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

John P. Kirwan, Luis F. Del Aguila, Jazmir M. Hernandez, David L. Williamson, Donal J. O'Gorman, Rebecca Lewis, Raj K. Krishnan

Research output: Contribution to journalArticlepeer-review


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 O2 uptake (V̇O(2max)) 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, V̇O(2max) of 44.4 ± 2.7 ml · kg-1 · min-1). A [6,6-2H] 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 (V̇O(2max)) 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.

Original languageEnglish (US)
Pages (from-to)797-803
Number of pages7
JournalJournal of applied physiology
Issue number2
StatePublished - Feb 2000
Externally publishedYes


  • Enzymes
  • Exercise training
  • Glucose metabolism
  • Insulin action
  • Insulin receptor substrate-1
  • Muscle
  • Phosphatidylinositol 3- kinase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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