It is well documented that obesity is associated with resistance to insulin-stimulated glucose uptake and may ultimately lead to the development of non-insulin-dependent diabetes. As over 80 percent of insulin-stimulated glucose clearance is mediated by skeletal muscle, it is of importance to evaluate interventions that may improve insulin action in skeletal muscle. Recently, leptin, the product of the ob gene, has been shown to reduce fat mass, hyperglycemia and hyperinsulinemia. Of particular interest, chronic leptin administration increases insulin-stimulated glucose uptake and transport in normal rat skeletal muscle. However, it is unknown if chronic leptin administration improves insulin-stimulated glucose uptake and transport in insulin-resistant skeletal muscle. Therefore, the aims of the present investigation are to determine whether chronic leptin administration improves whole body glucose tolerance in an insulin-resistant rodent model, whether chronic leptin administration improves insulin-stimulated skeletal muscle glucose uptake and transport in insulin-resistant skeletal muscle and whether the improvements in leptin-treatment insulin-resistant skeletal muscle result from alterations in enzymatic activity, glycogen concentration and/or GLUT4 protein. Additionally, it will be determined if chronic leptin administration alters the subcellular distribution of GLUT4, insulin-stimulated translocation of the GLUT4 protein and if improvements in leptin-treatment Insulin-resistant skeletal muscle may also result from alterations in insulin stimulated IRS-1-associated P1 3-klnase activity.
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