Alterations in GLUT4 content has functional and morphological consequences in the heart

Abstract

Due to its prominent role in glucose uptake in the heart, it was hypothesized that the cardiac tissue would be affected by differential expression of GLUT4. Previously, it has been shown that whole body GLUT4 knockouts, GLUT4 null mice, suffer from significant cardiac hypertrophy coincident with interstitial fibrosis.;Interestingly, global ablation of GLUT4 does not diminish cardiac glucose uptake. This appropriate uptake of glucose is not through GLUT4 or the modestly upregulated GLUT1, but through a significant increase in GLUTx1/GLUT8. Both Langendorff and in vivo ischemia/reperfusion studies demonstrate the ability of the GLUT4 null heart to resist ischemic damage. The decreased levels of fatty acid oxidation enzymes in addition to the increase in glycogen, phospho-Akt, and expression of hexokinase and GLUTx1/GLUT8 in the GLUT4 null heart contributes to the ischemic resistance. These results demonstrate the ability of the GLUT4 null heart to maintain normal glucose uptake and improved post-ischemic function.;Through genetic methods a line of mice expressing GLUT4 in heart only, GLUT4-HO was achieved. The GLUT4-HO exhibit a phenotype like the GLUT4 nulls, including normoglycemia and dramatically reduced body weight and fat pad mass compared to controls. Although the GLUT4-HO hearts express 75% normal levels of GLUT4, the insulin resistance seen in the GLUT4 null mice does not improve. The hypertrophy seen in the GLUT4 null hearts is abolished by the introduction of GLUT4 in the heart. Additionally, the cellular pathology seen in the GLUT4 null hearts was absent in the GLUT4-HO hearts.;To assess the role decreased global expression of GLUT4 has on the heart, GLUT4 heterozygotes (+/-) were generated. The GLUT4 +/- mice are not unlike type II diabetics, they exhibit decreased expression of GLUT4 while progressing to a hyperglycemic/hyperinsulinemic state. Although the cardiac morphology is not overtly disturbed, the GLUT4 +/- hearts are not normal, and consequently downregulate insulin signaling molecules like Akt.;The results demonstrate that appropriate expression of GLUT4 is required for normal cardiac morphology, while post-ischemic cardiac function seems to be enhanced when GLUT4 is not present. These studies describe the mechanisms cardiac tissues use to compensate for abnormal GLUT4 expression, including the identification of GLUTx1/GLUT8.