Phosphatidylinositol 4,5-bisphosphate reverses endothelin-1-induced insulin resistance via an actin-dependent mechanism

Andrew B. Strawbridge, Jeffrey Elmendorf

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 PIP 2 is a target of ET-1-induced signaling, we tested whether a change in insulin-stimulated PIP3 generation and signaling, PIP 2-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 PIP 2 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.

Original languageEnglish
Pages (from-to)1698-1705
Number of pages8
JournalDiabetes
Volume54
Issue number6
DOIs
StatePublished - Jun 2005

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Endothelin-1
Phosphatidylinositols
Insulin Resistance
Actins
Insulin
Polymerization
Phosphatidylinositol 3-Kinase
Glucose
Cell Membrane

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Phosphatidylinositol 4,5-bisphosphate reverses endothelin-1-induced insulin resistance via an actin-dependent mechanism. / Strawbridge, Andrew B.; Elmendorf, Jeffrey.

In: Diabetes, Vol. 54, No. 6, 06.2005, p. 1698-1705.

Research output: Contribution to journalArticle

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