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Ceramide- and Oxidant-Induced Insulin Resistance Involve Loss of Insulin-Dependent Rac-Activation and Actin Remodeling in Muscle Cells
Ist Teil von
Diabetes (New York, N.Y.), 2007-02, Vol.56 (2), p.394-403
Ort / Verlag
Alexandria, VA: American Diabetes Association
Erscheinungsjahr
2007
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Ceramide- and Oxidant-Induced Insulin Resistance Involve Loss of Insulin-Dependent Rac-Activation and Actin Remodeling in
Muscle Cells
Lellean JeBailey 1 2 ,
Oshrit Wanono 1 ,
Wenyan Niu 1 ,
Jessica Roessler 1 ,
Assaf Rudich 1 and
Amira Klip 1 2
1 Programme in Cell Biology, the Hospital for Sick Children, Toronto, Ontario, Canada
2 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
Address correspondence and reprint requests to Dr. Amira Klip, Programme in Cell Biology, The Hospital for Sick Children,
555 University Ave., Toronto, ON, Canada M5G 1X8. E-mail: amira{at}sickkids.ca
Abstract
In muscle cells, insulin elicits recruitment of the glucose transporter GLUT4 to the plasma membrane. This process engages
sequential signaling from insulin receptor substrate (IRS)-1 to phosphatidylinositol (PI) 3-kinase and the serine/threonine
kinase Akt. GLUT4 translocation also requires an Akt-independent but PI 3-kinase–and Rac-dependent remodeling of filamentous
actin. Although IRS-1 phosphorylation is often reduced in insulin-resistant states in vivo, several conditions eliciting insulin
resistance in cell culture spare this early step. Here, we show that insulin-dependent Rac activation and its consequent actin
remodeling were abolished upon exposure of L6 myotubes beginning at doses of C2-ceramide or oxidant-producing glucose oxidase
as low as 12.5 μmol/l and 12.5 mU/ml, respectively. At 25 μmol/l and 25 mU/ml, glucose oxidase and C2-ceramide markedly reduced
GLUT4 translocation and glucose uptake and lowered Akt phosphorylation on Ser473 and Thr308, yet they affected neither IRS-1
tyrosine phosphorylation nor its association with p85 and PI 3-kinase activity. Small interfering RNA–dependent Rac1 knockdown
prevented actin remodeling and GLUT4 translocation but spared Akt phosphorylation, suggesting that Rac and actin remodeling
do not contribute to overall Akt activation. We propose that ceramide and oxidative stress can each affect two independent
arms of insulin signaling to GLUT4 at distinct steps, Rac–GTP loading and Akt phosphorylation.
GLUT4myc, c-myc epitope–tagged GLUT4
IRS, insulin receptor substrate
NAC, N-acetyl-l-cysteine
PAK, p21-activated kinase
PI, phosphatidylinositol
siRNA, small interfering RNA
Footnotes
W.N. is currently affiliated with the Department of Immunology, Tianjin Medical University, Tianjin, China. A.R. is currently
affiliated with the Department of Clinical Biochemistry and the S. Daniel Abraham Center for Health and Nutrition, Ben Gurion
University, Beer Sheva, Israel.
Additional information can be found in an online appendix at http://dx.doi.org/10.2337/db06-0823 .
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.
Accepted October 19, 2006.
Received June 16, 2006.
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