Abstract
Muscle and fat cells develop insulin resistance when cultured under hyperinsulinemic conditions for sustained periods. Recent data indicate that early insulin signaling defects do not fully account for the loss of insulin action. Given that cortical filamentous actin (F-actin) represents an essential aspect of insulin regulated glucose transport, we tested to see whether cortical F-actin structure was compromised during chronic insulin treatment. The acute effect of insulin on GLUT4 translocation and glucose uptake was diminished in 3T3-L1 adipocytes exposed to a physiological level of insulin (5 nm) for 12 h. This insulin-induced loss of insulin responsiveness was apparent under both low (5.5 mm) and high (25 mm) glucose concentrations. Microscopic and biochemical analyses revealed that the hyperinsulinemic state caused a marked loss of cortical F-actin. Since recent data link phosphatidylinositol 4,5-bisphosphate (PIP(2)) to actin cytoskeletal mechanics, we tested to see whether the insulin-resistant condition affected PIP(2) and found a noticeable loss of this lipid from the plasma membrane. Using a PIP(2) delivery system, we replenished plasma membrane PIP(2) in cells following the sustained insulin treatment and observed a restoration in cortical F-actin and insulin responsiveness. These data reveal a novel molecular aspect of insulin-induced insulin resistance involving defects in PIP(2)/actin regulation.
Highlights
A continuous component of insulin resistance is hyperinsulinemia [1, 2]
Insulin-stimulated GLUT4 Translocation Is Impaired by Chronic Insulin Treatment—The generation of insulin resistance by exposure of 3T3-L1 adipocytes to a medium containing a high concentration of glucose and insulin has been well documented [20, 21, 24]
Fractions prepared from control 3T3-L1 adipocytes displayed a characteristic insulin-stimulated increase in GLUT4 compared with plasma membrane fractions prepared from untreated cells (Fig. 1B, compare lanes 1 and 2)
Summary
A continuous component of insulin resistance is hyperinsulinemia [1, 2]. This compensatory increase in insulin during the insulin-resistant state initially offsets the reduced ability of insulin to stimulate GLUT41 translocation and glucose uptake,. Chronic exposure to pharmacological doses of insulin (Ն100 nM) have been shown by several laboratories [17,18,19] to markedly attenuate expression levels and/or activity states of the IR, IRS-1, PI3K, Akt, and GLUT4 proteins in 3T3-L1 adipocytes and, produce a defect in the ability of the cell to respond to subsequent acute insulin stimulation with an increase in GLUT4 translocation and glucose transport.
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