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-lipoic acid on insulin signaling in skeletal muscle of obese Zucker rats
Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona 85721-0093
Submitted 9 January 2004 ; accepted in final form 29 March 2004
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ABSTRACT |
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-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 
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. insulin resistance; glucose transport; antioxidants; insulin receptor substrate-1; p85
Interventions that improve insulin resistance of skeletal muscle glucose transport include diet, loss of fat mass, and pharmaceutical and nutriceutical compounds. The R-(+)-enantiomer of -lipoic acid (R-ALA) is a nutriceutical compound that also displays antioxidant properties (23). R-ALA can modulate glucose metabolism in both insulin-sensitive (7, 10, 15) and insulin-resistant (19, 20, 29) muscle tissues. Furthermore, we have demonstrated that chronic in vivo treatment with R-ALA elicits improvements in whole body glucose tolerance and insulin sensitivity, as well as insulin action, on skeletal muscle glucose transport of insulin-resistant obese Zucker rats (25). Although the precise cellular mechanisms responsible for the stimulatory effect of R-ALA on insulin action have not been determined, we have shown that increased insulin action after R-ALA treatment in obese Zucker rats is associated with a reduction of oxidative stress (25).
Another effective intervention that improves insulin action in insulin-resistant states is exercise training (see recent review in Ref. 12). Moderate- to high-intensity exercise training increases glucose tolerance and glucose disposal in the insulin-resistant obese Zucker rat, primarily due to adaptations in the glucose transport activity (6, 17, 28) and translocation of GLUT4 protein (4, 8). We have recently demonstrated favorable metabolic adaptations in skeletal muscle of the insulin-resistant obese Zucker rat in response to treadmill training (25), including significant enhancements of insulin-stimulated glucose transport, GLUT4 protein expression, and activities of enzymes involved in glucose metabolism (25). Most importantly, we have recently shown that the combination of treatment with the antioxidant R-ALA and endurance exercise training is associated with greater improvements in insulin action on skeletal muscle glucose transport than either intervention individually (25). However, the potential cellular mechanisms, including the involvement of elements of the insulin-signaling pathway, that underlie the beneficial adaptations associated with R-ALA treatment and exercise training leading to enhanced insulin action on the insulin-resistant skeletal muscle were not elucidated in that study. Therefore, the purpose of the present study was to determine the effects of the R-ALA treatment and exercise training, individually and in combination, on glucose transport activity and protein expression and functionality of select insulin-signaling factors in skeletal muscle of the obese Zucker rat.
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METHODS |
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The obese rats were randomly assigned to one of the following groups: a sedentary, vehicle-treated control group, an R-ALA-treated group, an exercise-trained group, or a combined R-ALA-treated and exercise-trained group. Animals in the obese R-ALA-treated groups received 30 mg/kg body wt of the purified R-(+)-enantiomer of -lipoic acid (Viatris, Frankfurt, Germany), dissolved in 100 mM Tris buffer (pH 7.4), by intraperitoneal injection every evening for 15 days, and the obese sedentary control animals received 8.3 ml/kg body wt of 100 mM Tris buffer (pH 7.4). Animals in the obese exercise-trained groups ran in the morning on a 10-lane motor-driven rodent treadmill at 4% grade. These animals ran 7 days/wk for 15 days. The training protocol was quickly increased to 60 min/day by day 7, continuously rotating through the following 15-min cycles: 26 m/min for 10 min, 30 m/min for 3 min, and 24 m/min for 2 min (8). The obese combined-treatment animals performed the treadmill training protocol exactly as described above while also receiving daily treatments with R-ALA. The lean rats received 8.3 ml/kg body wt of 100 mM Tris buffer (pH 7.4) daily, and soleus muscles were used to assess the protein expression and functionality of insulin-signaling factors in a tissue with normal insulin sensitivity.
Peak aerobic capacity.
Peak aerobic capacity (
O2 peak) was assessed in each obese animal during a treadmill test by the method of Bedford et al. (3). No exercise was performed on the day before the O2 peak tests. However, R-ALA was given to the obese R-ALA-treated group and the obese, combined exercise and R-ALA group on this day. Animals ran on a motorized treadmill in an airtight Plexiglas chamber. Grade and speed of the treadmill were increased every 3 min from a basal level of 0% grade and 13.4 m/min through the following stages: 16.1 m/min at 5%, 21.4 m/min at 10%, 26.8 m/min at 10%, 32.2 m/min at 12%, 32.2 m/min at 15%, 32.2 m/min at 18%, and 32.2 m/min at 21%. The test was stopped when the rats were unable to keep pace with the treadmill belt. O2 (Ametek S-3A1, Applied Electrochemistry, Pittsburgh, PA) and CO2 (Ametek CD-3A) were measured in expired gases every 3 min for the determination of oxygen uptake (ml O2·kg body wt–1·min–1). Exercise training and R-ALA treatments were resumed the day after the O2 peak assessment.
Glucose transport activity.
Approximately 72 h after the O2 peak test, 24 h after the final exercise bout, and 15 h after the final R-ALA treatment, obese animals were weighed and deeply anesthetized with an intraperitoneal injection of pentobarbital sodium (50 mg/kg body wt). The determination of muscle glucose transport activity was initiated at 8 AM after an overnight food restriction (4 g of chow after 5 PM). One soleus and both epitrochlearis muscles were dissected and prepared for in vitro incubation. Whereas the epitrochlearis muscles were incubated intact, the soleus muscle was prepared in two strips (
25 mg each) and incubated. Each muscle was incubated for 1 h at 37°C in 3 ml of oxygenated (95% O2-5% CO2) Krebs-Henseleit buffer (KHB) supplemented with 8 mM glucose, 32 mM mannitol, and 0.1% BSA (radioimmunoassay grade; Sigma Chemical, St. Louis, MO). One epitrochlearis muscle and one soleus strip were incubated in the absence of insulin, and the contralateral epitrochlearis muscle and second soleus strip were incubated in the presence of a maximally effective concentration of insulin (5 mU/ml Humulin R; Eli Lilly, Indianapolis, IN).
After this initial incubation period, the muscles were rinsed for 10 min at 37°C in 3 ml of oxygenated KHB containing 40 mM mannitol, 0.1% BSA, and insulin, if previously present. Thereafter, the muscles were transferred to 2 ml of KHB, containing 1 mM 2-deoxy-[1,2-3H]glucose (2-DG, 300 µCi/mmol; Sigma Chemical), 39 mM [U-14C]mannitol (0.8 µCi/mmol; ICN Radiochemicals, Irvine, CA), 0.1% BSA, and insulin, if previously present. At the end of this final 20-min incubation period at 37°C, the muscles were removed, trimmed of excess fat and connective tissue, quickly frozen, weighed, and dissolved in 0.5 ml of 0.5 N NaOH. After the muscles were completely solubilized, 5 ml of scintillation cocktail were added, and the specific intracellular accumulation of 2-DG was determined as described previously (13, 14).
Insulin-signaling factors.
The contralateral soleus was removed, trimmed of fat and connective tissue, and quickly frozen in liquid nitrogen. Muscles were cut on dry ice, and pieces of the muscle were homogenized in ice-cold lysis buffer [50 mM HEPES (pH 7.4), 150 mM NaCl, 1 mM CaCl2, 1 mM MgCl2, 2 mM EDTA, 10 mM NaF, 20 mM sodium pyrophosphate, 20 mM 
-glycerophosphate, 10% glycerol, 1% Triton X-100, 2 mM Na3VO4, 10 µg/ml aprotinin and leupeptin, and 2 mM PMSF]. After a 20-min incubation on ice, the homogenates were centrifuged at 13,000 g for 20 min at 4°C. A portion of the lysates was analyzed for total protein concentration by use of the bicinchoninic acid (BCA) method (Sigma Chemical); the remainder was used for Western blot analysis of insulin-signaling protein expression. After denaturing by boiling with SDS-PAGE sample buffer, samples were separated on 7.5 or 12% polyacrylamide gels (Bio-Rad Laboratories, Hercules, CA) and blotted electrophoretically onto nitrocellulose paper. Blots were incubated with commercially available antibodies against insulin receptor -subunit (IR), COOH-terminal IRS-1, the p85 regulatory subunit of PI 3-kinase (Upstate Biotechnology, Lake Placid, NY), and Akt1/2 (Cell Signaling Technology, Beverly, MA). For evaluation of insulin receptor tyrosine phosphorylation and Akt serine phosphorylation in soleus muscle incubated in the absence or presence of insulin, blots were incubated with antibodies against Tyr1146 on the insulin receptor and against Ser473 on Akt (Cell Signaling). For assessment of IRS-1 tyrosine phosphorylation and tyrosine-phosphorylated IRS-1 associated with the p85 subunit of PI 3-kinase, 1 mg of homogenate protein was immunoprecipitated with either 10 µg of anti-phosphotyrosine antibody (PY99, Upstate Biotechnology) or 10 µg of IRS-1 antibody conjugated to agarose (Santa Cruz Biotechnology, Santa Cruz, CA). The immunoprecipitates were immunoblotted with antibody against either IRS-1 or the p85 subunit of PI 3-kinase (both Upstate Biotechnology). After incubation with horseradish peroxidase-conjugated secondary antibodies, proteins were visualized by enhanced chemiluminescence (Amersham Biosciences, Piscataway, NJ) on X-ray film (X-OMAT-AR; Kodak, Rochester, NY). Images were digitized by scanning, and band intensity was quantified on a GS-800 densitometer (Bio-Rad) using Quantity One software.
Biochemical assays. After muscles were removed for incubation, the plantaris muscles and the apex of the heart (containing the left ventricle) were removed and frozen in liquid nitrogen. Portions of these muscles and of the soleus (20 mg) were cut and homogenized in 30 volumes of ice-cold 20 mM HEPES (pH 7.4) containing 1 mM EDTA and 250 mM sucrose. These homogenates were used for determination of total protein (BCA method, Sigma Chemical), GLUT4 protein level (13), total hexokinase activity (31), and citrate synthase activity (27). The remaining piece of the soleus (20–40 mg) was used for assessment of triglyceride concentration. These pieces of soleus were homogenized in extraction buffer (20:10:3 of chloroform-methanol-butylated hydroxytoluene) and incubated at 4°C for 16 h. Separation of phases was obtained after addition of 0.9% saline, with centrifugation at 3,000 g for 60 min. The lower (organic) phase was evaporated to dryness in an N2-filled oven at 60°C for 60–90 min. The sample was reconstituted in extraction buffer, and triglyceride concentration was determined spectrophotometrically with an enzymatic colorimetric assay (Triglyceride GPO-Trinder, Sigma Chemical).
Statistical analysis. All values are expressed as means ± SE. The significance of differences among groups was assessed by a factorial ANOVA with a post hoc Fisher's protected least significant difference test (StatView version 5.0, SAS Institute, Cary, NC). In some cases, values from sedentary lean Zucker rats were used as a reference control. A level of P < 0.05 was set for statistical significance.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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O2 peak.
The obese exercise-trained and combined-treatment groups had slightly lower (7–10%) final body weights than either the obese sedentary or the obese R-ALA-treated group (Table 1). The obese exercise-trained group displayed the lowest (P < 0.05) average rate of body weight gain over the experimental period compared with the obese sedentary control and the obese R-ALA-treated groups. Animals in both obese exercise-trained and obese combined-treatment groups had significantly higher peak aerobic capacities compared with the obese sedentary control group (26 and 29%, respectively) or the obese R-ALA-treated group (20 and 24%, respectively; Table 1). Moreover, exercise training alone or in combination with R-ALA treatment resulted in significantly longer maximum run times compared with those of the obese sedentary control group (36 and 39%, respectively) or the obese R-ALA-treated group (38 and 41%, respectively; Table 1). It is clear that this 2-wk exercise training regimen (8) elicits similar adaptive responses in aerobic capacity to those observed after 6 wk or more of endurance training by the obese Zucker rat (6, 25, 28, 30).
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Intramuscular triglycerides. Triglyceride accumulation in the soleus of the obese Zucker rat was three- to fourfold higher (P < 0.05) than in the same tissue from insulin-sensitive lean Zucker rats (Fig. 5). Compared with the obese sedentary control group, R-ALA treatment and exercise training individually in obese animals caused significant reductions (44 and 37%, respectively) in soleus triglyceride levels. However, the combination of R-ALA treatment and exercise training did not induce a further decrease in lipid content in this muscle.
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, IRS-1, p85 regulatory subunit of PI 3-kinase (p85), and Akt1/2 after the interventions was determined in soleus muscle (Fig. 6). These parameters were expressed relative to the level obtained from soleus muscle of the age-matched insulin-sensitive lean Zucker rat. No significant differences in protein expression of IR, p85, and Akt1/2 were observed among experimental groups. However, the protein expression of IRS-1 in soleus muscle from the sedentary obese Zucker rat was 44% less than in the insulin-sensitive soleus muscle of lean Zucker rats. Compared with the obese sedentary group, R-ALA treatment alone or exercise training alone caused significant enhancements (30 and 31%, respectively) in IRS-1 protein expression. An additional increase in IRS-1 protein expression was observed in the soleus muscle from obese animals that received R-ALA treatment and underwent exercise training in combination (55% vs. sedentary and 19% vs. R-ALA alone or exercise trained alone; all P < 0.05).
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The ability of insulin to affect the phosphorylation state and interactions of select insulin-signaling factors was further assessed in the incubated soleus muscle. The insulin-mediated increase in Tyr1146 phosphorylation of the insulin receptor was not significantly enhanced by the interventions, although there was a trend (P = 0.073) for greater IR tyrosine phosphorylation in the obese exercise-trained group compared with the obese sedentary group (Fig. 7). Insulin-stimulated IRS-1 tyrosine phosphorylation in the obese soleus was only 55% of that in the lean soleus; however, when expressed relative to equal amounts of IRS-1 protein, there was no difference among obese groups for insulin-mediated IRS-1 tyrosine phosphorylation (data not shown). The insulin-mediated increase in IRS-1 associated with p85 in soleus of the obese sedentary group was only 17% of that measured in soleus of lean Zucker rats, and this parameter in the obese groups was significantly increased by R-ALA (317%) or exercise training (319%; both P < 0.05; Fig. 8). Moreover, the greatest enhancement of insulin-mediated IRS-1-associated p85 was seen in soleus of obese animals that received the combination of interventions (435%, P < 0.05). Whereas insulin-mediated Akt Ser473 phosphorylation in soleus of obese sedentary animals was only 65% of the lean control value, the R-ALA and exercise training interventions were ineffective in enhancing insulin action on this parameter (Fig. 9).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The 2-wk exercise training protocol employed in the present study was effective in enhancing whole body aerobic capacity (Table 1), maximal run time (Table 1), and insulin-stimulated glucose transport activity in skeletal muscle (Fig. 1). We have shown in the present (Figs. 2–4) and previous (25) investigations that the exercise training-induced improvements in insulin action are associated with enhanced GLUT4 protein expression and capacities for glucose phosphorylation (hexokinase) and glucose oxidation (citrate synthase). In addition, we have demonstrated in the present investigation that this 2-wk exercise training regimen was effective in significantly enhancing the protein expression of IRS-1 (Fig. 6) in the soleus muscle of the obese Zucker rat, which was markedly decreased compared with the level seen in the soleus muscle of the insulin-sensitive lean Zucker rat. These findings support the previous findings of Hevener et al. (16), who showed that IRS-1 protein expression in red quadriceps was substantially less in the obese Zucker rat than in the lean Zucker rat and could be increased with 3 wk of endurance exercise training. In contrast, Christ et al. (5), using the gastrocnemius muscle, could not demonstrate either a defect in IRS-1 protein expression in obese vs. lean Zucker rat or any enhancement of IRS-1 protein expression after 7 wk of exercise training by obese Zucker rats. It should be noted that the gastrocnemius muscle consists of a mixture of types I and II fibers (2), whereas the soleus and red quadriceps are made up of predominantly type I fibers (2), and the differences in muscles used and their fiber type compositions may account for the discrepant responses to exercise training for IRS-1 protein expression.
Lipoic acid is a water-soluble biological antioxidant that also displays antihyperglycemic effects (11). When administered acutely in vivo, lipoic acid decreases plasma glucose in hyperglycemic streptozotocin-diabetic rats (20). Previous findings from our research group (29) demonstrated that the beneficial metabolic effects of lipoic acid on glucose metabolism in the insulin-resistant state are stereospecific to the R-(+)-enantiomer (R-ALA). In addition, we have shown that chronic administration of R-ALA improves glucose tolerance and skeletal muscle glucose transport in the obese Zucker rat (25). Unlike exercise training, chronic R-ALA treatment has no effect on GLUT4 protein expression, hexokinase activity, or citrate synthase activity in muscle (Ref. 25; and in this study Figs. 2–4). In the present study, we have shown that 2-wk treatment of obese Zucker rats with R-ALA is associated with a substantial, although not statistically significant, enhancement of insulin-stimulated insulin receptor tyrosine phosphorylation (Fig. 7), significant increases in IRS-1 protein expression (Fig. 6), and insulin-mediated phosphotyrosine IRS-1 associated with the p85 subunit of PI 3-kinase (Fig. 8). However, the defect in insulin action on serine phosphorylation of Akt in soleus muscle of the obese Zucker rat was not affected by the antioxidant treatment (Fig. 9). Taken together, these results indicate that the improvements in insulin action on skeletal muscle glucose transport activity in R-ALA-treated obese Zucker rats are likely related to improvements in insulin stimulation of the IRS-1/PI 3-kinase pathway, but not Akt. The molecular mechanisms for these improvements in IRS-1 protein expression and IRS-1-p85 interaction remain to be investigated.
Increasing evidence in humans and animal models indicates that accumulation of muscle triglyceride is associated with decreased insulin action on glucose disposal by skeletal muscle (18, 22, 24), possibly related to locally elevated free fatty acids impairing insulin signaling at the level of IRS-1 and PI 3-kinase (32). Previous findings (25, 26) indicate that the concentration of circulating free fatty acid of the insulin-resistant obese Zucker rat is about two- to threefold higher than the value seen in the insulin-sensitive lean Zucker rat. In addition, we have shown in the present study that the triglyceride concentration in the insulin-resistant soleus muscle of the obese Zucker rat is also threefold higher than that in the soleus muscle of the lean Zucker rat (Fig. 5). Moreover, we have demonstrated that the triglyceride concentration in the obese soleus can be significantly reduced by exercise training or by R-ALA treatment (Fig. 5). These observations provide further support for the concept that elevated tissue triglyceride accumulation and systemic free fatty acids can negatively modulate skeletal muscle insulin action in the obese Zucker rat. However, because there was no further decrease in muscle triglyceride in the combined-treatment group, it is clear that the additional improvement in insulin action on glucose transport activity in this group was due to factors other than the triglyceride concentration.
Because of the multifactorial etiology of insulin resistance of skeletal muscle glucose transport and metabolism, it is unlikely that a single intervention in isolation will be adequate to bring about normalization of insulin action. The present investigation is one of several using obese Zucker rats demonstrating that exercise training combined with a pharmaceutical or nutriceutical intervention can improve whole body and skeletal muscle insulin action to a greater extent than can the individual treatments. Essentially additive interactions for improvement of insulin action in the obese Zucker rat have been demonstrated between exercise training and angiotensin-converting enzyme inhibitors (28), exercise training and thiazolidinediones (16), and exercise training and the antioxidant R-ALA (25, and the present study). An important goal of future investigations will be to determine whether these beneficial interactions seen in this animal model can be realized in clinical trials using human subjects with insulin resistance and type 2 diabetes.
In conclusion, we have demonstrated that 2 wk of exercise training alone or 2 wk of treatment with the antioxidant R-ALA in insulin-resistant obese Zucker rats causes improvements in insulin action on skeletal muscle glucose transport activity, and that these improvements in insulin action are associated with increases in insulin receptor tyrosine phosphorylation, IRS-1 protein expression, and IRS-1-associated p85 subunit of PI 3-kinase and with a decrease in triglyceride concentration. Most importantly, the combination of exercise training and antioxidant treatment in the obese Zucker rat resulted in the greatest enhancement of muscle insulin-mediated glucose transport activity, likely due to further enhancements of IRS-1 protein expression and insulin-mediated IRS-1-associated p85. These results further underscore the utility of a combination therapy involving endurance exercise training and a pharmaceutical intervention, including the antioxidant R-ALA, in beneficially modulating the molecular defects in insulin action observed in skeletal muscle of the obese Zucker rat.
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GRANTS |
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ACKNOWLEDGMENTS |
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-lipoic acid. |
FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes 45: 1798–1804, 1996.
-lipoic acid of glucose transport activity in skeletal muscle of lean and obese Zucker rats. Life Sci 61: 805–812, 1997.
-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. Diabetes 45: 1024–1029, 1996.
-Lipoic acid as a biological antioxidant. Free Rad Biol Med 19: 227–250, 1995.
-lipoic acid on glucose transport in obese Zucker rat. J Appl Physiol 91: 145–153, 2001.
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