Direct effects of glimepiride on protein expression of cardiac glucose transporters.
Freshly isolated rat cardiomyocytes, primary cultured cardiomyocytes and the cardiac cell line H9c2 were used to elucidate acute and chronic effects of the sulfonylurea glimepiride on basal and insulin-stimulated glucose uptake and on the expression of the transporter isoforms GLUT1 and GLUT4. Initial rates of 3-O-methylglucose transport in freshly isolated cardiocytes were not acutely affected by glimepiride (100 microM) both in the absence or presence of insulin (10(-7)M). Cells were then transferred to a serum-free culture for 20 h in the presence of glimepiride and a physiological insulin dose. Under these conditions the sulfonyl urea induced a dose-dependent increase in 2-deoxyglucose uptake reaching 186% of control at 10 microM glimepiride, an effect that could also be demonstrated in the absence of insulin during the culture period. Acute stimulation of glucose transport by insulin was additive to the effect of glimepiride and the insulin responsiveness of glucose transport remained unaltered in sulfonylurea treated cultures. Western blot analysis was then performed on crude membrane fractions obtained from primary cultured cardiocytes and H9c2 myotubes (14 days glimepiride). In the former cells the sulfonylurea increased the expression of both GLUT1 and GLUT4 to 164 +/- 21 and 148 +/- 5% of control, respectively. In the myotubes a large, stable increase of GLUT1 could be detected. It is concluded that glimepiride increases cardiac glucose uptake by an insulin-independent pathway most probably involving an increased protein expression of GLUT1 and GLUT4. The increased expression of glucose transporters may have therapeutic impact for the treatment of insulin resistant states and may be beneficial for the diabetic heart.
Laboratory of Molecular Cardiology, Diabetes Research Institute, Düsseldorf, Germany.
J
J
Eckel
D019325:3-O-Methylglucose / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; D013453:Sulfonylurea Compounds; D019325:3-O-Methylglucose; C057619:glimepiride