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Background <p>Beyond bone health, vitamin D plays a pivotal role in glucose and lipid homeostasis. Vitamin D deficiency is prevalent in type 2 diabetes (T2DM), potentially exacerbating β-cell dysfunction and dysregulated energy substrate utilization. This study aimed to characterize the complex, potentially non-linear relationship between serum 25-hydroxyvitamin D [25(OH)D], β-hydroxybutyrate (β-OHB), and pancreatic β-cell reserve.</p> Methods <p>Hospitalized T2DM patients were enrolled, excluding those with acute complications or severe organ dysfunction. C-peptide area under the curve (AUC₀–₃h) from a steamed bread meal test was used to assess β-cell reserve. Multiple linear and logistic regressions were employed to evaluate the 25(OH)D-β-OHB association, adjusting for covariates including demographics, glycemic control, lipid profile, comorbidities, and medications (Metformin, SGLT2 inhibitors, insulin). Non-linearity was examined using mean-centered quadratic terms, with robustness verified via Bootstrap resampling and restricted cubic spline (RCS) analysis.</p> Results <p>No independent linear association was observed between 25(OH)D and ln(β-OHB + 0.01) in the overall population (<i>P</i> &gt; 0.05). However, multivariate logistic regression identified 25(OH)D as an independent risk factor for elevated ketones (β-OHB ≥ 0.27 mmol/L; OR = 1.053, <i>P</i> = 0.006), an effect that was more pronounced in the preserved β-cell function group (C-peptide AUC ≥ 8 ng/mL⋅h; OR = 1.062, <i>P</i> = 0.011). Notably, a significant U-shaped relationship between 25(OH)D and β-OHB was confirmed in patients with stable metabolic status (HbA1c ≤ 8.5% and C-peptide AUC ≥ 8 ng/mL⋅h), with an inflection point at 20.5–22.4 ng/mL.</p> Conclusion <p>A robust U-shaped non-linear association exists between serum 25(OH)D and β-OHB, indicating a dual regulatory role of vitamin D in ketone metabolism. Maintaining 25(OH)D at a moderate level (~ 21 ng/mL) may optimize energy substrate utilization, a process significantly modulated by β-cell reserve. These findings underscore the clinical necessity for individualized vitamin D monitoring and precision intervention in T2DM management.</p>

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A U-shaped association between vitamin D and ketone levels in type 2 diabetes: a metabolic state–dependent dual regulation mechanism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Xiang-Yu Chen,
  • Yang Zhang,
  • Xiang-Xin Wang,
  • Li-Ying Hao,
  • Mei Xue,
  • Wen-Hua Xiao

摘要

Background

Beyond bone health, vitamin D plays a pivotal role in glucose and lipid homeostasis. Vitamin D deficiency is prevalent in type 2 diabetes (T2DM), potentially exacerbating β-cell dysfunction and dysregulated energy substrate utilization. This study aimed to characterize the complex, potentially non-linear relationship between serum 25-hydroxyvitamin D [25(OH)D], β-hydroxybutyrate (β-OHB), and pancreatic β-cell reserve.

Methods

Hospitalized T2DM patients were enrolled, excluding those with acute complications or severe organ dysfunction. C-peptide area under the curve (AUC₀–₃h) from a steamed bread meal test was used to assess β-cell reserve. Multiple linear and logistic regressions were employed to evaluate the 25(OH)D-β-OHB association, adjusting for covariates including demographics, glycemic control, lipid profile, comorbidities, and medications (Metformin, SGLT2 inhibitors, insulin). Non-linearity was examined using mean-centered quadratic terms, with robustness verified via Bootstrap resampling and restricted cubic spline (RCS) analysis.

Results

No independent linear association was observed between 25(OH)D and ln(β-OHB + 0.01) in the overall population (P > 0.05). However, multivariate logistic regression identified 25(OH)D as an independent risk factor for elevated ketones (β-OHB ≥ 0.27 mmol/L; OR = 1.053, P = 0.006), an effect that was more pronounced in the preserved β-cell function group (C-peptide AUC ≥ 8 ng/mL⋅h; OR = 1.062, P = 0.011). Notably, a significant U-shaped relationship between 25(OH)D and β-OHB was confirmed in patients with stable metabolic status (HbA1c ≤ 8.5% and C-peptide AUC ≥ 8 ng/mL⋅h), with an inflection point at 20.5–22.4 ng/mL.

Conclusion

A robust U-shaped non-linear association exists between serum 25(OH)D and β-OHB, indicating a dual regulatory role of vitamin D in ketone metabolism. Maintaining 25(OH)D at a moderate level (~ 21 ng/mL) may optimize energy substrate utilization, a process significantly modulated by β-cell reserve. These findings underscore the clinical necessity for individualized vitamin D monitoring and precision intervention in T2DM management.