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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 357, Issue 4, pp 385–392 | Cite as

Inhibition of insulin-stimulated glucose transport in 3T3-L1 cells by Clostridium difficile toxin B, Clostridium sordellii lethal toxin, and Clostridium botulinum C2 toxin

  • Gudrun Schmid
  • Annette Schürmann
  • Christine Huppertz
  • Fred Hofmann
  • Klaus Aktories
  • H.-G. Joost
Original article

Abstract

The role of the actin cytoskeleton and/or GTPases of the Rho/Rac-family in glucose transport regulation was investigated in 3T3-L1 cells with clostridial toxins which depolymerize actin by inactivation of Rho/Rac (Clostridium difficile toxin B and Clostridium sordellii lethal toxin (LT)) or by direct ADP-ribosylation (Clostridium botulinum C2 toxin). Toxin B and C2 reduced insulin-stimulated, but not basal, 2-deoxyglucose (2-DOG) uptake rates in 3T3-L1 fibroblasts. In parallel, the toxins produced morphological alterations of the cells reflecting disruption of the actin cytoskeleton. Both toxins reduced the maximum response to insulin but failed to alter the half-maximally stimulating concentrations of insulin. In 3T3-L1 adipocytes, the lethal toxin reduced the effect of insulin on 2-DOG uptake, whereas toxin B and C2 failed to affect glucose transport or cell morphology. When cells were exposed to the toxins after treatment with insulin, both toxin B and the lethal toxin, in contrast to the phosphatidylinositol (PI) 3-kinase inhibitor wortmannin, failed to reduce the 2-DOG uptake rates. Thus, both translocation to the plasma membrane and internalization of glucose transporters were inhibited by the toxins, whereas the PI 3-kinase inhibitor selectively affects translocation. The data suggest that the effects of the clostridial toxins on trafficking of glucose transporters are mediated by the depolymerization of the actin cytoskeleton and are an indirect consequence of Rho or Rac inactivation. It is suggested that pathways signalling through Rac or Rho may play a modulatory role in glucose transport regulation through their effects on the actin network.

Key words Insulin Signal transduction GTPases Rho-related proteins Clostridial toxins Glucose transport 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Gudrun Schmid
    • 1
  • Annette Schürmann
    • 1
  • Christine Huppertz
    • 1
  • Fred Hofmann
    • 2
  • Klaus Aktories
    • 2
  • H.-G. Joost
    • 1
  1. 1.Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Rheinisch-Westfälische Technische Hochschule Aachen, Wendlingweg 2, D-52057 Aachen, GermanyDE
  2. 2.Institut für Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg i.Br., GermanyDE

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