Muscle microvascular dysfunction in central obesity is related to muscle insulin insensitivity but is not reversed by high-dose statin treatment

Abstract

Objective: To test the hypotheses that decreased insulin-mediated glucose disposal in muscle is associated with a reduced muscle microvascular exchange capacity (Kf) and that 6 months of high-dose statin therapy would improve microvascular function in people with central obesity.

Research design and methods: We assessed skeletal muscle microvascular function, visceral fat mass, physical activity levels, fitness, and insulin sensitivity in skeletal muscle in 22 female and 17 male volunteers with central obesity whose age (mean +/- SD) was 51 +/- 9 years. We tested the effect of atorvastatin (40 mg daily) on muscle microvascular function in a randomized, double-blind, placebo-controlled trial lasting 6 months.

Results: Kf was negatively associated with a measure of glycemia (A1C; r = -0.44, P = 0.006) and positively associated with insulin sensitivity (the ratio of insulin-stimulated glucose effectiveness, or M value, to the mean insulin concentration, or I value; r = 0.39, P = 0.02). In regression modeling, A1C, visceral fat mass, and M:I explained 38% of the variance in Kf (in a linear regression model with Kf as the outcome [R2 = 0.38, P = 0.005]). M:I was associated with Kf independently of visceral fat mass (B coefficient 3.13 [95% CI 0.22-6.02], P = 0.036). Although 6 months' treatment with atorvastatin decreased LDL cholesterol by 51% (P < 0.001) and plasma high-sensitivity C-reactive protein by 75% (P = 0.02), microvascular function was unchanged.

Conclusions: Decreased insulin-mediated glucose uptake in skeletal muscle is associated with impaired muscle microvascular exchange capacity (Kf), independently of visceral fat mass. Muscle microvascular function is not improved by 6 months of high-dose statin treatment, despite marked statin-mediated improvements in lipid metabolism and decreased inflammation.

FIG. 1.

Baseline measurements of filtration capacity (K_f), resting limb blood flow (Qa), and endothelial integrity (P_vi) from 39 individuals. All values were derived using venous congestion plethysmography from the raw data (see supplemental information in the online appendix). Qa = resting (ml · 100 ml⁻¹ · min⁻¹); K_f = × 10⁻³ ml · min⁻¹ · 100 ml⁻¹ · mmHg⁻¹; P_vi = mmHg.

FIG. 2.

Scatter plots for the relationships between K_f and visceral fat, A1C, and M:I from 39 individuals at baseline. K_f was negatively associated with visceral fat (r = −0.43, P = 0.015) and A1C (r = −0.44, P = 0.006) and positively associated with M:I (r = 0.39, P = 0.02).

FIG. 3.

K_f, isovolumetric pressure (P_vi), and resting limb blood flow (Qa) measured before and after 26 weeks' treatment with atorvastatin (40 mg once daily) or matched placebo.