Decreased Myocardial Gene Expression of Glucose Transporter 1 (GLUT1) and Glucose Transporter 4 (GLUT4) in Adult Intrauterine Growth Retarded (IUGR) Rats ♦ 494

Abstract

Asymmetrical IUGR is associated with an increased prevalence and mortality of coronary artery disease in adult males. These adult males are characterized by hypertension, hyperlipidemia, and insulin resistance/NIDDM (Syndrome X). Syndrome X individuals exhibit decreased insulin stimulated glucose uptake in cardiac and skeletal muscle. The molecular basis for the cardiac insulin resistance is unknown. Transport of glucose across membranes is controlled by the glucose transporters (GLUT), a family of 7 structurally similar proteins. GLUT1 and GLUT4 are the predominant isoforms expressed in cardiac muscle. In cardiac muscle, both GLUT1 and GLUT4 are insulin sensitive. We therefore hypothesized that GLUT1 and GLUT4 gene expression would be decreased in adult male IUGR cardiac muscle. We performed maternal bilateral uterine artery ligation (a well characterized model of placental insufficiency and asymmetrical IUGR) and sham surgery (C) in pregnant rats on day 19 of gestation (term-21d). Litters are culled to 6 at birth. Male cardiac tissue was harvested at 120 days of life, and RNA and protein were isolated. GLUT1 and GLUT4 mRNA levels were quantitated using RT-PCR with an internal control, and GLUT1 and GLUT4 protein levels were quantitated by western blotting. RESULTS: Both GLUT1 mRNA and protein were significantly decreased in IUGR hearts (C= 1.O, IUGR GLUT1 mRNA=0.51 ±0.06, IUGR GLUT1 protein=0.56±0.09; p<0.05); in contrast, only GLUT4 protein was decreased (C=1.0, IUGR GLUT4 protein=0.35±0.08). GLUT4 mRNA was not significantly altered in IUGR male hearts. We conclude that GLUT1 mRNA and protein and GLUT4 protein are decreased in adult male IUGR cardiac muscle. These results are intriguing because of the increased mortality of coronary artery disease in adult males with syndrome X. Normal cardiac muscle responds to ischemia by increasing glucose oxidation (relative to fatty acid oxidation) to decrease subsequent oxygen consumption. We speculate the decreased GLUT expression may blunt this response and play a role in the mortality associated with syndrome X.