The inability of phosphatidylinositol 3-kinase activation to stimulate GLUT4 translocation indicates additional signaling pathways are required for insulin-stimulated glucose uptake

• Published in: Proceedings of the National Academy of Sciences - PNAS 1995-10, Vol.92 (22), p.10247-10251
• Main Authors: Isakoff, S.J. (New York University Medical Center, New York, NY.), Taha, C, Rose, E, Marcusohn, J, Klip, A, Skolnik, E.Y
• Format: Article
• Language: English
• Subjects: 3T3 Cells; ACTIVIDAD ENZIMATICA; ACTIVITE ENZYMATIQUE; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Animals; Antibodies; Biochemistry; Biological Transport - drug effects; Cell Differentiation; Cell lines; Cell Membrane - metabolism; Cell membranes; CELLULE; CELULAS; CRECIMIENTO; CROISSANCE; Deoxyglucose - metabolism; Enzyme Activation; Epidermal Growth Factor - pharmacology; ESTRUCTURA CELULAR; FIBROBLASTE; FIBROBLASTOS; FOSFORILACION; GLUCOSA; GLUCOSE; Glucose - metabolism; Glucose Transporter Type 4; HORMONAS; HORMONE; Insulin; Insulin - pharmacology; INSULINA; INSULINE; INTERLEUKINE; INTERLEUQUINAS; Kinetics; Lawns; METABOLISME DES PROTEINES; METABOLISMO PROTEICO; Mice; Molecules; Monosaccharide Transport Proteins - metabolism; MUSCLE; Muscle Proteins; MUSCULOS; Myoblasts; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; PHOSPHORYLATION; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Platelet-Derived Growth Factor - pharmacology; PROTEINAS; PROTEINAS AGLUTINANTES; PROTEINE; PROTEINE DE LIAISON; RATON; RECEPTEUR D'HORMONE; Receptor, Insulin - physiology; RECEPTORES DE HORMONAS; Receptors; Signal Transduction - drug effects; SOURIS; STRUCTURE CELLULAIRE; TEJIDO ADIPOSO; TISSU ADIPEUX; TRANSFERASAS; TRANSFERASE
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.22.10247

Recent experimental evidence has focused attention to the role of two molecules, insulin receptor substrate 1 (IRS-1) and phosphatidylinositol 3-kinase (PI3-kinase), in linking the insulin receptor to glucose uptake; IRS-1 knockout mice are insulin resistant, and pharmacological inhibitors of PI3-kinase block insulin-stimulated glucose uptake. To investigate the role of PI3-kinase and IRS-1 in insulin-stimulated glucose uptake we examined whether stimulation of insulin-sensitive cells with platelet-derived growth factor (PDGF) or with interleukin 4 (IL-4) stimulates glucose uptake; the activated PDGF receptor (PDGFR) directly binds and activates PI3-kinase, whereas the IL-4 receptor (IL-4R) activates PI3-kinase via IRS-1 or the IRS-1-related molecule 4PS. We found that stimulation of 3T3-L1 adipocytes with PDGF resulted in tyrosine phosphorylation of the PDGFR and activation of PI3-kinase in these cells. To examine whether IL-4 stimulates glucose uptake, L6 myoblasts were engineered to overexpress GLUT4 as well as both chains of the IL-4R (L6/IL-4R/GLUT4); when these L6/IL-4R/GLUT4 myoblasts were stimulated with IL-4, IRS-1 became tyrosine phosphorylated and associated with PI3-kinase. Although PDGF and IL-4 can activate PI3-kinase in the respective cell lines, they do not possess insulin's ability to stimulate glucose uptake and GLUT4 translocation to the plasma membrane. These findings indicate that activation of PI3-kinase is not sufficient to stimulate GLUT4 translocation to the plasma membrane. We postulate that activation of a second signaling pathway by insulin, distinct from PI3-kinase, is necessary for the stimulation of glucose uptake in insulin-sensitive cells.