Effects of diabetes on myocardial glucose transport system in rats: implications for diabetic cardiomyopathy.
Biochemical mechanisms underlying impaired myocardial glucose utilization in diabetes mellitus have not been elucidated. We studied sarcolemmal vesicles (SL) in control, streptozotocin-induced diabetic (D), and insulin-treated diabetic (Tx) rats and found that 3-O-methylglucose transport rates were decreased 53% in D rats and were normalized by insulin therapy. Immunoblot analyses of SL revealed that GLUT4 glucose transporters were decreased 56% in D and were normal in Tx rats. Thus diminished transport rates could be fully explained by reduced numbers of SL GLUT4 with normal functional activity. To determine whether SL GLUT4 were decreased due to tissue depletion or abnormal subcellular distribution, we measured GLUT4 in total membranes (SL plus intracellular fractions). Total GLUT4 (per mg membrane protein or per DNA) was decreased 45-51% in D [half time = 3.5 days after streptozotocin], and these values were restored to normal in Tx rats. Also, diabetes decreased GLUT4 mRNA levels by 43%, and this effect was reversed by insulin therapy. We conclude that, in diabetes, 1) impaired myocardial glucose utilization is the result of a decrease in glucose transport activity, and 2) transport rates are reduced due to pretranslational suppression of GLUT4 gene expression and can be corrected by insulin therapy. GLUT4 depletion could limit glucose availability under conditions of increased workload and anoxia and could cause myocardial dysfunction.
Garvey
W T
WT
Section of Endocrinology, Indianapolis Veterans Administration Medical Center, Indiana.
Hardin
D
D
Juhaszova
M
M
Dominguez
J H
JH
D019325:3-O-Methylglucose; D000818:Animals; D001692:Biological Transport; D009202:Cardiomyopathies / Q000209:etiology*; D002462:Cell Membrane / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D015151:Immunoblotting; D007328:Insulin / Q000627:therapeutic use; D007700:Kinetics; D008297:Male; D008757:Methylglucosides / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000378:metabolism
D051275:Glucose Transporter Type 4; D007328:Insulin; D008757:Methylglucosides; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495694:Slc2a4 protein, rat; D019325:3-O-Methylglucose; D005947:Glucose