Vitamin D status in relation to lower extremity arterial plaque and diabetic foot ulcers in type 2 diabetes

Abstract

Objectives

Limited evidence exists regarding the association of vitamin D status with lower extremity arterial plaque progression and diabetic foot ulcer outcomes. This study investigated the relationship between vitamin D status and the risk of lower extremity arterial plaque progression and diabetic foot ulcer development.

Methods

In this cross-sectional analysis of 7476 consecutively hospitalized type 2 diabetes patients (2018–2024), serum 25-hydroxyvitamin D level was measured using the electrochemiluminescence method. Vitamin D deficiency (<20 ng/mL) and insufficiency (20–30 ng/mL) were defined per the Endocrine Society guidelines. Lower extremity arterial plaque was identified using arterial Doppler ultrasonography, and diabetic foot ulcer was diagnosed using the International Working Group on the Diabetic Foot 2019 criteria. Multivariate logistic regression and receiver operating characteristic analyses were used to evaluate associations between parameters.

Results

Decreased 25-hydroxyvitamin D levels were correlated with adverse lipid profiles (high-density lipoprotein cholesterol: r = 0.152, P < 0.001) and elevated inflammatory markers (high-sensitivity C-reactive protein: r = −0.086, P < 0.001). Lower extremity arterial plaque patients (n = 4622) exhibited longer diabetes duration, higher glycosylated hemoglobin levels, and reduced 25-hydroxyvitamin D levels compared with those without lower extremity arterial plaque (19.98 vs. 23.41 ng/mL, P < 0.001). The prevalence of diabetic foot ulcer in lower extremity arterial plaque patients was 2.8%, and the levels of 25-hydroxyvitamin D were significantly lower in diabetic foot ulcer patients than in nondiabetic foot ulcer patients (14.77 vs. 19.98 ng/mL, P < 0.001). Adjusted models revealed that 25-hydroxyvitamin D level was an independent protective factor against lower extremity arterial plaque (odds ratio = 0.938, 95% confidence interval: 0.914–0.963) and diabetic foot ulcer (odds ratio = 0.938, 95% confidence interval: 0.932–0.944). Receiver operating characteristic curve analysis demonstrated that a 25-hydroxyvitamin D level ≤18.94 ng/mL predicted lower extremity arterial plaque, with an area under the curve value of 0.651, which improved to 0.703 when combined with the duration of diabetes and white blood cell count. For diabetic foot ulcer prediction, a 25-hydroxyvitamin D level ≤17.11 ng/mL achieved an area under the curve value of 0.674, which increased to 0.764 after adjusting for covariates.

Conclusion

Vitamin D insufficiency is independently associated with lower extremity arterial plaque severity and incident diabetic foot ulcer in type 2 diabetes. Therapeutic implications of vitamin D supplementation warrant prospective investigation.

Keywords

Type 2 diabetes lower extremity arterial plaque diabetic foot ulcer 25-hydroxyvitamin D

Introduction

Type 2 diabetes (T2D) represents a critical global public health challenge, with an estimated prevalence of 463 million affected adults in 2019, disproportionately impacting low- and middle-income countries. Projections indicate that this figure may escalate to 700 million by 2045.^1,2 Notably, patients with diabetes exhibit a substantially elevated incidence of lower extremity arterial disease, which induces chronic foot ischemia and hypoxia, thereby facilitating the development of diabetic foot ulcer (DFU). This pathological progression doubles the risks of limb amputation and all-cause mortality.^3–6

Vitamin D is a fat-soluble vitamin; few foods naturally contain vitamin D. Dermal synthesis after ultraviolet-B radiation remains the major route to obtain vitamin D, accounting for 90% of vitamin D replenishment.⁷ The biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)₂D), modulates calcium–phosphate homeostasis and inflammatory responses through vitamin D receptor-mediated signaling pathways.⁸

There is growing research interest in the role of vitamin D in the development of diabetes and its complications.^9,10 Vitamin D deficiency (VDD) demonstrates a significant correlation with the pathogenesis of atherosclerosis (AS) and DFU. A recent prospective cohort study involving postmenopausal women demonstrated that reduced serum 25(OH)D levels are independently associated with increased severity of coronary AS.¹¹

Researchers have found that low levels of vitamin D may be related to the development of diabetic foot infections.¹² Recent studies have shown potential beneficial effects of vitamin D on wound healing in DFU patients.¹³ Although the association of vitamin D with AS and DFU has been extensively investigated, the underlying mechanisms linking vitamin D levels with the development of lower extremity arterial plaque (LEAP), particularly in the context of LEAP in combination with DFU, have not been fully elucidated.

This study aimed to investigate the relationship between vitamin D status and LEAP risk in T2D patients as well as the relationship between vitamin D status and DFU risk in T2D patients with LEAP.

Participants and methods

Study population

In this cross-sectional study, we enrolled 7476 patients (4466 men and 3010 women aged 18–94 years) with T2D who were consecutively hospitalized at the Qingdao Endocrine and Diabetes Hospital from January 2018 to April 2024. A minimum sample size of 6458 was calculated based on a statistical power of 80%, alpha error of 0.05, and DFU prevalence of 5% in China using G*Power software.¹⁴ The diagnostic criteria for T2D and diabetic foot infections were based on the American Diabetes Association classification and the World Health Organization 1999 criteria. The exclusion criteria were as follows: (a) other types of diabetes; (b) pregnant or lactating women; (c) acute complications of diabetes or stress states, such as surgery and trauma; and (d) rheumatologic, serious hepatic, cardiac, renal failure, malignancy, and endocrine diseases that affect vitamin D metabolism. The Biomedical Research Ethics Committee of the Qingdao Endocrine and Diabetes Hospital approved the study protocol, and the need for informed consent was waived (approval number: DM20231208). We conducted this study in accordance with the Helsinki Declaration of 1975, as revised in 2024. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.¹⁵

Clinical and biochemical characteristics

Demographic, comorbidity, and laboratory data, including age, duration of diabetes, sex, smoking history, waist-to-hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure, glycosylated hemoglobin (HbA1c) level, triglyceride (TG) level, total cholesterol (TC) level, high-density cholesterol (HDL-C) level, low-density cholesterol (LDL-C) level, white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hs-CRP) level, and 25(OH)D level, were extracted from the electronic medical record system.

Diagnostic standard

Serum 25(OH)D levels were measured using the electrochemiluminescence assay. According to the Endocrine Society Clinical Practice Guideline 2011, VDD and vitamin D insufficiency were defined as serum 25(OH)D levels <20 ng/mL and 20–30 ng/mL, respectively. LEAP was identified via Doppler ultrasonography of the lower extremity arteries if arterial plaque formation, vascular stenosis, or occlusion was detected. DFU was diagnosed according to the guidelines on the diagnosis and treatment of foot infection in persons with diabetes provided by the International Working Group on the Diabetic Foot in 2019.

Statistical methods

The dataset was analyzed using SPSS 26.0 software. Non-normally distributed continuous variables were reported as median values and compared using the Mann–Whitney test. The chi-square test was used for categorical variables, which were summarized as frequency counts with percentages (n/%). Multivariate regression analysis was used to identify the association between vitamin D status and the risk of LEAP among T2D patients as well as the association of vitamin D and the risk of DFU in patients with T2D and LEAP. A P-value <0.05 was considered to indicate statistical significance. The receiver operating characteristic (ROC) curve method was employed to assess the role of 25(OH)D in detecting LEAP in T2D patients and DFU in T2D patients with LEAP.

Results

In total, only 28.6% of the patients had normal vitamin D status. Correlation analysis demonstrated significant inverse associations between serum 25(OH)D levels and multiple clinical parameters. Age (r =−0.045, P < 0.001), HbA1c level (r =−0.152, P < 0.001), TG level (r = −0.111, P < 0.001), TC level (r = −0.043, P < 0.001), LDL-C level (r = −0.045, P < 0.001), WBC count (r = −0.104, P < 0.001), ESR (r = −0.167, P < 0.001), and hs-CRP level (r = −0.086, P < 0.001) showed statistically significant negative correlations with serum 25(OH)D levels. In contrast, HDL-C level exhibited a weak positive correlation (r = 0.119, P < 0.001). No significant association was observed between serum 25(OH)D levels and duration of diabetes (r = 0.010, P = 0.410).

According to arterial ultrasonic Doppler analysis, all 7476 patients were categorized into non-LEAP (NLEAP; 38.2%) and LEAP (61.8%) subgroups. Compared with the NLEAP subgroup, the LEAP subgroup had longer duration of diabetes; higher prevalence of smoking; higher WHR, SBP, HbA1c level, WBC count, ESR, and hs-CRP level (all P < 0.05) but decreased levels of HDL-C and 25(OH)D (all P < 0.05) (Table 1).

Table 1.

Characteristics of patients with and without LEAP in the study.

	NLEAP patients	LEAP patients	z/χ ²	P
N	2854	4622
Age (years)	55.00 (48.00–62.00)	63.00 (55.00–69.00)	−28.774	<0.001
Duration of diabetes (years)	4.00 (2.00–10.00)	8.00 (3.00–15.00)	−18.804	<0.001
Male (%)	1373 (48.1%)	3096 (67.0%)	262.997	<0.001
Smoking history (%)	712 (24.9%)	1963 (42.5%)	236.695	<0.001
WHR	0.93 (0.89–0.97)	0.95 (0.91–0.98)	−14.334	<0.001
SBP (mmHg)	135.00 (121.00–150.00)	140.00 (127.00–153.00)	−8.892	<0.001
DBP (mmHg)	85.00 (78.00–93.00)	84.50 (77.00–93.00)	−0.651	0.515
HbA1c (%)	7.20 (6.10–9.00)	7.80 (6.70–9.30)	−10.856	<0.001
TG (mmol/L)	1.47 (1.00–2.22)	1.48 (1.03–2.19)	−0.107	0.915
TC (mmol/L)	5.24 (4.46–6.06)	5.21 (4.41–6.10)	−0.633	0.527
HDL-C (mmol/L)	1.20 (1.01–1.44)	1.15 (0.97–1.38)	−7.449	<0.001
LDL-C (mmol/L)	3.00 (2.33–3.69)	3.03 (2.31–3.75)	−1.283	0.200
WBC count (×10⁹/L)	5.61 (4.75–6.68)	5.94 (5.04–6.99)	−8.892	<0.001
ESR (mm/h)	10.63 (6.87–17.32)	11.30 (7.00–19.36)	−4.000	<0.001
hs-CRP (mg/L)	1.99 (1.09–3.98)	2.18 (1.26–4.15)	−3.606	<0.001
25(OH)D (ng/mL)	23.94 (19.30–29.85)	19.83 (14.84–25.89)	−22.045	<0.001

LEAP: lower extremity arterial plaque; NLEAP: non-lower extremity arterial plaque; WHR: waist-to-hip ratio; DBP: diastolic blood pressure; SBP: systolic blood pressure; 25(OH)D: 25-hydroxyvitamin D; HbA1c: glycosylated hemoglobin; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TC: total cholesterol; TG: triglyceride; WBC: white blood cell; hs-CRP: high-sensitivity C-reactive protein; ESR: erythrocyte sedimentation rate.

We found that 2.8% of the 4622 individuals with T2D and LEAP had DFU. The DFU subgroup had lower serum 25(OH)D levels than the non-DFU (NDFU) subgroup (14.77 vs. 19.98 ng/mL, P < 0.001). In addition, patients with DFU had longer duration of diabetes as well as higher SBP, HbA1c levels, WBC count, ESR, and hs-CRP levels (all P < 0.05). No significant difference was observed in smoking history, WHR, TC level, HDL-C level, or LDL-C level between the two subgroups (all P > 0.05) (Table 2).

Table 2.

Characteristics of patients with LEAP in NDFU and DFU subgroups.

	NDFU	DFU	z/χ²	P
N	4492	130
Age (years)	63.00 (55.00–69.00)	68.00 (62.00–77.00)	−6.458	<0.001
Duration of diabetes (years)	8.00 (3.00–15.00)	15.00 (8.75–20.00)	−7.229	<0.001
Male (%)	2999 (66.8%)	97 (74.6%)	3.522	0.061
Smoking history (%)	1908 (42.5%)	55 (42.3%)	0.001	0.970
WHR	0.95 (0.91–0.98)	0.96 (0.92–0.98)	−1.933	0.053
SBP (mmHg)	140.00 (127.00–153.00)	146.00 (133.00–157.00)	−2.852	0.004
DBP (mmHg)	85.00 (77.00–93.00)	80.00 (74.00–89.00)	−3.453	0.001
HbA1c (%)	7.80 (6.60–9.30)	8.65 (7.20–10.30)	−4.258	<0.001
TG (mmol/L)	1.49 (1.03–2.21)	1.25 (0.90–1.68)	−3.930	<0.001
TC (mmol/L)	5.22 (4.41–6.10)	5.07 (4.38–5.96)	−0.495	0.620
HDL-C (mmol/L)	1.15 (0.97–1.38)	1.10 (0.91–1.35)	−1.654	0.098
LDL-C (mmol/L)	3.02 (2.31–3.75)	3.12 (2.43–3.86)	−1.031	0.302
WBC count (×10⁹/L)	5.92 (5.03–6.95)	6.98 (5.67–8.55)	−6.452	<0.001
ESR (mm/h)	11.00 (7.00–18.90)	25.97 (13.92–60.59)	−10.283	<0.001
hs-CRP (mg/L)	2.15 (1.24–4.03)	5.39 (2.19–18.91)	−8.751	<0.001
25(OH)D (ng/mL)	19.98 (14.98–6.00)	14.77 (10.98–20.23)	−6.756	<0.001
ALB (g/L)	41.90 (39.40–44.20)	38.10 (35.10–41.10)	−9.255	<0.001
TP (g/L)	67.30 (63.70–70.90)	64.55 (61.30–68.80)	−4.660	<0.001

NDFU: nondiabetic foot ulcer; DFU: diabetic foot ulcer; LEAP: lower extremity arterial plaque; WHR: waist-to-hip ratio; DBP: diastolic blood pressure; SBP: systolic blood pressure; 25(OH)D: 25-hydroxyvitamin D; HbA1c: glycosylated hemoglobin; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TC: total cholesterol; TG: triglycerides; WBC: white blood cell; hs-CRP: high-sensitivity C-reactive protein; ESR: erythrocyte sedimentation rate; ALB: albumin; TP: total protein.

We further analyzed the risk of LEAP in patients with T2D, considering the presence of LEAP as the dependent variable. In the logistic regression model, serum 25(OH)D was identified as an independent protective factor against the risk of LEAP in patients with T2D (OR = 0.938, 95% confidence interval (CI): 0.914–0.963) after adjusting for age (OR = 1.042, 95% CI: 1.023–1.062), duration of diabetes (OR = 1.053, 95% CI: 1.031–1.076), SBP (OR = 1.010, 95% CI: 1.001–1.019), HbA1c level (OR = 1.128, 95% CI: 1.032–1.234), and WBC count (OR = 1.209, 95% CI: 1.134–1.289). Among patients with T2D who had LEAP, we further analyzed the risk factors for DFU. In the multivariate logistic regression model, serum 25(OH)D level (OR = 0.938, 95% CI: 0.914–0.963, P < 0.05) was an independent protective factor against DFU after adjusting for age, duration of diabetes, SBP, HbA1c level, and WBC count (Table 3).

Table 3.

Multivariate logistic regression modeling for risk stratification in patients with LEAP and those with DFU.

Variable	LEAP			DFU
Variable	OR	95% CI	P	OR	95% CI	P
Age (years)	1.069	1.063–1.075	<0.001	1.042	1.023–1.062	<0.001
Duration of diabetes (years)	1.041	1.032–1.050	<0.001	1.053	1.031–1.076	<0.001
SBP (mmHg)	1.008	1.005–1.011	<0.001	1.010	1.001–1.019	0.025
WBC count (×10⁹/L)	1.130	1.094–1.168	<0.001	1.209	1.134–1.289	<0.001
HbA1c (%)	1.055	1.026–1.085	<0.001	1.128	1.032–1.234	0.008
25(OH)D (ng/mL)	0.938	0.932–0.944	<0.001	0.938	0.914–0.963	<0.001

LEAP: lower extremity arterial plaque; DFU: diabetic foot ulcer; OR: odds ratio; CI: confidence interval; SBP: systolic blood pressure; HbA1c: glycosylated hemoglobin; WBC: white blood cell; 25(OH)D: 25-hydroxyvitamin D.

ROC curve analysis showed that the AUC values of duration of diabetes, HbA1c level, WBC count, and 25(OH)D level for predicting LEAP in patients with T2D were 0.629, 0.575, 0.561, and 0.651, respectively. Joint application of duration of diabetes, WBC count, and 25(OH)D level increased the AUC up to 0.703 (P < 0.05). In patients with LEAP, the corresponding AUC values for DFU prediction were 0.685, 0.609, 0.666, and 0.674, respectively. The joint corresponding AUC increased to 0.764 (P < 0.05) (Table 4 and Figure 1).

Table 4.

ROC analysis of clinical parameters for LEAP development in T2D and DFU prediction in patients with T2D and LEAP.

Variable	LEAP			DFU
Variable	AUC	P	95% CI	AUC	P	95% CI
Duration of diabetes (years)	0.629	<0.001	0.616–0.642	0.685	<0.001	0.640–0.730
HbA1c (%)	0.575	<0.001	0.561–0.588	0.609	<0.001	0.562–0.657
WBC count (×10⁹/L)	0.561	<0.001	0.548–0.574	0.666	<0.001	0.614–0.717
25(OH)D (ng/mL)	0.651	<0.001	0.639–0.664	0.674	<0.001	0.625–0.722
Combined biomarkers	0.703	<0.001	0.692–0.715	0.764	<0.001	0.721–0.808

LEAP: lower extremity arterial plaque; T2D: type 2 diabetes; DFU: diabetic foot ulcer; AUC: area under the curve; CI: confidence interval; HbA1c: glycosylated hemoglobin; WBC: white blood cell; 25(OH)D: 25-hydroxyvitamin D.

Figure 1.

(a) ROC analysis of clinical parameters for predicting LEAP development in T2D patients. (b) Utility of these parameters in predicting DFU risk among T2D individuals with confirmed LEAP is demonstrated through ROC curve analysis. ROC: receiver operating characteristic; LEAP: lower extremity arterial plaque; T2D: type 2 diabetes; DFU: diabetic foot ulcer.

Discussion

The current study found that the serum 25(OH)D levels in T2D patients with LEAP were significantly lower than those in T2D patients without LEAP. Moreover, in T2D patients with LEAP, vitamin D levels were significantly lower in the DFU subgroup than in the NDFU subgroup. VDD was identified as an independent risk factor for LEAP and LEAP-derived DFU, with a predictive cutoff value of 17–19 ng/mL. A previous study reported that severe VDD is associated with elevated inflammatory cytokine concentrations and suggested that a vitamin D concentration of <10 ng/mL can be used as the cutoff for unfavorable immunological alterations in diabetic patients.¹⁶

Emerging evidence suggests that vitamin D supplementation may ameliorate insulin resistance by enhancing insulin sensitivity, contributing to improved glycemic control.¹⁷ Some studies have shown that vitamin D supplements can affect the expression of insulin receptor substrate (IRS), peroxisome proliferator-activated receptor gamma, and nuclear factor-κB (NF-κB), leading to lower fasting blood glucose and HbA1c levels.¹⁸ Furthermore, 1,25(OH)₂D significantly enhanced the expression of insulin receptor and glucose transporter 2 in a hyperglycemic environment.¹⁹ In the current data analysis, a negative correlation was observed between 25(OH)D and HbA1c levels (r < 0, P < 0.05).

A negative correlation was observed between 25(OH)D and LDL-C, TC, and TG levels, while a positive correlation was observed between 25(OH)D and HDL-C levels. Recent studies have indicated that vitamin D might play a vital role in regulating lipid metabolism and preventing atherosclerotic cardiovascular disease (ASCVD).^20,21 Vitamin D regulates cholesterol metabolism via three mechanisms: the 1,25(OH)D-initiating INSIG/SREBP-mediated feedback, calcitriol 25(OH)D-inhibiting HMGCR activity, and vitamin D receptor (VDR)–encouraging CYP7A1 activity.²² Research has identified a RING-type E3 ubiquitin ligase, known as TRIM13, linked to AS, which obstructs the release of cholesterol and development of foam cell via ubiquitination, while dietary intake triggers TRIM13 expression.²³ A recent study demonstrated that feeding a high-fat diet for 9 weeks induced systemic dyslipidemia and exacerbated oxidative stress, ultimately resulting in a 40% delay in wound closure.²⁴

Previous studies have revealed a possible link between vitamin D status, inflammation, and the pathogenesis of vascular damage in diabetic patients.^25–29 The vitamin D level is correlated with the strength of the inflammatory response. Studies on pre-diabetic mice have shown that vitamin D reduces inflammation by inhibiting the TLR4/NF-κB pathway.³⁰ Numerous cells and tissues contain vitamin D receptors, which are crucial for the synthesis of cathelicidins, defensins, hepcidins, and neutrophil peptides; among these, cathelicidins are instrumental in controlling inflammation.³¹ AS onset is strongly associated with innate and adaptive immune reactions, with factors such as lipoproteins, cholesterol, and infections triggering inflammation in macrophages and foam cells.³² DFUs exhibit sustained inflammatory infiltration, where activated neutrophils and proinflammatory monocytes secrete matrix metalloproteinase-8 and reactive oxygen species.³³ Our study showed a negative correlation between serum 25(OH)D level and WBC count, hs-CRP level, and ESR. These inflammatory indicators differed between LEAP and NLEAP groups or DFU and NDFU subgroups. In this study, we found that the joint application of an inflammatory indicator and vitamin D level improved the predictive value for LEAP and LEAP-derived DFU.

Vitamin D mitigates AS through the following mechanisms: (a) modulating macrophage polarization by suppressing the proinflammatory M1 phenotype and promoting the anti-inflammatory M2 phenotype, thereby reducing the secretion of tumor necrosis factor-α and interleukin-6 and inhibiting the activation of the NF-κB pathway;^20,34 (b) suppressing scavenger receptor expression and endoplasmic reticulum stress to reduce macrophage cholesterol uptake while enhancing lipid droplet autophagy-mediated cholesterol efflux to inhibit foam cell formation;³⁵ and (c) downregulating vascular adhesion molecules (VCAM-1) to attenuate monocyte recruitment, and delaying vascular aging via the regulation of vascular smooth muscle cell (VSMC) proliferation/calcification and angiotensin II signaling.²¹ In a multicenter cohort study of 1484 post-myocardial infarction patients, Aleksova et al. demonstrated that VDD synergistically increased the risk of coronary artery disease progression in diabetic women.³⁶ Zhou et al. showed that vitamin D suppressed the abnormal proliferation of VSMCs triggered by the RBP4/JAK2/STAT3 signaling pathway.³⁷ Consistent with the previous findings, the LEAP subgroup in our study had significantly lower median serum 25(OH)D levels than the NLEAP subgroup (23.94 vs. 19.93 ng/mL, P < 0.05). This biomarker was further identified as an independent protective factor against T2D comorbid with LEAP (adjusted OR = 0.938, 95% CI: 0.932–0.944). However, preclinical rodent studies have demonstrated that chronic vitamin D supplementation may promote vascular calcification through dysregulated calcium–phosphate metabolism.³⁸ A recent population-based cohort study utilizing UK Biobank data revealed that vitamin D supplementation was associated with a marginally elevated risk of hypercalcemia; however, it showed no significant association with ASCVD incidence.³⁹

Vitamin D accelerates wound healing via the following mechanisms: (a) upregulating antimicrobial peptide cathelicidin via TLR2/1 signaling to disrupt drug-resistant biofilm and improve the wound microenvironment⁴⁰ and (b) enhancing keratinocyte migration, fibroblast collagen synthesis, and vascular endothelial growth factor–mediated angiogenesis to promote epithelial regeneration and tissue repair.^41,42 Clinical studies have demonstrated that VDD significantly increases the risk of DFU, correlating with larger ulcer areas and higher amputation rates.^43–45 Animal and in vitro studies have revealed that VDD genetically regulates epithelial–mesenchymal transition and extracellular matrix remodeling, while VDR knockout delays healing.^46,47 However, whether vitamin D supplementation improves DFU healing needs further evaluation. In this study, the DFU subgroup showed markedly reduced median serum 25(OH)D levels compared with the NDFU subgroup (14.77 vs. 19.98 ng/mL, P < 0.05), and this parameter also independently correlated with a decreased risk of LEAP comorbid with DFU (adjusted OR = 0.938, 95% CI: 0.914–0.963).

There are certain limitations in this study. We only included Chinese adults admitted to the Qingdao Endocrine & Diabetes Hospital. This conclusion may not be generalizable to patients from other races. In addition, this was a retrospective study; therefore, it was difficult to establish a causal relationship between vitamin D level and LEAP and LEAP-derived DFU. However, a retrospective study with a relatively large sample size, well-defined study population, and strong quality control may provide more accurate results. Further well-designed research is warranted to verify whether there exists any association between vitamin D level and LEAP-induced DFU and to assess the role and mechanism of vitamin D in the prevention and treatment of DFU.

Previous evidence supports a negative relationship between serum 25(OH)D levels and the risk of infectious diabetic foot. Our findings suggest that hypovitaminosis D in patients with T2D may accelerate peripheral AS through dual mechanisms of metabolic dysregulation and chronic low-grade inflammation. This pathophysiological cascade may predispose patients with T2D to LEAP development, which in turn significantly increases the risk of LEAP-derived DFU. Future prospective cohort studies should investigate potential pleiotropic effects of vitamin D on DFU outcomes and confirm the potential benefits of vitamin D supplementation in the prevention and management of LEAP-derived DFU.

Footnotes

Acknowledgments

We extend our sincere thanks to the staff of Qingdao Endocrine and Diabetes Hospital for their support.

Author contributions

Yuqing Liu: conceptualization, investigation, data curation, writing–review and editing, visualization, and supervision; Li You: investigation, validation, data curation, and writing–original draft; Weiguo Gao: writing–review & editing, and visualization; Yanhu Dong: conceptualization, validation, investigation, visualization, and supervision; Yan Gu: investigation, writing–original draft, writing–review & editing, and visualization; Lei Zhang: conceptualization, validation, investigation, data curation, writing–review and editing, visualization, and supervision.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declaration of conflicting interests

The authors declare no conflict of interest.

Ethical considerations

The Biomedical Research Ethics Committee of Qingdao Endocrine and Diabetes Hospital approved the study protocol, and the application for exemption of informed consent was accepted (approval number: DM20231208).

Funding

The current work was funded by IDF BRIDGES Research Net program (rn13-016).

ORCID iD

Lei Zhang

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