The studies proposed in this application are aimed at obtaining a more complete understanding of the mechanism of regulation of cellular glucose transport by thyroid and glucocorticoid hormones. The applicant has begun to test the hypothesis that the regulation of glucose transport by thyroid hormone occurs at the level of glucose transporter gene expression. Initial studies by the applicant have demonstrated that thyroid hormone increases the abundance of glucose transporter mRNA and protein in the cultured cell line, ARL 15, to the same extent that it increases glucose uptake. To define the mechanism subserving this effect, the applicant will measure and compare the rates of transcription of the erythroid-type glucose transporter gene expressed in these, cells before and after thyroid hormone treatment using the nuclear """"""""run-on"""""""" technique, and will compare the rates of degradation of this mRNA using the using a [3H] -uridine pulse/chase technique. The applicant has extended these cell culture studies to in vivo studies in the rat, showing that thyroid hormone increases muscle/fat-type (""""""""insulin-responsive"""""""") glucose transporter mRNA and protein in skeletal muscle, the major site of insulin-stimulated glucose uptake in vivo. By examining the effects of hypo-, eu-, and hyperthyroidism on glucose transporter mRNA levels, basal and insulin-stimulated glucose uptake, and insulin-induced recruitment of glucose transporters to the plasma membrane in perfused skeletal muscle, the applicant plans to test the hypothesis that regulation of expression of the muscle/fat-type glucose transporter gene by thyroid hormone regulates the ability of insulin to stimulate glucose uptake into skeletal muscle. Other studies will determine the effect of glucocorticoid on muscle/fat-type glucose transporter gene expression. These studies will explore the potential role of regulation of glucose transporter gene expression by thyroid hormone as a pace-setter for glucose utilization and metabolic rate, and, by demonstrating the relationship between glucose transporter gene expression and insulin responsiveness in skeletal muscle, may eventually lead to new therapeutic strategies in the treatment of patients with various forms of insulin resistance.
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