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, Amira Klip

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

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 esogenously 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.

Original languageEnglish
Pages (from-to)32233-32242
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number31
DOIs
StatePublished - 30 Jul 2004
Externally publishedYes

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