Lactate-induced translocation of GLUT1 and GLUT4 is not mediated by the phosphatidyl-inositol-3-kinase pathway in the rat heart.
We have determined the effect of lactate on the translocation of GLUT1 and GLUT4 and on the myocardial uptake and phosphorylation of the glucose analogues 2-deoxy-D-glucose (DG) and 2-18F-fluoro-2-deoxy-D-glucose (18FDG). The involvement of phosphatidyl-inositol-3-kinase (PI3K) in this translocation was determined using wortmannin. Hearts from fed and fasted male Wistar rats were perfused in the presence of 11 mM glucose +/- 10 mM lactate for two hours and the distribution of glucose transporters was determined using Western blot techniques. Two other groups of hearts from fed animals were perfused in the presence of 11 mM glucose +/- 10 mM lactate for two hours followed by perfusion for a further 30 minutes in the presence of 4 mM 2-deoxy-D-glucose. Using 31P NMR spectroscopy, the accumulation of 2-deoxy-D-glucose-6-phosphate (DG6P) was monitored over time. Another group of hearts from fed animals was initially perfused in the presence of 11 mM glucose for 100 minutes and then the perfusate was changed to 11 mM glucose + 10 mM lactate for a further 120 minutes. Using PET, the accumulation of 2-18F-fluoro-deoxy-D-glucose-6-phosphate (18FDG6P) was monitored throughout the whole protocol. Lactate induced the translocation of both GLUT1 and GLUT4 to the plasma membrane (from 67 +/- 1% to 82 +/- 2% and from 16 +/- 1% to 28 +/- 2%, respectively (P < 0.05)) in hearts from fed animals; similar translocations were observed in hearts from fasted animals. Wortmannin did not inhibit the translocation of either GLUT1 or GLUT4. Glucose transporter translocation was accompanied by a significant inhibition of DG6P accumulation (4.24 +/- 0.68 vs. 1.50 +/- 0.38; P < 0.001) and a decrease in the rate of 18FDG6P accumulation. In conclusion, lactate causes translocation of GLUT1 and GLUT4 to the plasma membrane, via a non-PI3K-mediated pathway. Despite this externalisation of the GLUT transporters, a marked decrease in the accumulation of both DG6P and 18FDG6P was observed.
Medina
Rodolfo A
RA
Department of Radiological Sciences, Guy's Hospital, London, UK.
Southworth
Richard
R
Fuller
William
W
Garlick
Pamela B
PB
D000730:Androstadienes / Q000494:pharmacology; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D019298:Glucose-6-Phosphate / Q000493:pharmacokinetics; D006321:Heart / Q000000981:diagnostic imaging; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000494:pharmacology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000201:enzymology*; D010477:Perfusion; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014055:Tomography, Emission-Computed; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019275:Radiopharmaceuticals; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; D019788:Fluorodeoxyglucose F18; D019344:Lactic Acid; D019298:Glucose-6-Phosphate; D019869:Phosphatidylinositol 3-Kinases; D000077191:Wortmannin