© 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
Time for primary review 00 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. H. Opie and J. Knuuti The adrenergic-Fatty Acid load in heart failure. J. Am. Coll. Cardiol., October 27, 2009; 54(18): 1637 - 1646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. ALZadjali, V. Godfrey, F. Khan, A. Choy, A. S. Doney, A. K. Wong, J. R. Petrie, A. D. Struthers, and C. C. Lang Insulin resistance is highly prevalent and is associated with reduced exercise tolerance in nondiabetic patients with heart failure. J. Am. Coll. Cardiol., March 3, 2009; 53(9): 747 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Sacca Heart Failure as a Multiple Hormonal Deficiency Syndrome Circ Heart Fail, March 1, 2009; 2(2): 151 - 156. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tuunanen, E. Engblom, A. Naum, K. Nagren, M. Scheinin, B. Hesse, K.E. Juhani Airaksinen, P. Nuutila, P. Iozzo, H. Ukkonen, et al. Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy Circulation, September 16, 2008; 118(12): 1250 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Martins, A. K. G. Vieira, E. P. G. de Souza, and A. S. Moura Early overnutrition impairs insulin signaling in the heart of adult Swiss mice J. Endocrinol., September 1, 2008; 198(3): 591 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Poornima, S. B. Brown, S. Bhashyam, P. Parikh, H. Bolukoglu, and R. P. Shannon Chronic Glucagon-Like Peptide-1 Infusion Sustains Left Ventricular Systolic Function and Prolongs Survival in the Spontaneously Hypertensive, Heart Failure-Prone Rat Circ Heart Fail, September 1, 2008; 1(3): 153 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Witteles and M. B. Fowler Insulin-Resistant Cardiomyopathy: Clinical Evidence, Mechanisms, and Treatment Options J. Am. Coll. Cardiol., January 15, 2008; 51(2): 93 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Saito, D. Fujioka, K.-i. Kawabata, T. Kobayashi, T. Yano, T. Nakamura, Y. Kodama, H. Takano, Y. Kitta, J.-e. Obata, et al. Statin reverses reduction of adiponectin receptor expression in infarcted heart and in TNF-{alpha}-treated cardiomyocytes in association with improved glucose uptake Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3490 - H3497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Neglia, A. De Caterina, P. Marraccini, A. Natali, M. Ciardetti, C. Vecoli, A. Gastaldelli, D. Ciociaro, P. Pellegrini, R. Testa, et al. Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3270 - H3278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Lionetti, L. Guiducci, A. Simioniuc, G. D. Aquaro, C. Simi, D. De Marchi, S. Burchielli, L. Pratali, M. Piacenti, M. Lombardi, et al. Mismatch between uniform increase in cardiac glucose uptake and regional contractile dysfunction in pacing-induced heart failure Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2747 - H2756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bhashyam, P. Parikh, H. Bolukoglu, A. H. Shannon, J. H. Porter, Y.-T. Shen, and R. P. Shannon Aging is associated with myocardial insulin resistance and mitochondrial dysfunction Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3063 - H3071. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sharma, P. H. Guthrie, S. S. Chan, S. Haq, and H. Taegtmeyer Glucose phosphorylation is required for insulin-dependent mTOR signalling in the heart Cardiovasc Res, October 1, 2007; 76(1): 71 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ashrafian, M. P. Frenneaux, and L. H. Opie Metabolic Mechanisms in Heart Failure Circulation, July 24, 2007; 116(4): 434 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Horowitz and J. A. Kennedy Time to Address the Cardiac Metabolic "Triple Whammy": Ischemic Heart Failure in Diabetic Patients J. Am. Coll. Cardiol., December 5, 2006; 48(11): 2232 - 2234. [Full Text] [PDF]
|
|
|
|
|
|
A.-M. Samuelsson, E. Bollano, R. Mobini, B.-M. Larsson, E. Omerovic, M. Fu, F. Waagstein, and A. Holmang Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H787 - H796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Murray, C. A. Lygate, M. A. Cole, C. A. Carr, G. K. Radda, S. Neubauer, and K. Clarke Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart Cardiovasc Res, July 1, 2006; 71(1): 149 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Zhao, P. Parikh, S. Bhashyam, H. Bolukoglu, I. Poornima, Y.-T. Shen, and R. P. Shannon Direct Effects of Glucagon-Like Peptide-1 on Myocardial Contractility and Glucose Uptake in Normal and Postischemic Isolated Rat Hearts J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1106 - 1113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fujioka, K.-i. Kawabata, Y. Saito, T. Kobayashi, T. Nakamura, Y. Kodama, H. Takano, J.-e. Obata, Y. Kitta, K. Umetani, et al. Role of adiponectin receptors in endothelin-induced cellular hypertrophy in cultured cardiomyocytes and their expression in infarcted heart Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2409 - H2416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Nikolaidis, I. Poornima, P. Parikh, M. Magovern, Y.-T. Shen, and R. P. Shannon The Effects of Combined Versus Selective Adrenergic Blockade on Left Ventricular and Systemic Hemodynamics, Myocardial Substrate Preference, and Regional Perfusion in Conscious Dogs With Dilated Cardiomyopathy J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1871 - 1881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Nikolaidis, D. Elahi, Y.-T. Shen, and R. P. Shannon Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2401 - H2408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Golfman, C. R. Wilson, S. Sharma, M. Burgmaier, M. E. Young, P. H. Guthrie, M. Van Arsdall, J. V. Adrogue, K. K. Brown, and H. Taegtmeyer Activation of PPAR{gamma} enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats Am J Physiol Endocrinol Metab, August 1, 2005; 289(2): E328 - E336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. C. Stanley, F. A. Recchia, and G. D. Lopaschuk Myocardial Substrate Metabolism in the Normal and Failing Heart Physiol Rev, July 1, 2005; 85(3): 1093 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. SHARMA, J. V. ADROGUE, L. GOLFMAN, I. URAY, J. LEMM, K. YOUKER, G. P. NOON, O. H FRAZIER, and H. TAEGTMEYER Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart FASEB J, November 1, 2004; 18(14): 1692 - 1700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Taegtmeyer Cardiac Metabolism as a Target for the Treatment of Heart Failure Circulation, August 24, 2004; 110(8): 894 - 896. [Full Text] [PDF]
|
|