Interactions of exercise training and lipoic acid on skeletal muscle glucose transport in obese Zucker rats.

Exercise training (ET) or the antioxidant R(+)-alpha-lipoic acid (R-ALA) individually increases insulin action in the insulin-resistant obese Zucker rat. The purpose of the present study was to determine the interactions of ET and R-ALA on insulin action and oxidative stress in skeletal muscle of the obese Zucker rat. Animals either remained sedentary, received R-ALA (30 mg x kg body wt(-1) x day(-1)), performed ET (treadmill running), or underwent both R-ALA treatment and ET for 6 wk. During an oral glucose tolerance test, ET alone or in combination with R-ALA resulted in a significant lowering of the glucose (26-32%) and insulin (29-30%) responses compared with sedentary controls. R-ALA alone decreased (19%) the glucose-insulin index (indicative of increased insulin sensitivity), and this parameter was reduced (48-52%) to the greatest extent in the ET and combined treatment groups. ET or R-ALA individually increased insulin-mediated glucose transport activity in isolated epitrochlearis (44-48%) and soleus (37-57%) muscles. The greatest increases in insulin action in these muscles (80 and 99%, respectively) were observed in the combined treatment group. Whereas the improvement in insulin-mediated glucose transport in soleus due to R-ALA was associated with decreased protein carbonyl levels (an index of oxidative stress), improvement because of ET was associated with decreased protein carbonyls as well as enhanced GLUT-4 protein. However, there was no interactive effect of ET and R-ALA on GLUT-4 protein or protein carbonyl levels. These results indicate that ET and R-ALA interact in an additive fashion to improve insulin action in insulin-resistant skeletal muscle. Because the further improvement in muscle glucose transport in the combined group was not associated with additional upregulation of GLUT-4 protein or a further reduction in oxidative stress, the mechanism for this interaction must be due to additional, as yet unidentified, factors.

Effects of exercise training and ACE inhibition on insulin action in rat skeletal muscle.

Our laboratory has demonstrated (Steen MS, Foianini KR, Youngblood EB, Kinnick TR, Jacob S, and Henriksen EJ, J Appl Physiol 86: 2044-2051, 1999) that exercise training and treatment with the angiotensin-converting enzyme (ACE) inhibitor trandolapril interact to improve insulin action in insulin-resistant obese Zucker rats. The present study was undertaken to determine whether a similar interactive effect of these interventions is manifest in an animal model of normal insulin sensitivity. Lean Zucker (Fa/-) rats were assigned to either a sedentary, trandolapril-treated (1 mg. kg(-1). day(-1) for 6 wk), exercise-trained (treadmill running for 6 wk), or combined trandolapril-treated and exercise-trained group. Exercise training alone or in combination with trandolapril significantly (P < 0.05) increased peak oxygen consumption by 26-32%. Compared with sedentary controls, exercise training alone or in combination with ACE inhibitor caused smaller areas under the curve for glucose (27-37%) and insulin (41-44%) responses during an oral glucose tolerance test. Exercise training alone or in combination with trandolapril also improved insulin-stimulated glucose transport in isolated epitrochlearis (33-50%) and soleus (58-66%) muscles. The increases due to exercise training alone or in combination with trandolapril were associated with enhanced muscle GLUT-4 protein levels and total hexokinase activities. However, there was no interactive effect of exercise training and ACE inhibition observed on insulin action. These results indicate that, in rats with normal insulin sensitivity, exercise training improves oral glucose tolerance and insulin-stimulated muscle glucose transport, whereas ACE inhibition has no effect. Moreover, the beneficial interactive effects of exercise training and ACE inhibition on these parameters are not apparent in lean Zucker rats and, therefore, are restricted to conditions of insulin resistance.

ACE inhibition and glucose transport in insulinresistant muscle: roles of bradykinin and nitric oxide.

Acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril enhances insulin-stimulated glucose transport activity in skeletal muscle of the insulin-resistant obese Zucker rat. The present study was designed to assess whether this effect is mediated by an increase in the nonapeptide bradykinin (BK), by a decrease in action of ANG II, or both. Obese Zucker rats (8-9 wk old) were treated for 2 h with either captopril (50 mg/kg orally), bradykinin (200 micrograms/kg ip), or the ANG II receptor (AT(1) subtype) antagonist eprosartan (20 mg/kg orally). Captopril treatment enhanced in vitro insulin-stimulated (2 mU/ml) 2-deoxyglucose uptake in the epitrochlearis muscle by 22% (251 +/- 7 vs. 205 +/- 9 pmol. mg(-1). 20 min(-1); P < 0.05), whereas BK treatment enhanced this variable by 18% (249 +/- 15 vs. 215 +/- 7 pmol. mg(-1). 20 min(-1); P < 0.05). Eprosartan did not significantly modify insulin action. The BK-mediated increase in insulin action was completely abolished by pretreatment with either the specific BK-B(2) receptor antagonist HOE 140 (200 micrograms/kg ip) or the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (50 mg/kg ip). Collectively, these results indicate that the modulation of insulin action by BK likely underlies the metabolic effects of ACE inhibitors in the insulin-resistant obese Zucker rat. Moreover, this modulation of insulin action by BK is likely mediated through B(2) receptors and by an increase in nitric oxide production and/or action in skeletal muscle tissue.