Interactions of exercise training and alpha-lipoic acid on insulin signaling in skeletal muscle of obese Zucker rats

Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E529-36. doi: 10.1152/ajpendo.00013.2004. Epub 2004 Apr 6.


We have shown previously (Saengsirisuwan V, Kinnick TR, Schmit MB, and Henriksen EJ. J Appl Physiol 91: 145-153, 2001) that the antioxidant R-(+)-alpha-lipoic acid (R-ALA), combined with endurance exercise training (ET), increases glucose transport in insulin-resistant skeletal muscle in an additive fashion. The purpose of the present study was to investigate possible cellular mechanisms responsible for this interactive effect. We evaluated the effects of R-ALA alone, ET alone, or R-ALA and ET in combination on insulin-stimulated glucose transport, protein expression, and functionality of specific insulin-signaling factors in soleus muscle of obese Zucker (fa/fa) rats. Obese animals remained sedentary, received R-ALA (30 body wt(-1).day(-1)), performed ET (daily treadmill running for < or =60 min), or underwent both R-ALA treatment and ET for 15 days. R-ALA or ET individually increased (P < 0.05) insulin-mediated (5 mU/ml) glucose transport (2-deoxyglucose uptake) in soleus muscle by 45 and 68%, respectively, and this value was increased to the greatest extent (124%) in the combined treatment group. Soleus insulin receptor substrate (IRS)-1 protein was significantly increased by R-ALA alone (30%) or ET alone (31%), and a further enhancement (55%) was observed after the combination treatment in the obese animals. Enhanced levels of IRS-1 protein expression after individual or combined interventions were significantly correlated with insulin action on glucose transport activity (r = 0.597, P = 0.0055). Similarly, insulin-mediated IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase was increased by R-ALA (317%) and ET (319%) and to the greatest extent (435%) (all P < 0.05) by the combination treatment. These results indicate that the improvements of insulin action in insulin-resistant skeletal muscle after R-ALA or ET, alone and in combination, were associated with increases in IRS-1 protein expression and IRS-1 associated with p85.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Biological Transport
  • Body Weight
  • Female
  • Glucose / metabolism
  • Glucose Transporter Type 4
  • Insulin / metabolism*
  • Monosaccharide Transport Proteins / metabolism
  • Muscle Proteins*
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism*
  • Obesity / metabolism*
  • Obesity / pathology
  • Oxygen Consumption
  • Physical Conditioning, Animal*
  • Rats
  • Rats, Zucker
  • Signal Transduction / drug effects*
  • Thioctic Acid / pharmacology*


  • Antioxidants
  • Glucose Transporter Type 4
  • Insulin
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Slc2a4 protein, rat
  • Thioctic Acid
  • Glucose