Phosphatidylinositol 4,5-bisphosphate reverses endothelin-1-induced insulin resistance via an actin-dependent mechanism.
Phosphatidylinositol (PI) 4,5-bisphosphate (PIP(2)) plays a pivotal role in insulin-stimulated glucose transport as an important precursor to PI 3,4,5-trisphosphate (PIP(3)) 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 PIP(3) 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 PIP(2). Despite decreased insulin-stimulated PI 3-kinase activity and PIP(3) generation, ET-1 did not diminish downstream signaling to Akt-2. Furthermore, addition of exogenous PIP(2), but not PIP(3), restored insulin-regulated GLUT4 translocation and glucose transport impaired by ET-1. Microscopic and biochemical analyses revealed a PIP(2)-dependent loss of cortical filamentous actin (F-actin) in ET-1-treated cells. Restoration of insulin sensitivity by PIP(2) 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 PIP(2)-regulated actin polymerization and not PIP(2)-dependent signaling.
Strawbridge
Andrew B
AB
Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana 46202, USA.
Elmendorf
Jeffrey S
JS
D041721:3T3-L1 Cells; D000199:Actins / Q000502:physiology*; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D003599:Cytoskeleton / Q000502:physiology; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000502:physiology*; D015398:Signal Transduction
D000199:Actins; D019332:Endothelin-1; D007328:Insulin; D019269:Phosphatidylinositol 4,5-Diphosphate; D005947:Glucose