Early acarbose treatment ameliorates resistance of insulin-regulated GLUT4 trafficking in obese Zucker rats.
Genetically (fa/fa) obese Zucker rats represent an established model of impaired glucose tolerance, with profound insulin resistance. Acarbose, an inhibitor of alpha-glucosidases, attenuates postprandial blood glucose peaks, and improves glucose tolerance in these animals. In the present study, we have tested the hypothesis that the effect of acarbose is associated with improved glucose transporter isoform 4 (GLUT4) trafficking in muscle tissue. Acarbose was administered to Zucker rats as a dietary admix (40 mg/100 g diet) for 12 weeks starting at the age of 6 weeks. Serum insulin and leptin were reduced by acarbose from 44 to 19 and 144 to 62 ng/ml, respectively. Glucose tolerance test was performed by i.v. injection of glucose (1 g/kg) and determination of serum glucose up to 60 min. Marked impaired glucose tolerance was observed in obese animals with a profound correction of this defect in acarbose-treated rats. Insulin-regulated translocation of GLUT4 to the plasma membrane in soleus muscle was increased twofold in lean animals, with a totally blunted response in obese rats. Acarbose feeding restored a 1.6-fold effect of insulin on GLUT4 translocation. The exocytotic GLUT4 storage pool in cardiac muscle was completely insulin-insensitive in obese animals, with a largely improved response after acarbose feeding. Activation of Akt, an insulin signaling event upstream of GLUT4, was completely normalized in acarbose-treated rats. In conclusion, we show here that early application of acarbose to obese Zucker rats can prevent the development of impaired glucose tolerance and obesity-associated insulin resistance at the level of the muscle cell, as reflected by an amelioration of defective GLUT4 trafficking in both cardiac and skeletal muscles.
Ledwig
Daniela
D
Molecular Cardiology, German Diabetes Research Institute, Auf'm Hennekamp 65, D-40225 Düsseldorf, Germany.
Müller
Heidi
H
Bischoff
Hilmar
H
Eckel
Jürgen
J
D020909:Acarbose / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; D020909:Acarbose