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. 2019 Oct 25;8(11):1792.
doi: 10.3390/jcm8111792.

Plasma Levels of Retinol Binding Protein 4 Relate to Large VLDL and Small LDL Particles in Subjects with and without Type 2 Diabetes

Hanna Wessel  1   2 , Ali Saeed  2   3 , Janette Heegsma  2   4 , Margery A Connelly  5 , Klaas Nico Faber  2   4 , Robin P F Dullaart  1
Affiliations

Plasma Levels of Retinol Binding Protein 4 Relate to Large VLDL and Small LDL Particles in Subjects with and without Type 2 Diabetes

Hanna Wessel et al. J Clin Med. .

Abstract

Background: Retinol binding protein 4 (RBP4) carries retinol in plasma, but is also considered an adipokine, as it is implicated in insulin resistance in mice. Plasma RBP4 correlates with total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and may confer increased cardiovascular risk. However, controversy exists about circulating RPB4 levels in type 2 diabetes mellitus (T2DM) and obesity. Here, we analyzed the relationships of RBP4 and retinol with lipoprotein subfractions in subjects with and without T2DM.

Methods: Fasting plasma RBP4 (enzyme-linked immunosorbent assay) and retinol (high performance liquid chromatography) were assayed in 41 T2DM subjects and 37 non-diabetic subjects. Lipoprotein subfractions (NMR spectroscopy) were measured in 36 T2DM subjects and 27 non-diabetic subjects. Physical interaction of RBP4 with lipoproteins was assessed by fast protein liquid chromatography (FPLC).

Results: Plasma RBP4 and retinol were strongly correlated (r = 0.881, p < 0.001). RBP4, retinol and the RBP4/retinol ratio were not different between T2DM and non-diabetic subjects (all p > 0.12), and were unrelated to body mass index. Notably, RBP4 and retinol were elevated in subjects with metabolic syndrome (p < 0.05), which was attributable to an association with elevated triglycerides (p = 0.013). Large VLDL, total LDL and small LDL were increased in T2DM subjects (p = 0.035 to 0.003). Taking all subjects together, RBP4 correlated with total cholesterol, non-HDL cholesterol, LDL cholesterol, triglycerides and apolipoprotein B in univariate analysis (p < 0.001 for each). Age-, sex- and diabetes status-adjusted multivariable linear regression analysis revealed that RBP4 was independently associated with large VLDL (β = 0.444, p = 0.005) and small LDL particles (β = 0.539, p < 0.001). Its relationship with large VLDL remained after further adjustment for retinol. RBP4 did not co-elute with VLDL nor LDL particles in FPLC analyses.

Conclusions: Plasma RBP4 levels are related to but do not physically interact with large VLDL and small LDL particles. Elevated RBP4 may contribute to a proatherogenic plasma lipoprotein profile.

Keywords: Type 2 diabetes mellitus; large VLDL; lipoprotein subfractions; metabolic syndrome; nuclear magnetic resonance spectroscopy; retinol; retinol binding protein 4; small LDL.

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Conflict of interest statement

M.A.C. is an employee of LabCorp. The rest of the authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
(A) Plasma retinol binding protein 4 (RBP4) and retinol in 41 subjects with and 37 subjects without Type 2 diabetes mellitus; (B) Plasma retinol binding protein 4 (RBP4) and retinol in 36 subjects with and 42 without the metabolic syndrome (MetS). Data are expressed in box and whiskers plots with mean and minimum to maximum values. All data points are shown.
Figure 2
Figure 2
Correlation of total plasma retinol with retinol binding protein 4 (RBP4) in 41 subjects with and 37 without type 2 diabetes mellitus. All subjects: r = 0.881, p < 0.001; diabetic subjects: r = 0.900, p < 0.001; non-diabetic subjects: r = 0.859, p < 0.001.
Figure 3
Figure 3
Total protein, retinol binding protein 4 (RBP4), cholesterol and triglyceride concentrations in fast protein liquid chromatography (FPLC) fractions from plasma of a representative control subject. The location of peak fractions of very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) particles, as well as of the soluble proteins are indicated.
See this image and copyright information in PMC

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