Regulation of GLUT2 glucose transporter expression in liver by thyroid hormone: evidence for hormonal regulation of the hepatic glucose transport system.

The extent to which the glucose transport system in hepatocytes is regulated in states of altered hepatic glucose metabolism is unclear. Because thyroid hormone is known to increase hepatic glucose output, we hypothesized that thyroid hormone might up-regulate expression of the principal hepatic glucose transporter, GLUT2, facilitating increased glucose efflux across the hepatocyte plasma membrane. GLUT2 protein concentration in crude liver membranes was twice as high in chronically hyperthyroid vs. hypothyroid animals, with intermediate levels in euthyroid controls. Similar results were obtained for total GLUT2 protein, measured in detergent extracts of liver. Northern analysis of total liver RNA demonstrated parallel changes in GLUT2 messenger RNA (mRNA) concentration per g tissue (hypothyroid, 76 +/- 6%; euthyroid, 100 +/- 11%; hyperthyroid, 158 +/- 12%; data expressed as percentage of mean euthyroid values). The daily administration of a large dose of T3 (100 micrograms/100 g BW) to hypothyroid rats caused a prompt increase in hepatic GLUT2 mRNA concentration (2.5-fold at 1 day), but only a modest and gradual change in hepatic GLUT2 protein concentration (+40% at 4 days), suggesting that the GLUT2 protein in liver may have a long half-life. We conclude that thyroid hormone regulates hepatic GLUT2 mRNA and protein expression. Up-regulation of GLUT2 protein expression by thyroid hormone may serve to facilitate increased hepatic glucose output. These results suggest that the hepatic GLUT2 glucose transporter, like the enzymes of gluconeogenesis and glycolysis, is indeed a regulatory target for hormones that control hepatic glucose metabolism.