Influence of apolipoproteins on the association between lipids and insulin sensitivity: a cross-sectional analysis of the RISC Study

Abstract

Objective: We evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence.

Research design and methods: This study included a cross-sectional analysis of the RISC Study, a multicenter European clinical investigation in 1,017 healthy volunteers balanced in sex (women 54%) and age strata (range 30-60 years). Insulin sensitivity (M/I in µmol ⋅ min(-1) ⋅ kgFFM(-1) ⋅ nM(-1)) was measured by the clamp technique and apolipoproteins (ApoB, -C3, -A1, and -E) by Multiplex Technology.

Results: The center-, sex-, and age-adjusted standardized regression coefficients (STDβ) with M/I were similar for HDL and triglycerides (+19.9 ± 1.9 vs. -20.0 ± 2.0, P < 0.0001). Further adjustment for triglycerides (or HDL), BMI, and adiponectin (or nonesterified fatty acid) attenuated the strength of the association of M/I with both HDL (STDβ +6.4 ± 2.3, P < 0.01) and triglycerides (-9.5 ± 2.1, P < 0.001). Neither ApoA1 nor ApoE and ApoB showed any association with M/I independent from plasma HDL cholesterol and triglycerides. ApoC3, in contrast, in both men and women, was positively associated with M/I independently of plasma lipids. A relative enrichment of plasma lipids with ApoC3 is associated with lower body fat percentage and lower plasma alanine amino transferase.

Conclusions: Our results suggest that HDL cholesterol modulates insulin sensitivity through a mechanism that is partially mediated by BMI and adiponectin but not by ApoA1. Similarly, the influence of triglycerides on insulin sensitivity is in part mediated by BMI and is unrelated to ApoE or ApoB, but it is significantly modulated by ApoC3, which appears to protect from the negative effect of plasma lipids.

Figure 1

Estimated effects (and SE) of +1 SD of serum HDL cholesterol (top) and +1 SD of serum triglycerides (bottom) on insulin sensitivity (expressed as M/I). The lowercase letters indicate the different set of variables that were included in the different models: center, age, and sex (a); a + serum triglycerides for HDL or serum HDL cholesterol for triglycerides (b); b + BMI (c); c + smoking and physical activity (d); d + adiponectin for HDL and FFA for triglycerides (e); e + ApoA1 for HDL or ApoC3 for triglycerides (f).

Figure 2

A: Regression lines and 95% CI for the slopes of insulin sensitivity (M/I) vs. ApoC3 (top) in univariate (gray) and after adjusting (black) for triglycerides. B: Regression lines and 95% CI for the slopes of insulin sensitivity (M/I) vs. triglycerides in univariate analysis (gray) and after adjusting for ApoC3 (black). In the inset, the values of the slopes are presented separately for men and women in both univariate and bivariate regression. P values indicate the level of statistical significance of the comparison between the slopes. Tg, triglyceride.

Figure 3

Body fat % (A) and serum ALT (B) in female (light gray histogram) and male (dark gray histogram) according to tertiles of the ratio ApoC3/triglycerides. P values indicate the statistical significance of the ANOVA. Tg, triglyceride.