Endothelin‐1 impairs glucose transporter trafficking via a membrane‐based mechanism

Abstract

Endothelin-1 (ET-1) disrupts insulin-regulated glucose transporter GLUT4 trafficking. Since the negative consequence of chronic ET-1 exposure appears to be independent of signal disturbance along the insulin receptor substrate-1/phosphatidylinositol (PI) 3-kinase (PI3K)/Akt-2 pathway of insulin action, we tested if ET-1 altered GLUT4 regulation engaged by osmotic shock, a PI3K-independent stimulus that mimics insulin action. Regulation of GLUT4 by hyperosmotic stress was impaired by ET-1. Because of the mutual disruption of both insulin- and hyperosmolarity-stimulated GLUT4 translocation, we tested whether shared signaling and/or key phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated cytoskeletal events of GLUT4 trafficking were targets of ET-1. Both insulin and hyperosmotic stress signaling to Cbl were impaired by ET-1. Also, plasma membrane PIP2 and cortical actin levels were reduced in cells exposed to ET-1. Exogenous PIP2, but not PI 3,4,5-bisphosphate, restored actin structure, Cbl activation, and GLUT4 translocation. These data show that ET-1-induced PIP2/actin disruption impairs GLUT4 trafficking elicited by insulin and hyperosmolarity. In addition to showing for the first time the important role of PIP2-regulated cytoskeletal events in GLUT4 regulation by stimuli other than insulin, these studies reveal a novel function of PIP2/actin structure in signal transduction.

“Actin”g on GLUT4: Membrane & Cytoskeletal Components of Insulin Action

“…Thus, these recent data define a novel diabetic-state alteration and reveal a counteractive tactic to normalize insulin sensitivity. Data from another set of studies demonstrates a strikingly similar importance of plasma membrane PIP 2 and cortical F-actin in the development of insulin resistance induced by endothelin-1 [206,207]. This vasoactive peptide is welldocumented to diminish insulin sensitivity by a direct effect on one or more mechanisms involved in insulin-stimulated glucose transport and not from a vasoconstrictive decrease in skeletal muscle blood flow [208][209][210][211].…”

Dual Endothelin Receptor Blockade Acutely Improves Insulin Sensitivity in Obese Patients With Insulin Resistance and Coronary Artery Disease

“…Accordingly, ET-1 decreases the expression of insulin receptor substrate-1 and its activation of phosphatidylinositol 3-kinase pathway and insulin-stimulated Akt phosphorylation in skeletal muscle vascular smooth muscle cells (21,26). Furthermore, a recent study (27) suggests that ET-1 impairs glucose transporter GLUT4 trafficking via interference with phosphatidylinositol 4,5-bisphosphateregulated cytoskeletal events. These observations suggest that ET receptor blockade may result in increased insulin sensitivity via effects on insulin signaling.…”

New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus

“…1). Additional pathways involved are impaired translocation of GLUT4 via phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated cytoskeletal events (Strawbridge and Elmendorf, 2006) and increased cytoplasmic accumulation of RIP140 (Ho et al, 2011), which are independent of the PI3-K and Akt pathway, and G-protein couple receptor kinase-2-mediated IRS-1 Ser phosphorylation and degradation (Usui et al, 2005) . However, the signaling pathway mediating insulin resistance and reduction glucose uptake by ET-1 is far from understood and remains to be clarified in future studies.…”