ACTION OF METFORMIN ON GLUCOSE-TRANSPORT AND GLUCOSE-TRANSPORTER GLUT1 AND GLUT4 IN HEART-MUSCLE CELLS FROM HEALTHY AND DIABETIC RATS

The effects of the antidiabetic drug metformin on glucose transport we re investigated in freshly isolated heart muscle cells from healthy an d streptozotocin-diabetic rats. In vivo treatment of diabetic rats wit h metformin failed to affect the basal and insulin-stimulated rate of glucose transport measured in isolated cells. In vitro exposure to the rapeutic concentrations (less than or equal to 10(-4) M) of metformin did not influence glucose transport, even upon incubation times up to 5 h or in the presence of high glucose (20 mM). In contrast, higher me tformin concentrations produced an 8- to la-fold increase in glucose u ptake (with a lag of 90 min, and a maximum at 180 min and similar to 5 mM). In the presence of submaximal insulin concentrations (less than or equal to 3.10(-10) M), the effects of metformin (5 mM) and of insul in were more than additive, whereas, at saturating insulin concentrati ons (10(-8) M), partial additivity was observed. Like insulin, metform in caused an approximately 1.6-fold increase in the content of both gl ucose transporter isoforms GLUT1 and GLUT4 in the plasma membrane of c ardiac myocytes, with a corresponding decrease in an intracellular mem brane fraction. cAMP-elevating treatments depressed the metformin-, bu t not the insulin-dependent glucose uptake, by 20-30%. In myocytes fro m diabetic rats, the rate of metformin-activated glucose transport was similar to that of cells from control animals, whereas basal and insu lin-stimulated transport were substantially diminished. Finally, metfo rmin (5 mM) induced a slight depression of oxygen consumption and ener gy metabolism of myocytes (as determined by measuring their level of e nergy-rich phosphates) comparable to the effects of hypoxia in rat hea rts. In conclusion, these data do not provide evidence in favor of the hypothesis that glucose uptake by muscle tissue represents the site o f metformin's therapeutic action in vivo. On the other hand, the large , insulin-independent effect of metformin at high concentrations (simi lar to mM) in, vitro may be related to the action of hypoxia and occur s through a redistribution of glucose carriers from an intracellular l ocus to the plasma membrane. The mechanism (or signal) involved in met formin's action is likely to differ from that triggered by insulin and is not impaired in the diabetic state.