INVITED REVIEW Nish Patel Æ Carol Huang Æ Amira Klip Cellular location of insulin-triggered signals and implications for glucose uptake Received: 17 May 2005 / Accepted: 2 June 2005 / Published online: 12 November 2005 Ó Springer-Verlag 2005 Abstract Insulin stimulation of glucose uptake into muscle and fat cells requires movement of GLUT4- containing vesicles from intracellular compartments to the plasma membrane. Accordingly, insulin-derived signals must arrive at and be recognized by the appro- priate intracellular GLUT4 pools. We describe the insulin signals participating in GLUT4 translocation, and review evidence that they are recruited to intracel- lular membranes in conjunction with cytoskeletal ele- ments. Such segregation may facilitate the encounter between signals and target vesicles. In most animal and cellular models of insulin resistance, insulin-stimulated GLUT4 translocation to the plasma membrane is re- duced. Insulin resistance caused by oxidative stress does not affect early insulin signals, rather their intracellular localization is altered. In this and several other insulin- resistant states, insulin-induced actin remodelling is concomitantly diminished. We summarize evidence suggesting that spatial localization of signals is critical for efficient insulin action, and that the cytoskeleton may act as a scaffold to promote efficient translocation of GLUT4 to the cell surface. Keywords Insulin Æ Glucose transporter 4 (GLUT4) Æ Actin Æ Diabetes Æ Insulin receptor substrate (IRS) Æ Phosphatidylinositol 3-kinase (PI3-kinase) Æ Akt Introduction Muscle and adipose cells are the principal tissues dis- playing insulin-dependent glucose uptake. Insulin in- creases such uptake primarily via glucose transporter isoform 4 (GLUT4) [88]. In the basal state, approxi- mately 5–10% of the GLUT4 is located at the cell sur- face and >90% in intracellular compartments. The steady-state distribution of GLUT4 is the resultant of the fast endocytosis and slow exocytosis of this protein [69, 115]. Insulin shifts the steady-state distribution of GLUT4 towards the plasma membrane by elevating the exocytic rate of GLUT4, with a minor reduction in its endocytic rate [92]. Insulin also enhances GLUT4 transit through early and recycling endosomes [33, 46], pre- sumably en route to a specialized storage compartment. The specialized storage GLUT4 pool is not static but appears to be in dynamic equilibrium with elements of either the recycling endosome or the trans-Golgi net- work (for review see [11]). A corollary of these obser- vations is that insulin-derived signals must impinge on the specific insulin-sensitive GLUT4 compartment(s) in order to enhance its traffic to the cell surface. Insulin activates a complex signalling cascade involving tyro- sine, threonine/serine and lipid kinases that regulate the mobilization of GLUT4 from its storage compartment to the cell surface. In parallel to this, insulin induces marked remodelling of actin filaments. In muscle cells in culture, the result is an intricate actin mesh that pro- motes formation of dorsal membrane ruffles [60]. In adipose cells in culture, where the cytoplasmic space is more restricted, actin forms a dynamic peripheral band of filaments emanating from caveolae [55, 56]. Cyto- skeletal dynamics and perhaps even the presence of an intact actin cytoskeleton are essential for insulin- dependent GLUT4 translocation to the cell surface and glucose uptake, based on the use of diverse pharmaco- logical and molecular strategies that prevent actin fila- ment reorganization [55, 81, 103]. As expected, insulin- derived signals must govern the insulin-dependent actin N. Patel Æ C. Huang Æ A. Klip (&) Programme in Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada E-mail: amira@sickkids.ca Tel.: +416-813-6392 Fax: +416-813-5028 N. Patel Æ A. Klip Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada Present address: C. Huang Department of Paediatrics, Alberta Children’s Hospital, Calgary, T2T 5C7, Alberta Pflugers Arch – Eur J Physiol (2006) 451: 499–510 DOI 10.1007/s00424-005-1475-6