Regulation of the GLUT4/muscle-fat glucose transporter mRNA in adipose tissue of insulin-deficient diabetic rats.

Previous studies have documented that streptozotocin-induced insulin deficiency results in a marked decrease in adipose tissue GLUT4 glucose transporter mRNA levels (Sivitz, W.I., DeSautel, S.L., Kayano, T., Bell, G.I., and Pessin, J.E. (1989) Nature 340, 72-74). In this study, nuclear run-on analysis performed on diabetic and insulin-treated diabetic rats demonstrated that the decrease in GLUT4 mRNA occurs via a diabetes-induced decrease in GLUT4 transcription rate. The decrease in GLUT4 mRNA levels could be prevented by treatment of the diabetic animals with the adenosine receptor agonist phenylisopropyl-adenosine (PIA). Under these conditions, PIA completely blocked the elevation of intracellular cAMP levels associated with insulin deficiency. Surprisingly, isolation of primary rat adipocytes from control animals resulted in a rapid decrease (approximately 20-fold) in GLUT4 mRNA levels by 24 h with a concomitant increase (approximately 70-fold) in GLUT1 mRNA levels. This rapid loss of GLUT4 expression did not correlate with changes in adipocyte cAMP levels and was not prevented by treatment of the cells with either insulin and/or PIA. These data demonstrate that the decrease in GLUT4 transcription induced by insulin deficiency in vivo predominantly results from an increase in intracellular cAMP levels. In contrast, although GLUT4 transcription also decreases in adipocytes when removed from their normal physiological environment, this occurs independent of changes in cAMP levels.