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Diabetes 54:1698-1705, 2005
© 2005 by the American Diabetes Association, Inc.
Phosphatidylinositol 4,5-Bisphosphate Reverses Endothelin-1–Induced Insulin Resistance via an Actin-Dependent Mechanism
1 Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana
2 Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana
Phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) plays a pivotal role in insulin-stimulated glucose transport as an important precursor to PI 3,4,5-trisphosphate (PIP3) and a key regulator of actin polymerization. Since endothelin (ET)-1 impairs insulin sensitivity and PIP2 is a target of ET-1–induced signaling, we tested whether a change in insulin-stimulated PIP3 generation and signaling, PIP2-regulated actin polymerization, or a combination of both accounted for ET-1–induced insulin resistance. Concomitant with a time-dependent loss of insulin sensitivity, ET-1 caused a parallel reduction in plasma membrane PIP2. Despite decreased insulin-stimulated PI 3-kinase activity and PIP3 generation, ET-1 did not diminish downstream signaling to Akt-2. Furthermore, addition of exogenous PIP2, but not PIP3, restored insulin-regulated GLUT4 translocation and glucose transport impaired by ET-1. Microscopic and biochemical analyses revealed a PIP2-dependent loss of cortical filamentous actin (F-actin) in ET-1–treated cells. Restoration of insulin sensitivity by PIP2 add-back occurred concomitant with a reestablishment of cortical F-actin. The corrective effect of exogenous PIP2 in ET-1–induced insulin-resistant cells was not present in cells where cortical F-actin remained experimentally depolymerized. These data suggest that ET-1–induced insulin resistance results from reversible changes in PIP2-regulated actin polymerization and not PIP2-dependent signaling.
Address correspondencereprint requests to Jeffrey S. Elmendorf, 635 Barnhill Dr., MS308A, Indianapolis, Indiana 46202. E-mail: jelmendo{at}iupui.edu
Abbreviations: DMEM, Dulbecco’s modified Eagle’s medium; EGFP, enhanced green fluorescence protein; ET, endothelin; F-actin, filamentous actin; G-actin, globular actin; IR, insulin receptor; IRS, IR substrate; PI, phosphatidylinositol; PI3K, PI 3-kinase; PIP2, PI 4,5-bisphosphate; PIP3, PI 3,4,5-trisphosphate; PLC, phospholipase C
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