ABSTRACT
Correspondence should be addressed to E.D.A; (e-mail dale.abel@hmbg.utah.edu).
SUMMARY
Glucose enters the heart via two facilitative transport proteins GLUT1 and GLUT4. GLUT4 is the most abundant isoform in the heart and is known to translocate to the plasma membrane in response to insulin, hypoxia and ischemia (Mueckler, 1990; Slot et al., 1991; Sun et al., 1994). Mice which lack GLUT4 in all tissues develop striking cardiac hypertrophy and die prematurely (Katz et al., 1995). It is uncertain if the cardiac phenotype reflects the impact of GLUT4 deficiency or is secondary to changes in the supply of cardiac metabolic substrates which result from absence of the transporter in skeletal muscle and adipose tissue. Therefore to clarify the role of GLUT4 on cardiac function in vivo, cre-loxP recombination has been utilized to generate mice with selective inactivation of GLUT4 in the heart. In these mice with GLUT4 expression in adipose tissue and skeletal muscle there are normal concentrations of insulin, and key cardiac metabolic substrates such as free fatty acids, lactate and ß hydroxy butyrate. Glucose tolerance is normal and the mice exhibit a normal lifespan. Basal glucose uptake and GLUT1 expression was increased 2-4 fold in knockout mice, but insulin mediated glucose transport is completely abolished. Despite the absence of GLUT4, contractile function is preserved and the marked hypertrophy observed in GLUT4 null mice is greatly attenuated. The absence of GLUT4 leads to increased susceptibility of the heart to ischemic injury.
