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Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart.
Cardiovasc Res. 2006 Jul 01; 71(1):149-57.CR

Abstract

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.

METHODS AND 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.

Authors+Show Affiliations

University Laboratory of Physiology, University of Oxford, Parks Rd., Oxford, OX1 3PT, England, UK. andrew.murray@physiol.ox.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16616054

Citation

Murray, Andrew J., et al. "Insulin Resistance, Abnormal Energy Metabolism and Increased Ischemic Damage in the Chronically Infarcted Rat Heart." Cardiovascular Research, vol. 71, no. 1, 2006, pp. 149-57.
Murray AJ, Lygate CA, Cole MA, et al. Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart. Cardiovasc Res. 2006;71(1):149-57.
Murray, A. J., Lygate, C. A., Cole, M. A., Carr, C. A., Radda, G. K., Neubauer, S., & Clarke, K. (2006). Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart. Cardiovascular Research, 71(1), 149-57.
Murray AJ, et al. Insulin Resistance, Abnormal Energy Metabolism and Increased Ischemic Damage in the Chronically Infarcted Rat Heart. Cardiovasc Res. 2006 Jul 1;71(1):149-57. PubMed PMID: 16616054.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart. AU - Murray,Andrew J, AU - Lygate,Craig A, AU - Cole,Mark A, AU - Carr,Carolyn A, AU - Radda,George K, AU - Neubauer,Stefan, AU - Clarke,Kieran, Y1 - 2006/03/10/ PY - 2005/11/10/received PY - 2006/02/13/revised PY - 2006/02/28/accepted PY - 2006/4/18/pubmed PY - 2007/3/30/medline PY - 2006/4/18/entrez SP - 149 EP - 57 JF - Cardiovascular research JO - Cardiovasc Res VL - 71 IS - 1 N2 - 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. METHODS AND 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. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/16616054/Insulin_resistance_abnormal_energy_metabolism_and_increased_ischemic_damage_in_the_chronically_infarcted_rat_heart_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1016/j.cardiores.2006.02.031 DB - PRIME DP - Unbound Medicine ER -