GLUCOSE-TRANSPORT AND GLUCOSE-TRANSPORTER GLUT4 ARE REGULATED BY PRODUCT(S) OF INTERMEDIARY METABOLISM IN CARDIOMYOCYTES

Alternative substrates of energy metabolism are thought to contribute to the impairment of heart and muscle glucose utilization in insulin-r esistant states. We have investigated the acute effects of substrates in isolated rat cardiomyocytes. Exposure to lactate, pyruvate, propion ate, acetate, palmitate, beta-hydroxybutyrate or alpha-oxoglutarate le d to the depression of glucose transport by up to 50%, with lactate, p yruvate and propionate being the most potent agents. The percentage in hibition was greater in cardiomyocytes in which glucose transport was stimulated with the alpha-adrenergic agonist phenylephrine or with a s ubmaximal insulin concentration than in basal or fully insulin-stimula ted cells. Cardiomyocytes from fasted or diabetic rats displayed a sim ilar sensitivity to substrates as did cells from control animals. On t he other hand, the amination product of pyruvate (alanine), as well as valine and the aminotransferase inhibitors cycloserine and amino-oxya cetate, stimulated glucose transport about 2-fold. In addition, the ef fect of pyruvate was counteracted by cycloserine. Since reversible tra nsamination reactions are known to affect the pool size of the citrate cycle, the influence of substrates, amino acids and aminotransferase inhibitors on citrate, malate and glutamate content was examined. A si gnificant negative correlation was found between alterations in glucos e transport and the levels of citrate (P < 0.01) or malate (P < 0.01), and there was a positive correlation between glucose transport and gl utamate levels (P < 0.05). In contrast, there was no correlation with changes in [1-C-14]pyruvate oxidation or in glucose-6-phosphate levels . Finally, pyruvate decreased the abundance of GLUT4 glucose transport ers at the surface of phenylephrine- or insulin-stimulated cells by 34 % and 27% respectively, as determined by using the selective photoaffi nity label [H-3]ATB-BMPA zi-2,2,2-trifluoroethyl)benzoyl]-1,3-bis-(D-m annos amine}. In conclusion, cardiomyocyte glucose transport is subjec t to counter-regulation by alternative substrates. The glucose transpo rt system appears to be controlled by (a) compound(s) of intermediary metabolism (other than glucose 6-phosphate), but in a different way th an pyruvate dehydrogenase. Transport inhibition eventually occurs via a decrease in the amount of glucose transporters in the plasma membran e.