Phosphatidylinositol 4,5-Bisphosphate Reverses Endothelin-1–Induced Insulin Resistance via an Actin-Dependent Mechanism

  1. Andrew B. Strawbridge1 and
  2. Jeffrey S. Elmendorf12
  1. 1Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana
  2. 2Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana
  1. Address correspondencereprint requests to Jeffrey S. Elmendorf, 635 Barnhill Dr., MS308A, Indianapolis, Indiana 46202. E-mail: jelmendo{at}iupui.edu

Abstract

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.

Footnotes

  • 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 March 21, 2005.
    • Received May 20, 2004.
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