Interactions of exercise training and alpha-lipoic acid on insulin signaling in skeletal muscle of obese Zucker rats.
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 mg.kg 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.
Saengsirisuwan
Vitoon
V
Department of Physiology, University of Arizona College of Medicine, Tucson 85721-0093, USA.
Perez
Felipe R
FR
Sloniger
Julie A
JA
Maier
Thomas
T
Henriksen
Erik J
EJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001692:Biological Transport; D001835:Body Weight; D005260:Female; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption; D010805:Physical Conditioning, Animal; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects*; D008063:Thioctic Acid / Q000494:pharmacology*
D000975:Antioxidants; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; D008063:Thioctic Acid; D005947:Glucose