risk of DPN. In a case-control study, Zhuang et al. (37) observed that DPN patients had significantly lower serum UA levels than non-DPN patients, with a serum UA cutoff value of 324 μmol/L, below which the risk of DPN was found to increase(Figure). As Zhang et al. (38) have also found that, lower serum UA is an independent risk factor for DPN in T2DM patients, and decreased UA levels may specifically influence the motor conduction velocity of the tibial nerve.

Conversely, data have shown the positive associations between elevated serum UA and increased DPN risk (Figure). A multicenter study conducted in Iran found that, patients with DPN had significantly higher serum UA levels than patients without DPN. The risk of DPN increased progressively as serum UA levels increased (39). A meta-analysis encompassing 20 studies (5 cohort and 15 cross-sectional) also confirmed a positive association between elevated serum UA levels and increased DPN risk in patients with T2DM (36). Furthermore, both Kaewput et al. (40) and Zhang et al. (36) reported that elevated serum UA remained an independent predictor of DPN even after adjusting for traditional risk factors. As demonstrated by Zhang et al. (41), a dose-response effect was established, indicating that a each 1 mg/dL (approximately 59.48 μmol/L) increase in serum UA level was associated with a 17% higher risk of developing DPN. The underlying mechanism through which UA exerts its effects on DPN has been investigated in db/db diabetic mouse models, which revealed that UA exacerbates diabetic neuropathy by augmenting oxidative stress, and Xanthine oxidase inhibitors, pharmacological agents that reduce serum UA levels, could alleviate delayed nerve conduction velocity and improve intraepidermal nerve fiber density (42). (Figure 1).

The inconsistent outcomes of these studies are likely attributable to the non-linear dose-response relationship of UA, which functions as an antioxidant at physiological concentrations but as a pro-oxidant when elevated. Discrepancies in methodological approaches across studies, including variations in study design, ethnic background, and the adjustment for confounders such as renal function, further contribute to the heterogeneity observed.

The accessibility of metabolic biomarkers (hepatic and renal function, lipids, and uric acid) facilitates practical DPN risk stratification. The application of an integrated panel approach has the potential to facilitate more effective identification of high-risk patients than the use of isolated markers. It is, therefore, recommended that future research should establish optimal thresholds and determine whether targeted metabolic interventions can effectively delay the onset of DPN.

Emerging evidence suggests a correlation between elevated levels of multiple inflammatory parameters derived from routine hematology test and the development of microvascular and macrovascular complications of diabetes. These inflammatory parameters include the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the C-reactive protein-to-albumin ratio (CAR). For instance, in a meta-analysis of 16 studies, Shahrabi et al. (44) found that patients with DPN had significantly higher NLR than those without DPN. In a prospective study, Chen et al. (45) found that elevated NLR and PLR were associated with DPN, with PLR exhibited higher diagnostic value in T1DM and NLR in T2DM. Elevated baseline NLR also predicts future DPN development in T1DM patients (Figure). Similarly, Aktas (46) found that the CAR in T2DM patients with DPN was significantly higher than those without neuropathy (Figure), and high CAR was found to be independently associated with the increased risk of neuropathy and might function as a potential biomarker for DPN in the T2DM population (Figure 1).

Studies have explored the associations between peripheral inflammatory cytokines and the risk of DPN (47, 48). Ascaso et al. (49) and Abdulrhaman et al. (50) both found that levels of inflammatory cytokines (e.g., chemokine (C-X-C motif) ligand 10 (CXCL10), tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) were significantly higher in patients with DPN compared to patients without DPN (Figure). Furthermore, numerous investigations have demonstrated a positive correlation between elevated levels of various inflammatory markers and increased DPN susceptibility, such as C-reactive protein (CRP), interleukins (ILs), TNF-α, nuclear factor-kappa B (NF-κB), interferon-gamma (IFN-γ), and CXCL10 (47, 48) (Figure). Nevertheless, some inflammatory factors, such as interleukin-9 (IL-9) and stem cell factor (SCF), have been shown to exert protective effects against DPN (47), suggesting the presence of complex regulatory inflammatory pathways in DPN (Figure).

Thus, circulating inflammatory markers may enhance the risk stratification of DPN and represent a novel target for therapeutic intervention.

Previous studies conducted by Patel et al. (56) and Mehalingam et al. (57) have consistently found no significant association between overt hyperthyroidism and DPN, nor with other diabetic complications (Table 2). Notably, the specific association between subclinical hyperthyroidism and diabetic neuropathy remains largely unexplored, as original investigations addressing this clinical question are virtually absent (Table 2).

Growing evidence has identified a correlation between clinical and subclinical hypothyroidism (SCH) and diabetic complications, including DPN. In a cross-sectional study, Patel et al. (56) found that hypothyroidism was positively associated with DPN and was an independent risk factor for DPN (Table 2). As Allam et al. (58) found, patients with DPN who also had SCH exhibited more severe neuropathy symptoms compared to those without SCH. Furthermore, SCH was found to be an independent predictor of DPN severity (Table 2). Fan et al. (59) investigated the potential mechanisms underlying this association, in which T2DM mice with SCH developed more severe peripheral neuropathy compared to diabetic mice without SCH. This exacerbation was attributed to palmitoylation-induced modifications of the thyroid-stimulating hormone receptor (TSHR) on Schwann cell surfaces, which consequently triggered increased reactive oxygen species (ROS) generation and mitochondrial dysfunction, contributing to accelerated peripheral nerve damage in DPN.

Free Triiodothyronine (FT3): Studies have indicated an inverse correlation between serum FT3 levels and the prevalence of DPN in T2DM patients with euthyroidism (60–62) (Table 2), suggesting that lower FT3 levels, even when within the normal reference range, may contribute to the development of peripheral nerve dysfunction. However, Sun et al. (63) found no significant association between FT3 and DPN (Table 2). Variations in study population might contribute to these inconsistent findings.

Free Thyroxine (FT4): The evidence regarding the association of FT4 with DPN in euthyroid T2DM patients is also inconsistent. Several studies have found the correlations between lower FT4 levels within the normal range and increased risk of DPN (60, 63, 64) (Table 2). As demonstrated by Lin et al. (61), a positive correlation was found between FT4 and DPN prevalence(Table 2). Whether a U-shaped relationship exists between FT4 levels and DPN risk remains unclear and requires further investigation.

Thyroid-Stimulating Hormone (TSH): conclusions regarding TSH and DPN in euthyroid T2DM patients are also conflicting. In a retrospective analysis of 248 euthyroid patients with T2DM, Hu et al. (60) described a positive correlation between TSH levels and DPN (Table 2). However, Sun et al. (63) found a weak inverse correlation between TSH and DPN after adjusting for potential confounding variables (Table 2).

Notable inconsistencies in the associations between thyroid parameters and DPN among euthyroid T2DM patients likely reflect heterogeneity in study populations, methodological variations, and disparate confounder adjustment strategies. Although routine thyroid screening represents a cost-effective approach for DPN risk stratification, particularly given established links between subclinical hypothyroidism and neuropathy progression, conflicting data regarding euthyroid hormone levels underscore the need for standardized, large-scale prospective studies to clarify causal relationships and facilitate integration of thyroid status into personalized risk prediction models.

Vitamin B12 (cobalamin) plays a pivotal role in maintaining the integrity of the nervous system, primarily by supporting myelin synthesis and facilitating nerve regeneration (65). Vitamin B12 deficiency has been well-documented as a cause of both motor and painful neuropathies, irrespective of other etiologies (66). Clinical evidence has indicated a strong association between vitamin B12 deficiency and DPN (Figure). As indicated by the findings of Jin et al. (67), there is a bidirectional association between vitamin B12 deficiency and DPN, with B12 deficiency significantly increasing DPN risk and conversely, DPN patients exhibiting a higher incidence of B12 deficiency. In a longitudinal cohort study, Bell (68) found that long-term metformin use frequently leads to vitamin B12 deficiency, which may subsequently contribute to the development or exacerbation of distal symmetrical polyneuropathy and autonomic neuropathy in diabetic patients.

The administration of vitamin B12 supplementation has been shown to have therapeutic potential in the treatment of DPN. In a 12-month intervention study, Didangelos et al. (69) found that patients who received oral mecobalamin (a bioavailable form of vitamin B12) showed significant improvements across multiple clinical and neurophysiological outcomes relative to untreated controls, including increased serum vitamin B12 levels, enhanced neurophysiological parameters, improved sweating function, reduced pain scores and improved quality of life (Figure 1).

Vitamin D plays crucial role in DM and its complications, with deficiency consistently implicated in the onset and progression of these conditions (70, 71). Beyond its metabolic effects, vitamin D exerts neuroprotective effects mediated by its receptors, which are widely expressed in neurons, oligodendrocytes, and glial cells—key cell types involved in peripheral nerve function and repair (72).

The correlations between vitamin D levels with diabetic neuropathy has been widely discussed in recent years. Clinical studies have shown that patients with diabetic neuropathy exhibit lower levels of vitamin D compared to those without diabetic neuropathy (73, 74). Moreover, vitamin D deficiency has been identified as an independent risk factor for DPN (75) and PDPN (76, 77) (Figure). In elderly patients with T2DM, Fei et al. (75) found that vitamin D deficiency may promote development of DPN by prolonging the neural motor latency in large-diameter nerve fibers. Notably, however, it had no significant impact on small-fiber nerve function. A prospective study (78) indicated that elevated serum 25-hydroxyvitamin D(25- (OH) D) levels were associated with a reduced risk of diabetic microvascular complications, including neuropathy. However, a Mendelian randomization analysis by Huang et al. (79) failed to detect a causal relationship between serum 25- (OH) D levels and diabetic neuropathy in the Chinese population (Figure). Despite this, administration of vitamin D supplement has been found to improve neuropathic pain in patients with DM, suggesting a potential for vitamin D supplements to promote neurological recovery, and impede the progression of nerve damage (80–83).

In a large cross-sectional study of 4,435 T2DM patients, Yang et al. (84) observed an inverse association between serum 25-(OH)D levels and neuropathy symptoms(Figure). However, this relationship was dependent on vitamin D status: within the vitamin D insufficiency group, patients with symptomatic DPN paradoxically had significantly higher serum 25(OH)D levels than asymptomatic patients, whereas within the vitamin D sufficiency group, symptomatic individuals had significantly lower 25(OH)D levels. Therefore, the association between serum 25(OH)D and neuropathy symptoms is influenced by an individual’s baseline vitamin D status (Figure 1).

These findings highlight the clinical utility of routine screening and correction of vitamin B12 and D deficiencies as strategies to attenuate DPN progression. Nevertheless, the implementation of randomized controlled trials is warranted to establish causal relationships, optimize supplementation protocols, and elucidate potential synergistic benefits of combined vitamin administration.