Diabetic peripheral neuropathy (DPN) ranks among the most prevalent complications of diabetes and is present in more than 50% of patients with type 2 diabetes (T2DM) aged over 60 years (1). DPN encompasses conditions such as distal symmetric polyneuropathy (DSPN), radiculopathy, mononeuropathy, as well as autonomic neuropathy or treatment-induced neuropathy (2). DPN significantly contributes to disability in diabetes, affecting patients’ overall quality of life and imposing substantial economic burdens on society (3, 4). The early prevention and management of DPN is of great importance. However, over half of DPN patients are asymptomatic (5). Timely and intensive interventions can improve subclinical DPN and reduce the risk of DPN progression (5–7).

Vitamin D deficiency has emerged as a progressively serious global concern, with association with multiple diseases such as cardiovascular diseases, metabolic syndrome, cancer, autoimmune disorders, and Alzheimer’s disease (8). Beyond its role in regulating calcium, phosphorus, and bone metabolism, vitamin D is also implicated in insulin secretion and resistance (9). Vitamin D insufficiency is prevalent among T2DM patients (10, 11). Recently, the correlation between vitamin D and DPN has garnered increasing attention. While existing cross-sectional studies have indicated relationship between vitamin D deficiency and the risk of DPN (12–16), these studies often have limitations such as small sample sizes (15) or reliance on subjective diagnostic criteria (12). Previous research relied on clinical symptoms and/or physical signs, providing limited evidence regarding the association between vitamin D and subclinical DPN. Furthermore, the precise relationship between vitamin D and distinct subtypes of DPN remains unclear at present.

This study aims to clarify the relationship between vitamin D and subclinical DPN, as well as its distinct subtypes including DSPN, radiculopathy and mononeuropathy by recruiting a large sample of asymptomatic DPN individuals verified through nerve conduction study (NCS). We seek to provide evidence that contributes to the early prevention and treatment of DPN.

In this study, we aimed to investigated the association between vitamin D and subclinical diabetic peripheral neuropathy in T2DM patients. Our results show that in all age groups, vitamin D deficiency was related to a higher risk of DSPN and this relationship was independent of sex, age, weight, blood pressure, HbA1c, T2DM duration, calcium, phosphorus, parathyroid hormone, lipids and renal function. However, we didn’t find a similar relationship between vitamin D and other subtypes of DPN, like mononeuropathy or radiculopathy. These findings suggest new possibilities for better DPN screening and treatment.

The association between vitamin D and DPN has been reported. Significantly lower vitamin D levels were found in DPN patients (36.9 nmol/L), compared to non-DPN patients (58.32 nmol/L) (15). In a 25-year observational study, individuals with 25(OH)D < 50 nmol/L experienced a higher cumulative incidence of macrovascular and microvascular events than those with 25(OH)D ≥ 50 nmol/L (21). Similarly, cross-sectional studies have indicated that insufficient vitamin D levels might increase the risk of DPN. In a study including 861 T2DM patients, multivariate logistic regression analysis showed that vitamin D deficiency was an independent factor contributing to DPN (β=0.88, P<0.01) (16). The severity of vitamin D deficiency was also closely correlated with the severity of neuropathy (22, 23). Clinical trials involving topical compounds containing vitamin D (24) or vitamin D supplementation have demonstrated significant therapeutic benefits in DPN patients (22). Similarly, our study confirmed the inverse correlation between vitamin D and DPN, specifically within the DSPN subtype. A previous study utilizing restricted cubic splines analysis proposed a nonlinear connection between vitamin D and DPN, where the risk of DPN remained notable until vitamin D reached 30 nmol/L, after which it started to lose significance. In essence, lower vitamin D levels might increase the risk of DPN (25). In our outcomes, a linear relationship emerged between vitamin D and subclinical DSPN, with the odds ratio of subclinical DSPN exhibiting a significant increase as 25(OH)D levels decreased below 50 nmol/L. Our cohort comprised individuals with subclinical DPN devoid of neurological symptoms, which diverged from previous typical DPN studies, potentially accounting for results inconsistency. Our findings suggested that vitamin D supplementation may potentially delay the occurrence of subclinical DSPN, which held considerable implications for the early prevention and management of DSPN.

Older adults are at risk for vitamin D deficiency as a result of decreased dietary intake and calcium absorption, as well as decline in renal function (26). Yang Niu (27) reported that low vitamin D was associated with DPN in patients of ≥ 65 years but not in young and middle-aged patients. However, our study found independent association between vitamin D deficiency and subclinical DSPN in all age groups. The cause for the difference may be due to the different cohort (a larger sample size and more young patients) and different diagnostic criteria (subclinical or asymptomatic DSPN). The result highlights the importance of preventing vitamin D deficiency in non-elderly people.

The potential mechanisms of vitamin D improving DSPN may include the following aspects: 1) Neuroprotection: Vitamin D could potentially shield neuronal cells against apoptosis and neurodegeneration. Vitamin D could trigger the generation of nerve growth factors (28–32), contributing to the preservation of neurons. In diabetic rats, an elevated expression of vitamin D receptors in neurons of the dorsal root ganglion bolsters their sensitivity (33). 2) Enhanced blood circulation: Vitamin D deficiency in rodents lead to compromised vascular relaxation and capillary constriction, diminished antioxidant activity, and heightened endothelium-dependent contraction (34, 35). Thus vitamin D might play a role in maintaining proper blood circulation by facilitating angiogenesis and endothelial repair. 3) Anti-inflammatory effects: Clinical research has suggested that administering high doses of vitamin D to patients with DPN was linked to a reduction in serum IL-6 levels and an elevation in IL-10 concentrations, implying alleviated inflammation (36). DSPN is frequently related to a chronic course and stems from fiber-predominant small nerve lesions, primarily induced by factors such as glucotoxicity, lipotoxicity, oxidative stress, impaired endothelial cell function, dysregulation of the Na+-K+-ATP pump, and endoplasmic reticulum stress (37). These mechanisms are related to neurotrophic disorders. In contrast, radiculopathy often has acute onset, encompassing the lumbar-sacral or cervical plexus and is associated with ischemic damage and microvascular inflammation. Mononeuropathy typically affects oculomotor and median nerves, and may be related to compression or ischemia. Vitamin D mainly plays a role in promoting the production of nerve growth factor and improving microcirculation, which may account for its stronger correlation with chronic progression of DSPN in our study. However, whether the mechanisms underlying non-DSPN neuropathies share similarities remains uncertain (38). Distinct mechanisms underlying the development of various DPN subtypes also require further investigation.

This study has several strengths. Firstly, we employed nerve conduction study to accurately identify subclinical DPN in asymptomatic T2DM patients, enabling a focused analysis of risk factors specific to subclinical DPN. Secondly, our study included different subtypes of subclinical DPN and featured a relatively substantial sample size. Additionally, our research introduced a novel finding: Vitamin D deficiency was associated with the increased prevalence of subclinical DSPN rather than other DPN subtypes. And there was a linear association between 25(OH)D and subclinical DSPN.

Nevertheless, the current study has some limitations. Firstly, as it was a cross-sectional study, the long-term outcomes for patients with different 25(OH)D levels remain unknown. Secondly, vitamin D levels are affected by factors like ethnicity, geographical location, dietary habits, sunlight exposure, and variations in single nucleotide polymorphisms of vitamin D receptor. Thirdly, the quantitative analysis of the correlation between 25(OH)D levels and neuro-conduction parameters was not conducted in this study.

In summary, it is advisable to enhance the screening and assessment of DSPN in diabetes patients with vitamin D deficiency. Avoid vitamin D deficiency could potentially offer advantages in preventing subclinical DSPN. Nonetheless, more large-scale, forward-looking, and multi-center investigations are needed to unravel the role of vitamin D in preventing and treating DSPN.

In conclusion, our study demonstrated that vitamin D deficiency was independently associated with subclinical DSPN in all age groups, rather than other subtypes of DPN. Although further studies are needed to clarify the effect of vitamin D on DSPN development, the study supports that special attention should be paid to the patients with vitamin D deficiency for their susceptibility to DSPN.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by Ethics Committee of Zhongshan Hospital Fudan University [B2021-160(2)]. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

XS: Visualization, Methodology, Investigation, Formal analysis, Writing – review & editing, Writing – original draft. XY: Data curation, Writing – review & editing, Writing – original draft, Methodology, Investigation. XZ: Writing – review & editing, Writing – original draft, Methodology, Investigation. YM: Writing – review & editing, Writing – original draft, Resources, Project administration, Methodology. XL: Writing – original draft, Formal analysis, Data curation. YZ: Writing – original draft, Investigation. QL: Writing – original draft, Methodology. CF: Writing – original draft, Investigation. MZ: Writing – original draft, Investigation. BX: Writing – original draft, Data curation. YX: Writing – original draft, Validation, Methodology. XG: Writing – review & editing, Conceptualization. JD: Writing – review & editing, Supervision, Methodology, Investigation, Data curation, Conceptualization. MX: Writing – review & editing, Supervision, Investigation, Funding acquisition, Conceptualization. HB: Writing – review & editing, Writing – original draft, Supervision, Project administration, Investigation, Funding acquisition, Data curation, Conceptualization.