REGULATION OF MEMBRANE TRANSPORT BY THYROID HORMONE

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Thyroid hormone stimulates cellular glucose uptake, an effect which is likely to play a key role in the enhancement of metabolic rate by the hormone. In the studies proposed herein the regulation of the glucose transporter gene by thyroid hormone will be examined in a cell culture system (ARL 15, a T3-responsive cell line derived from rat liver), and the in-vivo effects of thyroid hormone on tissue-specific forms of the glucose transporter will be determined. The effects of thyroid hormone on the rate of glucose transporter gene transcription and mRNA stability will be determined in ARL 15 cells, using a cDNA probe for the rat brain type of glucose transporter, whose mRNA is expressed in these cells and is increased by T3. In particular, the hypothesis that T3 may directly regulate glucose transporter gene transcription will be examined. In in-vivo studies in the rat, the effects of thyroid hormone on the expression of three recently described tissue-specific forms of the glucose transporter will be determined in skeletal muscle, heart, and liver. We will directly test the hypothesis that up-regulation of the muscle-type ("insulin-regulatable") glucose transporter gene expression by thyroid hormone is an important determinant of insulin sensitivity. In addition, the mechanism by which T3 regulates the abundance of this protein will be examined at the levels of gene transcription and messenger RNA stability, and the potential regulation of the liver-type transporter will be examined. By linking the stimulation of cellular glucose uptake by thyroid hormone to increased glucose transporter gene transcription, these studies may provide evidence that T3 regulates a gene whose expression is closely related to the enhancement of metabolic rate by thyroid hormone, confirming the importance of the transcriptional pathway of thyroid hormone action, and establishing the basis for future work on the regulation of glucose transporter gene expression. Moreover, the above studies have direct relevance to aspects of human disease, since regulation of the glucose transporter gene may play a role in the pathophysiology of diabetes mellitus, and may serve as a pace-setter for fuel utilization and metabolic rate in specific tissues in starvation and chronic illness.