Contraction signaling to glucose transport in skeletal muscle.
Contracting skeletal muscles acutely increases glucose transport in both healthy individuals and in people with Type 2 diabetes, and regular physical exercise is a cornerstone in the treatment of the disease. Glucose transport in skeletal muscle is dependent on the translocation of GLUT4 glucose transporters to the cell surface. It has long been believed that there are two major signaling mechanisms leading to GLUT4 translocation. One mechanism is insulin-activated signaling through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The other is an insulin-independent signaling mechanism that is activated by contractions, but the mediators of this signal are still unknown. Accumulating evidence suggests that the energy-sensing enzyme AMP-activated protein kinase plays an important role in contraction-stimulated glucose transport. However, more recent studies in transgenic and knockout animals show that AMP-activated protein kinase is not the sole mediator of the signal to GLUT4 translocation and suggest that there may be redundant signaling pathways leading to contraction-stimulated glucose transport. The search for other possible signal intermediates is ongoing, and calcium, nitric oxide, bradykinin, and the Akt substrate AS160 have been suggested as possible candidates. Further research is needed because full elucidation of an insulin-independent signal leading to glucose transport would be a promising pharmacological target for the treatment of Type 2 diabetes.
Jessen
Niels
N
Research Div., Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
Goodyear
Laurie J
LJ
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D015444:Exercise / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006801:Humans; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D009119:Muscle Contraction / Q000502:physiology*; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009097:Multienzyme Complexes; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose