Physiology - Theses
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ItemExercise and GLUT4 expression in type 2 diabetes( 2010)Peripheral insulin resistance is characterised by reduced insulin-stimulated glucose uptake in skeletal muscle and adipose tissue, and the condition represents one of the earliest hallmarks in the development of type 2 diabetes (T2D). In patients with T2D, protein expression of the insulin-stimulated glucose transporter, GLUT4, is reduced in adipose tissue, but preserved in skeletal muscle. Transgenic studies in rodents provide evidence that overexpression of GLUT4 selectively in either skeletal muscle or adipose tissue enhances whole-body insulin action. Since skeletal muscle accounts for the majority of insulin-stimulated glucose disposal, the effect of adipose tissue GLUT4 on insulin sensitivity is thought to be secondary to an altered secretion of adipokines which affect insulin action in muscle, in the context of a ‘metabolic crosstalk’ between insulin sensitive tissues. Increasing GLUT4 expression in skeletal muscle and adipose tissue could be an effective therapy in the treatment of insulin resistance and T2D. Exercise training increases GLUT4 protein expression in skeletal muscle of patients with T2D. This adaptation occurs in the face of enhanced insulin sensitivity, and results from the cumulative and transient increase in GLUT4 mRNA following each acute exercise bout. Less is known regarding the regulation of skeletal muscle GLUT4 expression by a single bout of exercise in patients with T2D, or the effect of exercise training on GLUT4 expression in adipose tissue. The primary aim of the studies undertaken for this thesis was to enhance understanding of exercise-mediated GLUT4 expression in skeletal muscle and adipose tissue of patients with T2D. The first investigation determined the effect of a single bout of exercise on skeletal muscle GLUT4 mRNA, and the signalling pathways which regulate GLUT4 expression, in patients with T2D and healthy control volunteers, matched for age and BMI. Increased (p<0.05) expression of GLUT4 and PGC-1α mRNA, together with increased (p<0.05) phosphorylation of AMPK and p38 MAPK was observed following exercise in patients with T2D, to a similar extent as in age- and BMI-matched control subjects. These findings lead to the conclusion that exercise-mediated regulation of GLUT4 expression is normal in patients with T2D. The second investigation of this thesis sought to identify the effect of a 4 week exercise training program on skeletal muscle and adipose tissue GLUT4 expression in patients with T2D. It was found that exercise training increased (p<0.05) GLUT4 protein expression by ~36% and ~20% in adipose tissue and skeletal muscle, respectively. These adaptations occurred in the absence of changes in insulin sensitivity or plasma levels of adipokines, adiponectin and resistin. Accordingly, the third study of this thesis sought to identify novel adipokines that regulate peripheral glucose metabolism in an adipocyte model of GLUT4 overexpression. Amyloid precursor protein (APP) was reduced (p<0.05) in culture media of GLUT4 overexpressing adipocytes, and the APP cleavage product, amyloid-beta (Aβ), reduced (p<0.05) insulin-stimulated Akt phosphorylation in L6 myocytes in vitro. These observations lead to the conclusion that increased adipose tissue GLUT4 expression may influence whole body glucose metabolism through reduced levels of Aβ. The primary aim of the final study undertaken was to identify novel changes in the abundance of proteins in skeletal muscle following exercise training in patients with T2D, including proteins of glucose metabolism, which may regulate of GLUT4 expression. Exercise training altered the abundance of several proteins involved in energy metabolism, as well as some novel proteins which may play a role in cytoskeleton interactions with mitochondria. In summary, this thesis demonstrated that skeletal muscle from patients with T2D responds normally to an acute exercise bout in terms of increased GLUT4 mRNA expression. In addition, it was shown that exercise training increased GLUT4 protein expression, not only in skeletal muscle, but also in adipose tissue of patients with T2D. This is significant because adipose tissue GLUT4 overexpression enhances insulin sensitivity. Data from this thesis suggest that improvements in insulin sensitivity may be secondary to altered secretion of Aβ from adipose tissue. Collectively, the findings provide a number of therapeutic targets for the treatment of insulin resistance and T2D.