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

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) activat ion is an important step in the insulin-signaling pathway and appears to re gulate glucose metabolism via GLUT-4 translocation in skeletal muscle, To e xamine the effects of regular exercise on PI3-kinase activation, 2-h hyperi nsulinemic (40 mU . m(-2) min(-1))-euglycemic (5.0 mM) clamps were performe d on eight healthy exercise-trained [24 +/- 1 yr, 71.8 +/- 2.0 kg, maximal O-2 uptake (VO2max) of 58.1 +/- 2.5 ml . kg(-1) . min(-1)] and eight health y sedentary men and women (24 +/- 1 yr, 64.7 +/- 4.4 kg, VO2max of 44.4 +/- 2.7 ml . kg(-1) . min(-1)). A [6,6(-2)H] glucose tracer was used to measur e hepatic glucose output. A muscle biopsy was obtained from the vastus late ralis muscle at basal and at 2 h of hyperinsulinemia to measure insulin rec eptor substrate-1(IRS-1)-associated PI3-kinase activation. Insulin concentr ations during hyperinsulinemia were similar for both groups (293 +/- 22 and 311 +/- 22 pM for trained and sedentary, respectively). Insulin-mediated g lucose 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 activa tion was also greater (P < 0.004) in the trained compared with the sedentar y group (3.8 +/- 0.5- vs. 1.8 +/- 0.2-fold increase from basal). Endurance capacity (VO2max) was positively correlated with PI3-kinase activation (r = 0.53, P < 0.04). There was no correlation between PI3-kinase and muscle mo rphology. However, increases in GDR were positively related to PI3-kinase a ctivation (r = 0.60, P < 0.02). We conclude that regular exercise leads to greater insulin-stimulated IRS-l-associated PI3-kinase activation in human skeletal muscle, thus facilitating enhanced insulin-mediated glucose uptake .