Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart
E. Dale Abel, … , Joanne S. Ingwall, Barbara B. Kahn
E. Dale Abel, … , Joanne S. Ingwall, Barbara B. Kahn
Published December 15, 1999
Citation Information: J Clin Invest. 1999;104(12):1703-1714. https://doi.org/10.1172/JCI7605.
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Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart

Abstract

Glucose enters the heart via GLUT1 and GLUT4 glucose transporters. GLUT4-deficient mice develop striking cardiac hypertrophy and die prematurely. Whether their cardiac changes are caused primarily by GLUT4 deficiency in cardiomyocytes or by metabolic changes resulting from the absence of GLUT4 in skeletal muscle and adipose tissue is unclear. To determine the role of GLUT4 in the heart we used cre-loxP recombination to generate G4H–/– mice in which GLUT4 expression is abolished in the heart but is present in skeletal muscle and adipose tissue. Life span and serum concentrations of insulin, glucose, FFAs, lactate, and β-hydroxybutyrate were normal. Basal cardiac glucose transport and GLUT1 expression were both increased approximately 3-fold in G4H–/– mice, but insulin-stimulated glucose uptake was abolished. G4H–/– mice develop modest cardiac hypertrophy associated with increased myocyte size and induction of atrial natriuretic and brain natriuretic peptide gene expression in the ventricles. Myocardial fibrosis did not occur. Basal and isoproterenol-stimulated isovolumic contractile performance was preserved. Thus, selective ablation of GLUT4 in the heart initiates a series of events that results in compensated cardiac hypertrophy.

Authors

E. Dale Abel, Helen C. Kaulbach, Rong Tian, James C.A. Hopkins, John Duffy, Thomas Doetschman, Timo Minnemann, Mary-Ellen Boers, Ed Hadro, Corinna Oberste-Berghaus, William Quist, Bradford B. Lowell, Joanne S. Ingwall, Barbara B. Kahn

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Evidence for impaired GLUT4-mediated glucose uptake in GLUT4-ablated hea...
Evidence for impaired GLUT4-mediated glucose uptake in GLUT4-ablated hearts. (a) Representative 31P NMR spectra in wild-type and G4H–/– hearts, illustrating absence of insulin-mediated augmentation of 2-DG-P accumulation in GLUT4-deficient hearts. The decline in phosphocreatine (PCr) after insulin stimulation in wild-type mice probably represents transfer of phosphates to 2-DG-P. PPA, phenylphosphonic acid standard; Pi, inorganic phosphate. γ, α, and β represent the 3 phosphates on adenosine in ATP. (b) Basal and insulin-stimulated 2-DG uptake in wild-type and G4H–/– mice. Bars represent mean ± SEM; individual data points are illustrated by the closed circles. Number of animals in each group: Wild-type males: basal, n = 5; insulin-stimulated (Ins), n = 5. G4H–/– males: basal, n = 4; insulin-stimulated, n = 3. Wild-type females: basal, n = 5; insulin-stimulated, n = 5. G4H–/– females: basal, n = 5; insulin-stimulated, n = 5. *P < 0.05 vs. wild-type basal of either sex (ANOVA). ‡‡P < 0.0001, **P < 0.004 vs. wild-type basal of the same sex (paired 2-tailed t test).