Reduced glucose transporter GLUT4 in skeletal muscle predicts insulin resistance in non-diabetic chronic heart failure patients independently of body composition

Abstract

Background In chronic heart failure (CHF) skeletal muscle insulin resistance occurs independently of etiology and contributes to impaired energy metabolism. GLUT4, the predominant glucose transporter in the skeletal muscle promotes the rate-limiting step of glucose utilization in skeletal muscle. The significance of skeletal muscle GLUT4 in patients with CHF has not been studied in detail. Methods In patients with CHF and free of diabetes mellitus ( n = 29; mean NYHA class 2.3 ± 0.1, peak VO 2 18.8 ± 1.1 mL/kg/min) and healthy control subjects of similar age ( n = 7), GLUT4 protein was assessed from percutaneous skeletal muscle biopsies. Skeletal muscle insulin sensitivity was assessed by intravenous glucose tolerance testing using a minimal modeling technique. Body composition was analyzed by dual energy X-ray absorptiometry (DEXA) scanning. Results Skeletal muscle GLUT4 was lower in CHF patients than in controls (0.75 ± 0.07 vs 1.24 ± 0.19 density units, P < 0.01) and decreased in parallel to severity of CHF, being lowest in NYHA III/IV (0.596 ± 0.08, ANOVA P < 0.01 vs controls). GLUT4 was lower in patients with an ischemic etiology compared to dilated cardiomyopathy and controls (ANOVA P < 0.01). Patients and controls were similar for global parameters of body composition (weight: 78 ± 4 vs 76 ± 4 kg, BMI 25.5 ± 0.8 vs 25.8 ± 1.5 kg/m 2), and total tissue amount and regional distribution of fat and lean tissue (all P > 0.2). Low GLUT4 predicted impaired insulin sensitivity, i.e. insulin resistance ( r = 0.55, P < 0.01). In multivariate analysis, GLUT4 levels predicted insulin sensitivity independently of age and parameters of body composition (including weight, BMI, and total and regional fat and lean tissue distribution). Conclusion In non-diabetic patients with CHF, skeletal muscle GLUT4 transport protein is reduced in parallel to disease severity, independently of body composition. Low skeletal muscle GLUT4 contributes to insulin resistance in CHF.