Insulin and ischemia stimulate glycolysis by acting on the same targets through different and opposing signaling pathways.
The stimulation of heart glycolysis by insulin and ischemia involves the recruitment of the glucose transporter GLUT4 to the plasma membrane and the activation of 6-phosphofructo-2-kinase (PFK-2), which in turn increases the concentration of fructose 2,6-bisphosphate, a well-known stimulator of glycolysis. This review focuses on the mechanisms responsible for PFK-2 activation by insulin and ischemia in heart. Heart PFK-2 is phosphorylated by various protein kinases, including protein kinase B (PKB), thought to mediate most, if not all, short-term effects of insulin, and the AMP-activated protein kinase (AMPK), known to be activated under anaerobic conditions. We found that PKB is not required for PFK-2 activation by insulin and we partially purified an insulin-sensitive PFK-2 kinase, that differs from PKB and from other insulin-stimulated protein kinases. We also demonstrated that AMPK mediates PFK-2 activation by ischemia. Finally, our study of the interaction between the signaling pathways of insulin and ischemia revealed opposite effects on signaling. Intracellular acidosis induced by ischemia inhibited insulin signaling, whereas insulin pretreatment antagonized AMPK activation by ischemia.
Hue
Louis
L
Hormone and Metabolic Research Unit, Christian de Duve International Institute of Cellular and Molecular Pathology, and University of Louvain Medical School, Avenue Hippocrate, 75, B-1200, Brussels, Belgium. hue@horm.ucl.ac.be
Beauloye
Christophe
C
Marsin
Anne-Sophie
AS
Bertrand
Luc
L
Horman
Sandrine
S
Rider
Mark H
MH
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001693:Biological Transport, Active; D002462:Cell Membrane / Q000378:metabolism; D004734:Energy Metabolism; D004789:Enzyme Activation; D051275:Glucose Transporter Type 4; D006019:Glycolysis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009124:Muscle Proteins; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D025481:Phosphofructokinase-2 / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009097:Multienzyme Complexes; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; D025481:Phosphofructokinase-2; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases