Regular exercise enhances insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle

Abstract

Insulin action in skeletal muscle is enhanced by regular exercise. Whether insulin signaling in human skeletal muscle is affected by habitual exercise is not well understood. Phosphatidylinositol 3-kinase (PI3-kinase) activation is an important step in the insulin-signaling pathway and appears to regulate glucose metabolism via GLUT-4 translocation in skeletal muscle. To examine the effects of regular exercise on PI3-kinase activation, 2-h hyperinsulinemic (40 mU ⋅ m−2⋅ min−1)-euglycemic (5.0 mM) clamps were performed on eight healthy exercise-trained [24 ± 1 yr, 71.8 ± 2.0 kg, maximal O 2 uptake (V˙o 2 max) of 56.1 ± 2.5 ml ⋅ kg−1⋅ min−1] and eight healthy sedentary men and women (24 ± 1 yr, 64.7 ± 4.4 kg,V˙o 2 max of 44.4 ± 2.7 ml ⋅ kg−1⋅ min−1). A [6,6-2 H]glucose tracer was used to measure hepatic glucose output. A muscle biopsy was obtained from the vastus lateralis muscle at basal and at 2 h of hyperinsulinemia to measure insulin receptor substrate-1(IRS-1)-associated PI3-kinase activation. Insulin concentrations during hyperinsulinemia were similar for both groups (293 ± 22 and 311 ± 22 pM for trained and sedentary, respectively). Insulin-mediated glucose disposal rates (GDR) were greater ( P < 0.05) in the exercise-trained compared with the sedentary control group (9.22 ± 0.95 vs. 6.36 ± 0.57 mg ⋅ kg fat-free mass−1⋅ min−1). Insulin-stimulated PI3-kinase activation was also greater ( P< 0.004) in the trained compared with the sedentary group (3.8 ± 0.5- vs. 1.8 ± 0.2-fold increase from basal). Endurance capacity (V˙o 2 max) was positively correlated with PI3-kinase activation ( r = 0.53, P < 0.04). There was no correlation between PI3-kinase and muscle morphology. However, increases in GDR were positively related to PI3-kinase activation ( r = 0.60, P < 0.02). We conclude that regular exercise leads to greater insulin-stimulated IRS-1-associated PI3-kinase activation in human skeletal muscle, thus facilitating enhanced insulin-mediated glucose uptake.