Muscle Microvascular Dysfunction in Central Obesity Is Related to Muscle Insulin Insensitivity but Is Not Reversed by High-Dose Statin Treatment

Muscle Microvascular Dysfunction in Central Obesity Is Related to Muscle Insulin Insensitivity but Is Not Reversed by High-Dose Statin Treatment Geraldine F. Clough 1 , Magdalena Turzyniecka 1 , Lara Walter 1 , Andrew J. Krentz 1 , Sarah H. Wild 2 , Andrew J. Chipperfield 3 , John Gamble 4 and Christopher D. Byrne 1 1 School of Medicine, University of Southampton, Southampton, U.K.; the 2 Public Health Sciences, University of Edinburgh, Edinburgh, U.K.; the 3 School of Engineering, University of Southampton, Southampton, U.K.; and the 4 University of Birmingham, Birmingham, U.K. Corresponding author: Christopher D. Byrne, c.d.byrne{at}soton.ac.uk . Abstract OBJECTIVE To test the hypotheses that decreased insulin-mediated glucose disposal in muscle is associated with a reduced muscle microvascular exchange capacity ( K f ) 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 K f 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 K f (in a linear regression model with K f as the outcome [ R 2 = 0.38, P = 0.005]). M : I was associated with K f 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 ( K f ), 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 decrea