Relationship of Serum Vitamin D Levels with Diabetic Microvascular Complications in Patients with Type 2 Diabetes Mellitus
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, which leads to long-term complications affecting multiple organs. Among these, microvascular complications such as diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN) are particularly prevalent in patients with type 2 diabetes mellitus (T2DM). These complications significantly impair the quality of life and are associated with increased morbidity and mortality. Vitamin D, a fat-soluble secosteroid, has been implicated in various physiological processes beyond its classical role in calcium and phosphorus metabolism. It has been reported to influence inflammation, immune response, insulin resistance, and insulin secretion. Recent studies have suggested a potential link between vitamin D deficiency and diabetic microvascular complications. However, most prior research has focused on individual complications rather than examining the relationship between vitamin D and microvascular complications as a whole. This study aimed to explore the association between serum vitamin D levels and the prevalence and severity of DR, DN, and DPN in patients with T2DM.
Study Design and Methodology
This cross-sectional study involved 815 patients with T2DM who were hospitalized in the Department of Endocrinology and Metabolism at a tertiary care hospital in Shanghai, China, between April 2015 and November 2019. The diagnosis of T2DM was based on the 2012 American Diabetes Association criteria. Patients with type 1 diabetes, acute diabetic complications, liver or renal dysfunction, parathyroid diseases, severe cardiovascular or cerebrovascular diseases, malignant tumors, pregnancy, or lactation were excluded. Additionally, patients with eye diseases that could interfere with fundus photography or those taking medications or supplements affecting vitamin D metabolism were also excluded.
Clinical and laboratory data were collected from medical records, including demographic information, duration of diabetes, body mass index (BMI), blood pressure, fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipid profiles, serum creatinine, cystatin C, and serum 25-hydroxyvitamin D (25(OH)D) levels. Vitamin D status was categorized as deficiency (25(OH)D < 10 ng/mL), insufficiency (10 ng/mL ≤ 25(OH)D < 20 ng/mL), or sufficiency (25(OH)D ≥ 20 ng/mL).
Microvascular complications were assessed as follows:
- Diabetic Peripheral Neuropathy (DPN): Diagnosed based on the presence of at least two positive findings of sensory symptoms, reflex abnormalities, or abnormal nerve conduction test results in two or more nerves.
- Diabetic Nephropathy (DN): Defined as an average urinary albumin excretion rate (AER) of ≥30 mg/24 h, with further classification into normoalbuminuria (<30 mg/24 h), microalbuminuria (30–300 mg/24 h), and macroalbuminuria (≥300 mg/24 h).
- Diabetic Retinopathy (DR): Diagnosed by fundoscopy, with either non-proliferative or proliferative retinopathy classified as DR.
Results
Patient Characteristics
The study cohort had a mean age of 59.64 years and a mean diabetes duration of 11.27 years. Patients with microvascular complications, particularly DPN and DN, had significantly longer diabetes duration, higher systolic blood pressure, BMI, HbA1c, blood urea nitrogen (BUN), and cystatin C levels compared to those without complications. Notably, patients with DPN or DN exhibited lower serum 25(OH)D levels (14.61 ng/mL and 13.78 ng/mL, respectively) than those without complications (16.23 ng/mL). However, no significant difference in 25(OH)D levels was observed between patients with DR and those without complications.
Association Between Vitamin D and Microvascular Complications
Patients were stratified into three groups based on their 25(OH)D levels: deficiency, insufficiency, and sufficiency. The prevalence of DPN and DN increased significantly as vitamin D levels decreased. In the vitamin D deficiency group, 46.63% of patients had DPN, and 38.20% had DN, compared to 31.80% and 15.39%, respectively, in the sufficiency group. In contrast, no significant difference in DR prevalence was observed across the vitamin D groups.
Univariate analysis revealed that 25(OH)D levels were significantly correlated with DPN and DN but not with DR. After adjusting for confounding factors, multiple logistic regression confirmed that 25(OH)D was an independent protective factor for DPN (odds ratio [OR]: 0.968, P = 0.004) and DN (OR: 0.962, P = 0.006). Other significant risk factors for DPN included age, HbA1c, and diabetes duration, while BMI, BUN, HbA1c, and systolic blood pressure were associated with DN.
Vitamin D and Comorbidity of DPN and DN
Patients with both DPN and DN had the lowest serum 25(OH)D levels compared to those with either complication alone or no complications. In the vitamin D deficiency group, 20.22% of patients had both DPN and DN, a prevalence four times higher than in the sufficiency group. Additionally, the prevalence of macroalbuminuria increased sharply with decreasing vitamin D levels, from 1.54% in the sufficiency group to 15.73% in the deficiency group. Patients with DPN and vitamin D insufficiency had a higher prevalence of macroalbuminuria (15.32%) compared to those without DPN (4.91%).
Vitamin D and Albuminuria
Patients with normoalbuminuria had higher 25(OH)D levels than those with microalbuminuria or macroalbuminuria. The prevalence of macroalbuminuria increased more abruptly than that of microalbuminuria across the vitamin D tertiles. Specifically, the prevalence of macroalbuminuria was 1.54%, 8.23%, and 15.73% in the sufficiency, insufficiency, and deficiency groups, respectively. In contrast, the prevalence of microalbuminuria increased gradually from 13.92% to 22.47% across the same groups.
Discussion
This study provides comprehensive insights into the relationship between serum vitamin D levels and diabetic microvascular complications in patients with T2DM. The findings highlight that vitamin D deficiency is independently associated with a higher risk of DPN and DN but not DR. Furthermore, lower vitamin D levels were linked to increased severity of DN, as evidenced by the higher prevalence of macroalbuminuria.
Vitamin D and Diabetic Peripheral Neuropathy
The association between vitamin D deficiency and DPN has been previously reported, and this study corroborates those findings. Vitamin D is known to play a role in nerve health by stimulating the secretion of nerve growth factor (NGF), which is crucial for nerve repair and regeneration. The study also revealed a dose-effect relationship, with the prevalence of DPN significantly higher in the vitamin D deficiency group compared to the insufficiency and sufficiency groups. This suggests that maintaining vitamin D levels above 10 ng/mL may help mitigate the risk of DPN.
Vitamin D and Diabetic Nephropathy
Vitamin D deficiency was strongly associated with DN, consistent with prior studies. Vitamin D and its analogs have been shown to reduce albuminuria and slow the progression of DN. The study also demonstrated that the prevalence of macroalbuminuria increased sharply with decreasing vitamin D levels, indicating that vitamin D status may serve as a predictor of DN severity. The findings suggest that vitamin D supplementation could be a potential therapeutic strategy for managing DN in patients with T2DM.
Vitamin D and Diabetic Retinopathy
Unlike DPN and DN, no significant association was observed between vitamin D levels and DR. This finding contrasts with some previous studies that reported a link between vitamin D deficiency and DR. However, the relatively low vitamin D levels in all patient groups in this study may explain the lack of association. It is possible that vitamin D exerts its effects on retinopathy only at higher concentrations, which warrants further investigation.
Vitamin D and Comorbidity of Microvascular Complications
The study also explored the influence of vitamin D on the comorbidity of DPN and DN. Patients with both complications had the lowest serum 25(OH)D levels, suggesting that vitamin D deficiency may increase the risk of multiple microvascular complications. This finding underscores the importance of monitoring and addressing vitamin D deficiency in patients with T2DM to prevent the progression of complications.
Limitations
This study has several limitations. Its cross-sectional design precludes the establishment of causal relationships between vitamin D levels and microvascular complications. Prospective studies are needed to confirm whether vitamin D deficiency predicts the onset of DN and DPN. Additionally, large-scale randomized controlled trials are required to determine whether vitamin D supplementation can prevent or mitigate these complications.
Conclusion
In conclusion, this study demonstrates that vitamin D deficiency is independently associated with a higher risk of DPN and DN in patients with T2DM. Lower vitamin D levels were linked to increased severity of DN, as evidenced by the higher prevalence of macroalbuminuria. However, no significant association was found between vitamin D levels and DR. These findings suggest that maintaining adequate vitamin D levels may help reduce the risk and severity of diabetic microvascular complications, particularly DPN and DN. Future research should focus on the potential therapeutic benefits of vitamin D supplementation in managing these complications.
doi.org/10.1097/CM9.0000000000001364
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