Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart.
OBJECTIVE
Many patients with heart failure have whole-body insulin resistance and reduced cardiac fluorodeoxyglucose uptake, but whether these metabolic changes have detrimental effects on the heart is unknown. Here, we tested whether there is a link between insulin resistance and ischemic damage in the chronically infarcted Wistar rat heart, postulating that the heart would have decreased insulin sensitivity, with lower GLUT4 glucose transporter protein levels due to high circulating free fatty acid (FFA) concentrations. A decreased capacity for glucose uptake would lower glycolytic adenosine triphosphate (ATP) production and thereby increase ischemic injury in the infarcted heart.


RESULTS
In vivo left ventricular ejection fractions, measured using echocardiography, were 40% lower in rats 10 weeks after coronary artery ligation than in sham-operated control rats. Insulin-stimulated D[2-3H]glucose uptake was 42% lower in isolated, perfused, infarcted hearts. Myocardial GLUT4 glucose transporter protein levels were 28% lower in the infarcted hearts and correlated negatively with ejection fractions and with fasting plasma FFA concentrations. Compared with controls, chronically infarcted hearts had 46% lower total glucose uptake and three-fold faster ATP hydrolysis rates, measured using phosphorus-31 nuclear magnetic resonance spectroscopy, during 32-min ischemia at 0.4 ml/min/gww. During reperfusion, recovery of left ventricular developed pressure in infarcted hearts was 42% lower than in control hearts.


CONCLUSIONS
Glucose uptake, in response to insulin or ischemia, was lower in the chronically infarcted rat heart and associated with increased circulating FFA concentrations and decreased GLUT4 levels. Thus, infarcted hearts had greater ATP depletion, and consequently incurred greater damage, during ischemia.
Murray
Andrew J
AJ
University Laboratory of Physiology, University of Oxford, Parks Rd., Oxford, OX1 3PT, England, UK. andrew.murray@physiol.ox.ac.uk
Lygate
Craig A
CA
Cole
Mark A
MA
Carr
Carolyn A
CA
Radda
George K
GK
Neubauer
Stefan
S
Clarke
Kieran
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004452:Echocardiography; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D007328:Insulin; D000255:Adenosine Triphosphate; D006003:Glycogen; D005947:Glucose