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J. Biol. Chem., Vol. 279, Issue 31, 32233-32242, July 30, 2004

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Intracellular Delivery of Phosphatidylinositol (3,4,5)-Trisphosphate Causes Incorporation of Glucose Transporter 4 into the Plasma Membrane of Muscle and Fat Cells without Increasing Glucose Uptake^*

Gary Sweeney¶, Rami R. Garg, Rolando B. Ceddia, Dailin Li, Manabu Ishiki||, Romel Somwar, Leonard J. Foster**, Paul O. Neilsen, Glenn D. Prestwich, Assaf Rudich¶¶, and Amira Klip||||

From the Programme in Cell Biology, the Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada, Echelon Biosciences, Salt Lake City, Utah 84108, and the Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112

Insulin stimulates glucose uptake into muscle and fat cells by translocating glucose transporter 4 (GLUT4) to the cell surface, with input from phosphatidylinositol (PI) 3-kinase and its downstream effector Akt/protein kinase B. Whether PI 3,4,5-trisphosphate (PI(3,4,5)P₃) suffices to produce GLUT4 translocation is unknown. We used two strategies to deliver PI(3,4,5)P₃ intracellularly and two insulin-sensitive cell lines to examine Akt activation and GLUT4 translocation. In 3T3-L1 adipocytes, the acetoxymethyl ester of PI(3,4,5)P₃ caused GLUT4 migration to the cell periphery and increased the amount of plasma membrane-associated phospho-Akt and GLUT4. Intracellular delivery of PI(3,4,5)P₃ using polyamine carriers also induced translocation of myc-tagged GLUT4 to the surface of intact L6 myoblasts, demonstrating membrane insertion of the transporter. GLUT4 translocation caused by carrier-delivered PI(3,4,5)P₃ was not reproduced by carrier-PI 4,5-bisphosphate or carrier alone. Like insulin, carrier-mediated delivery of PI(3,4,5)P₃ elicited redistribution of perinuclear GLUT4 and Akt phosphorylation at the cell periphery. In contrast to its effect on GLUT4 mobilization, delivered PI(3,4,5)P₃ did not increase 2-deoxyglucose uptake in either L6GLUT4myc myoblasts or 3T3-L1 adipocytes. The ability of exogenously delivered PI(3,4,5)P₃ to augment plasma membrane GLUT4 content without increasing glucose uptake suggests that input at the level of PI 3-kinase suffices for GLUT4 translocation but is insufficient to stimulate glucose transport.

Received for publication, March 15, 2004 , and in revised form, May 17, 2004.

^* This work was supported in part by Canadian Institutes of Health Research Grant MT7307 (to A. K.) and National Institutes of Health Grants NS29632 (to G. D. P.) and GM62734-03 (to P. O. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Recipient of a fellowship from the Banting and Best Diabetes Centre/Novo Nordisk.

^|| Recipient of a fellowship from the Canadian Diabetes Association.

^** Recipient of a doctoral studentship from the Canadian Institutes of Health Research.

^¶¶ Recipient of the Albert Renold career development award of the European Foundation for the Study of Diabetes and a fellowship from the Hospital for Sick Children Research Training Centre.

^|||| To whom correspondence should be addressed: Programme in Cell Biology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-6392; Fax: 416-813-5028; E-mail: amira{at}sickkids.ca.

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