Differential seasonal performance of C3-epi-D3 level and proportion on multiple metabolic disorders in patients with type 2 diabetes mellitus

Background and aim: Recent Mendelian randomization and meta analysis suggest a controversial causality between C3-epimer of 25 hydroxyvitamin D3 (C3-epi-D3) and type 2 diabetes mellitus (T2DM). The clinical evidence regarding the impact of C3-epi-D3 on the progression of T2DM is currently insufficient. This study aims to investigate whether C3-epi-D3 has any effect on metabolic disorders of T2DM patients.

Methods: A total of 1222 patients with T2DM were prospectively enrolled in this study and followed up every 1 to 2 months for 3 to 6 months. Kidney biomarkers, lipids, electrolytes, and 25 hydroxyvitamin D (25-OHD) metabolites were measured as required during follow-up, to investigate the association of C3-epi-D3 levels and %C3-epi-D3 with metabolic disorders, including dyslipidemia, chronic kidney disease (CKD), and calcium-phosphorus metabolic disorder.

Results: Among these T2DM patients, there were age and seasonal differences in C3-epi-D3 levels (χ² = 10.419 and 19.609, P = 0.034 and < 0.001), but only seasonal difference in %C3-epi-D3 (χ² = 79.299, P < 0.001). C3-epi-D3 levels showed an evident correlation with calcium-phosphorus product during autumn and winter (ρ = - 0.336 and - 0.304, both P < 0.001), and was confirmed as an independent factor on calcium-phosphorus metabolic disorder during autumn and winter by subsequent partial correlation analysis (r_partial = - 0.300 and - 0.319, both P < 0.001). Both C3-epi-D3 levels and %C3-epi-D3 showed evident correlation with the severity of chronic kidney disease (CKD) in summer (ρ = 0.344 and 0.445, both P < 0.001). But subsequent multinomial logistic regression confirmed that only %C3-epi-D3 independently associated with moderate CKD severity in summer (OR = 1.348, P < 0.001), as well as serious CKD severity in spring, summer, and autumn (OR = 1.324, 1.342, and 1.698, all P < 0.001). Additionally, no evident correlation was observed between C3-epi-D3 and dyslipidemia.

Conclusion: Our study releases a seasonally differential impact of C3-epi-D3 levels and proportions on metabolic disorders of T2DM patients, considering to be potentially related to their pathogenesis of different metabolic disorders. The independent association between %C3-epi-D3 and CKD suggests a potential pathological relevance involving C3-epi-D3 itself.