Remnant cholesterol, iron status and diabetes mellitus: a dose-response relationship and mediation analysis

Abstract

Background: Remnant cholesterol (RC) is recognized as a risk factor for diabetes mellitus (DM). Although iron status has been shown to be associated with cholesterol metabolism and DM, the association between RC, iron status, and DM remains unclear. We examined the relationship between RC and iron status and investigated the role of iron status in the association between RC and DM.

Methods: A total of 7308 patients were enrolled from the China Health and Nutrition Survey. RC was calculated as total cholesterol minus low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Iron status was assessed as serum ferritin (SF) and total body iron (TBI). DM was ascertained by self-reported physician diagnosis and/or antidiabetic drug use and/or fasting plasma glucose ≥ 126 mg/dL and/or glycated haemoglobin ≥ 6.5%. General linear models were used to evaluate the relationships between RC and iron status. Restricted cubic splines were used to assess the association between RC and DM. Mediation analysis was used to clarified the mediating role of iron status in the association between the RC and DM.

Results: The average age of the participants was 50.6 (standard deviation = 15.1) years. Higher RC was significantly associated with increased SF (β = 73.14, SE = 3.75, 95% confidence interval [CI] 65.79-80.49) and TBI (β = 1.61, SE = 0.08, 95% CI 1.44-1.78). J-shape relationships were found in the association between RC levels with DM, as well as iron status with DM. Significant indirect effects of SF and TBI in the association between RC and DM were found, with the index mediated at 9.58% and 6.37%, respectively.

Conclusions: RC has a dose-response relationship with iron status. The association between RC and DM was mediated in part by iron status. Future studies are needed to confirm these findings and further clarify the underlying mechanism.

Keywords: Diabetes mellitus; Iron; Mediation; Remnant cholesterol.

Fig. 1

Study flowchart. RC Remnant cholesterol

Fig. 2

Association of RC with iron state. Values outside the 97.5th percentile of RC are not included. RC Remnant cholesterol, SF Serum ferritin, TBI Total body iron

Fig. 3

The restricted spline curve for the association between RC, iron status markers and DM. The histogram of the distribution of lgRC, lgSF, and TBI, and the RCS for the associations between lgRC, lgSF, TBI, and DM with four knots. The red line and shadow area represent odds ratios (ORs, solid lines) and 95% confidence intervals (CIs) after multivariable adjustment for age, sex, BMI, residence, occupation, education, smoking, alcohol consumption, eGFR, LDL-C, HDL-C, antidiabetic drug, average energy intake, average carbohydrate intake, average fat intake, and average protein intake based on the RCS models. RC and SF were lg-transformed and the concentration of lgRC and lgSF were -0.45 and 1.9 [OR = 1] as the reference concentration, respectively. While the concentration of TBI was 34 mg/kg [OR = 1] as the reference concentration. Values outside the 97.5th percentile of RC are not included. RC Remnant cholesterol, OR Odds ratio, CI Confidence interval, SF Serum ferritin, TBI Total body iron

Fig. 4

Mediation analysis of the association between RC and DM. DM Diabetes mellitus, RC Remnant cholesterol, SF Serum ferritin, TBI Total body iron