Correlation of vitamin D levels with TNF-α and IL-6 expression in insulin-resistant type 2 diabetes mellitus patients

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and chronic low-grade inflammation. Pro-inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), contribute to impaired insulin signaling and metabolic dysfunction. Vitamin D possesses immunomodulatory properties and may influence inflammatory pathways associated with insulin resistance. This study aimed to evaluate the association between serum vitamin D levels, TNF-α and IL-6 expression, and glycemic control among insulin-resistant patients with T2DM. A hospital-based case-control study was conducted between September 2025 and February 2026 among 556 participants, including 426 insulin-resistant patients with T2DM and 130 age- and sex-matched healthy controls. Fasting blood samples were analyzed for serum vitamin D, TNF-α, IL-6, fasting blood glucose, insulin, and HbA1c. Insulin resistance was assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Serum cytokine concentrations were measured using enzyme-linked immunosorbent assay (ELISA), while adipose tissue TNF-α and IL-6 gene expression was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Correlation and multivariable regression analyses were performed to examine associations between vitamin D status, inflammatory markers, insulin resistance, and glycemic indices. Serum vitamin D levels were significantly lower among T2DM patients than controls (17.9 ± 6.8 ng/mL vs. 31.4 ± 7.6 ng/mL, p < 0.001). Conversely, serum TNF-α (18.4 ± 5.2 pg/mL vs. 9.8 ± 3.1 pg/mL, p < 0.001) and IL-6 (12.6 ± 4.7 pg/mL vs. 5.3 ± 2.0 pg/mL, p < 0.001) were significantly elevated in T2DM patients. Adipose tissue analysis demonstrated a 2.8-fold increase in TNF-α expression and a 3.2-fold increase in IL-6 expression among cases compared with controls (p < 0.001). Vitamin D levels were inversely correlated with TNF-α (r = - 0.42), IL-6 (r = - 0.38), HbA1c (r = - 0.35), and HOMA-IR (r = - 0.39) (all p < 0.001). Multivariable regression analysis demonstrated that vitamin D remained an independent negative predictor of TNF-α and IL-6 expression after adjustment for potential confounding variables. Vitamin D deficiency was significantly associated with increased TNF-α and IL-6 expression, greater insulin resistance, and poorer glycemic control among patients with T2DM. These findings support a potential role of vitamin D in metabolic inflammation; however, prospective studies and randomized controlled trials are needed to determine whether improving vitamin D status can favorably influence inflammatory and metabolic outcomes in T2DM.