Skeletal muscle Na+K+-ATPase function in Type II diabetes

Insulin resistance is a common factor in metabolic disorders, such as obesity and Type II diabetes mellitus. In skeletal muscle, insulin can induce the translocation of both glucose transporters and the α-subunit of the Na+K+-ATPase to the plasma membrane. Whilst the detrimental effects of insulin resistance upon insulin-mediated glucose uptake is well recognized, little is known about the effect on Na+K+-ATPase function and the potential benefits antidiabetic therapies, such as exercise training and Rosiglitazone can have on Na+K+-ATPase function in insulin resistant skeletal muscle. Therefore the primary aim of this dissertation was to determine the effect of insulin resistance on Na+K+-ATPase content and maximal in vitro activity in skeletal muscle and the possible beneficial effects of the insulin sensitising drug, Rosiglitazone and exercise training on Na+K+-ATPase. Since Na+K+-ATPase is a membrane-bound enzyme and its function is dependant upon the membrane lipid milieu surrounding it, a second focus of this thesis was to examine a possible link between changes in enzyme activities and membrane phospholipids. The results of the studies undertaken for this thesis repeatedly demonstrated that insulin resistance has a detrimental effect on Na+K+-ATPase function in skeletal muscle. This was shown in both the genetically predisposed obese Zucker and high fat (HF) diet induced Sprague Dawley rat models of insulin resistance. This may have been due to changes seen in the phospholipid profile however this may depend on the insulin resistant animal model used. The findings indicate compromised Na+K+-ATPase function, causing a reduced reserve for Na+K+-ATPase activation in insulin resistant skeletal muscle. This may predispose diabetics to early muscle fatigue with associated impaired exercise tolerance and may further progress the development of type II diabetes and its associated complications. Despite insulin sensitivity increasing through Rosiglitazone, Na+K+-ATPase activity was reduced in the lean rats only. Rosiglitazone had either no effect on Na+K+-ATPase in skeletal muscle of obese Zucker rats or, its effect was not seen because it was not additive to the decrease already observed with insulin resistance alone. Rosiglitazone treatment also did not have any effect on Na+K+-ATPase function in skeletal muscle of the HF fed rats. The other important finding from this thesis was the positive effect exercise training had on the reduced Na+K+-ATPase capacity found with insulin resistance. For the first time, it was shown that chronic exercise training increased Na+K+-ATPase activity and content, reversing the negative effect of insulin resistance on Na+K+-ATPase function