SUBSTRATE AUTOREGULATION OF GLUCOSE-TRANSPORT - HEXOSE 6-PHOSPHATE MEDIATES THE CELLULAR-DISTRIBUTION OF GLUCOSE TRANSPORTERS

Exposure of rat skeletal muscle and skeletal muscle cell lines to high glucose levels results in a time- and dose-dependent reduction of the rate of hexose uptake, paralleled by a reduction in the plasma membra ne density of glucose transporters, The mechanism of this process was investigated in cultured L8 myocytes, Low concentrations (0.5-2.0 mmol /l) of deoxyglucose mimicked the downregulatory action of 20 mmol/l gl ucose both regarding the time-course and magnitude of the effect, but in an irreversible manner. A dose-dependent relationship between intra cellular accumulation of deoxyglucose 6-phosphate and the magnitude of the downregulatory response was observed. Depletion of intracellular deoxyglucose 6-phosphate restored the rate of hexose transport to the control level. The reduction of hexose transport activity by deoxygluc ose occurred independently of ATP depletion which by itself produced t he opposite effect. The effects of deoxyglucose and high glucose on he xose transport were associated with reduced transport maximal velocity and GLUT1 transporter abundance in the plasma membranes of myocytes, as assessed by cell surface biotinylation. The reduction of myocyte GL UT1 mRNA content, observed after exposure to high glucose, did not acc ompany the transport downregulatory action of deoxyglucose. We suggest that hexose 6-phosphate is the mediator of the downregulatory signal for subcellular redistribution of GLUT1 in L8 myocytes. The signal res ponsible for reducing the GLUT1 mRNA level may be related to glucose m etabolites downstream of the hexokinase reaction.