Exercise training improves skeletal muscle insulin sensitivity in the obese Zucker rat. The purpose of this study was to investigate whether the improvement in insulin action in response to exercise training is associated with enhanced insulin receptor signaling. Obese Zucker rats were trained for 7 wk and studied by using the hindlimb-perfusion technique 24 h, 96 h, or 7 days after their last exercise training bout. Insulin-stimulated glucose uptake (traced with 2-deoxyglucose) was significantly reduced in untrained obese Zucker rats compared with lean controls (2.2 +/- 0.17 vs. 5.4 +/- 0.46 micromol x g(-1) x h(-1)). Glucose uptake was normalized 24 h after the last exercise bout (4.9 +/- 0.41 micromol x g(-1) x h(-1)) and remained significantly elevated above the untrained obese Zucker rats for 7 days. However, exercise training did not increase insulin receptor or insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, phosphatidylinositol 3-kinase (PI3-kinase) activity associated with IRS-1 or tyrosine phosphorylated immunoprecipitates, or Akt serine phosphorylation. These results are consistent with the hypothesis that, in obese Zucker rats, adaptations occur during training that lead to improved insulin-stimulated muscle glucose uptake without affecting insulin receptor signaling through the PI3-kinase pathway.

We compared the chronic effect of intermittent hypoxia and endurance training on the glucose tolerance and GLUT4 protein expression in rat skeletal muscle. Thirty-two Sprague-Dawley rats were matched for weight and assigned to one of the following four groups: control, endurance training, hypoxia, or hypoxia followed by endurance training. Hypoxic treatment consisted of breathing 14% O2 for 12 h/day under normobaric conditions, and the training protocol consisted of making animals swim 2 times for 3 h/day. At the end of the 3rd week, an oral glucose tolerance test (OGTT) was performed 16 h after treatments. At the end of the 4th week, GLUT4 protein, mRNA, and glycogen storage in skeletal muscle were determined. Endurance training significantly improved OGTT results. Glycogen content and GLUT4 protein expression in the plantaris and red gastrocnemius, but not in the soleus or white gastrocnemius muscles, were also elevated. Chronic intermittent hypoxia also improved OGTT results, but did not alter GLUT4 protein expression. Additionally, hypoxia followed by exercise training produced significant increases in GLUT4 protein and mRNA in a greater number of muscles compared to endurance training alone. Both exercise training and hypoxia significantly reduced body mass, and an additive effect of both treatments was found. In conclusion, chronic intermittent hypoxia improved glucose tolerance in the absence of increased GLUT4 protein expression. This treatment facilitated the exercise training effect on muscle GLUT4 expression and glycogen storage. These new findings open the possibility of utilizing intermittent hypoxia, with or without exercise training, for the prevention and clinical treatment of type 2 diabetes or insulin resistance.

The ubiquitously expressed G protein alpha-subunit G(s)alpha is required for receptor-stimulated intracellular cAMP responses and is an important regulator of energy and glucose metabolism. We have generated skeletal muscle-specific G(s)alpha-knockout (KO) mice (MGsKO) by mating G(s)alpha-floxed mice with muscle creatine kinase-cre transgenic mice. MGsKO mice had normal body weight and composition, and their serum glucose, insulin, free fatty acid, and triglyceride levels were similar to that of controls. However, MGsKO mice were glucose intolerant despite the fact that insulin sensitivity and glucose-stimulated insulin secretion were normal, suggesting an insulin-independent mechanism. Isolated muscles from MGsKO mice had increased basal glucose uptake and normal responses to a stimulator of AMP-activated protein kinase (AMPK), which indicates that AMPK and its downstream pathways are intact. Compared with control mice, MGsKO mice had reduced muscle mass with decreased cross-sectional area and force production. In addition, adult MGsKO mice showed an increased proportion of type I (slow-twitch, oxidative) fibers based on kinetic properties and myosin heavy chain isoforms, despite the fact that these muscles had reduced expression of peroxisome proliferator-activated receptor coactivator protein-1alpha (PGC-1alpha) and reduced mitochondrial content and oxidative capacity. Therefore G(s)alpha deficiency led to fast-to-slow fiber-type switching, which appeared to be dissociated from the expected change in oxidative capacity. MGsKO mice are a valuable model for future studies of the role of G(s)alpha signaling pathways in skeletal muscle adaptation and their effects on whole body metabolism.

The effects of exercise training on cell surface GLUT-4 in skeletal muscle of the obese (fa/fa) Zucker rat were investigated using the impermeant glucose transporter photoaffinity reagent 2-N-4-(1-azi-2,2,2-trifluoroethyl)-benzoyl-1,3-bis- (D-mannos-4-yloxy)-2-propylamine (ATB-BMPA). In the absence of insulin, 3-O-methyl-D-glucose transport activity was no different in either fast-twitch (epitrochlearis) or slow-twitch (soleus) muscles of trained and sedentary obese rats. Likewise, basal ATB-BMPA-labeled GLUT-4 was not altered in these muscles with training. In contrast, the trained group exhibited significantly greater insulin-stimulated (2 mU/ml) glucose transport activity in epitrochlearis muscles than the sedentary group (0.53 +/- 0.03 vs. 0.18 +/- 0.03 mumol.g-1 x 10 min-1 for trained and sedentary, respectively), which was paralleled by a significant enhancement of insulin-stimulated cell surface GLUT-4 (5.33 +/- 0.20 vs. 1.57 +/- 0.14 disintegrations.min-1.mg-1 for trained and sedentary, respectively). Exercise training, however, did not alter insulin-stimulated glucose transport activity or cell surface GLUT-4 in soleus muscles. Finally, exercise training did not alter the ability of muscle contraction to elevate glucose transport activity or cell surface GLUT-4 in either epitrochlearis or soleus muscles of the obese rat. These results indicate that training improves insulin-stimulated glucose transport in muscle of the obese Zucker rat by increasing GLUT-4 content and by altering the normal intracellular distribution of these transporters such that they are now capable of migrating to the cell surface in response to the insulin stimulus.