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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

Loss of cortical actin filaments in insulin-resistant skeletal muscle cells impairs GLUT4 vesicle trafficking and glucose transport

Departments of ¹Cellular and Integrative Physiology and ³Biochemistry and Molecular Biology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis; and ²Eli Lilly and Company, Indianapolis, Indiana

Submitted 9 March 2006 ; accepted in final form 2 June 2006

Study has demonstrated an essential role of cortical filamentous actin (F-actin) in insulin-regulated glucose uptake by skeletal muscle. Here, we tested whether perturbations in F-actin contributed to impaired insulin responsiveness provoked by hyperinsulinemia. In L6 myotubes stably expressing GLUT4 that carries an exofacial myc-epitope tag, acute insulin stimulation (20 min, 100 nM) increased GLUT4myc translocation and glucose uptake by 2-fold. In contrast, a hyperinsulinemic state, induced by inclusion of 5 nM insulin in the medium for 12 h decreased the ability of insulin to stimulate these processes. Defects in insulin signaling did not readily account for the observed disruption. In contrast, hyperinsulinemia reduced cortical F-actin. This occurred concomitant with a loss of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP₂), a lipid involved in cytoskeletal regulation. Restoration of plasma membrane PIP₂ in hyperinsulinemic cells restored F-actin and insulin responsiveness. Consistent with these in vitro observations suggesting that the hyperinsulinemic state negatively affects cortical F-actin structure, epitrochlearis skeletal muscle from insulin-resistant hyperinsulinemic Zucker fatty rats displayed a similar loss of F-actin structure compared with that in muscle from lean insulin-sensitive littermates. We propose that a component of insulin-induced insulin resistance in skeletal muscle involves defects in PIP₂/F-actin structure essential for insulin-regulated glucose transport.

hyperinsulinemia; phosphatidylinositol 4,5-bisphosphate

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