© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy
aCardiovascular Research Institute and the Department of Medicine, Allegheny General Hospital, 320 East North Ave., Pittsburgh, PA 15212, USA
bUniversity of Massachusetts Medical Center, Worcester, MA 02114, USA
cMerck Research Laboratories, West Point, PA 19486, USA
* Corresponding author. Tel.: +1-412-359-3022; fax: +1-412-359-8152. rshannon{at}wpahs.org
Background: The failing heart demonstrates a preference for glucose as its metabolic substrate. Advanced, severe DCM is characterized by depletion of adenosine triphosphate (ATP) stores, which may be a consequence of impaired insulin mediated glucose uptake and oxidation at a time when the myocardium prefers glucose as its substrate. We examined the time course and magnitude of myocardial insulin resistance during the evolution of dilated cardiomyopathy. Methods and results: Thirty-four conscious, chronically instrumented dogs were studied at four stages during the evolution of dilated cardiomyopathy (DCM) induced by rapid RV pacing [control, early, late and advanced severe]. Transmyocardial glucose, lactate, and non-esterified fatty acid (NEFA) concentrations were measured in the fasting state. The cellular insulin signaling cascade and ATP levels were measured on myocardial samples. NEFA and insulin concentrations increased early and progressively in DCM in association with increased norepinephrine concentrations and progressive hemodynamic impairment. In advanced DCM but not earlier stages, myocardial ATP levels were decreased by 34%. There was decreased myocardial glucose uptake evident under both basal (–29±5%) and insulin stimulated (–32±4%) conditions in advanced, severe DCM, associated with a 31% reduction in GLUT-4 translocation. Importantly, there were no alterations in proximal steps in insulin signaling, but significant reductions in serine (Ser473) phosphorylation of Akt-1. Conclusions: Advanced, severe DCM is associated with the development of myocardial insulin resistance. There is impaired myocardial glucose uptake and altered myocardial insulin signaling, involving decreased Ser 473 phosphorylation of Akt-1. Myocardial insulin resistance in advanced, severe DCM was also associated with reduced myocardial ATP levels.
KEYWORDS Insulin resistance; NEFA; Norepinephrine; Dilated cardiomyopathy; Akt-1; GLUT-4
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