To better understand how insulin resistance develops, a variety of models have been utilized. The high fat fed rodent model displays many commonalities to the abdominal obesity syndrome found in insulin resistant adults. However, the basis of skeletal muscle insulin resistance in this model is unclear due to reports that PI 3-kinase activity is decreased, and equivocal if Akt activation, atypical Protein Kinase C phosphorylation, GLUT4 protein concentration and GLUT4 translocation are altered. The insulin signaling cascade and glucose transporter effector system is considerably more complex than what has been previously evaluated and more importantly, the mechanism by which high fat feeding induces these alterations has not been addressed. In addition, while skeletal muscle insulin resistance can be reversed, the basis for these improvements in a high fat fed rodent model have not been fully elucidated. Therefore, the aims of this proposal are to determine: 1) the mechanism of chronic high fat feeding induced skeletal muscle insulin resistance, how the defects are manifested in the insulin signaling cascade and glucose transporter effector system and if the IkB-alpha pathway contributes to the development of skeletal muscle insulin resistance and 2) if those factors associated with high fat feeding-induced skeletal muscle insulin resistance can be corrected or if improvements in insulin-stimulated glucose transport result from a compensatory mechanism. The resolution of these issues has implications for advancing our understanding of how dietary composition induces impairments in carbohydrate metabolism and how skeletal muscle insulin resistance can be corrected. ? ?
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