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J. Biol. Chem., Vol. 277, Issue 6, 3809-3812, February 8, 2002

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ACCELERATED PUBLICATION
Insulin Acutely Regulates Munc18-c Subcellular Trafficking
ALTERED RESPONSE IN INSULIN-RESISTANT 3T3-L1 ADIPOCYTES^*

Bryce A. Nelson^§, Katherine A. Robinson, and Maria G. Buse^¶

From the  Department of Medicine, Division of Endocrinology, Diabetes and Medical Genetics and the ^¶ Department of Biochemistry/Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425

Preincubation of 3T3-L1 adipocytes in high glucose or glucosamine decreases acute insulin (100 nM)-stimulated glucose transport provided that insulin (0.6 nM) is included during preincubation. GLUT4 expression is unchanged (Nelson, B. A., Robinson, K. A., and Buse, M. G. (2000) Diabetes 49, 981-991). Munc18-c, a Syntaxin 4-binding protein, is a proposed regulator of the docking/fusion of GLUT4-containing vesicles with the plasma membrane. We examined the subcellular distribution of Munc18-c in response to acute (15-min) insulin (100 nM) stimulation after preincubation in 5 or 25 mM glucose ± 0.6 nM insulin. Immunoblotting detected Munc18-c mainly in the Triton X-100-soluble plasma membrane (TS-PM) and the Triton X-100-insoluble low density microsomal (TI-LDM) fraction. Under each condition except high glucose + insulin preincubation, acute insulin increased Munc18-c (~50-200%) in TS-PM and decreased Munc18-c (~60%) in TI-LDM. Munc18-c traffic was time-dependent with a lag time of ~3 min compared with GLUT4. Preincubation with high glucose + 0.6 nM insulin significantly impaired acute insulin-stimulated Munc18-c trafficking and decreased basal Munc18-c in the TI-LDM. Preincubation with glucosamine + insulin had similar effects. Total cellular Munc18-c remained unchanged. In conclusion, acute insulin stimulation promotes the translocation of Munc18-c, apparently from a TI-LDM-associated compartment to the TS-PM. Chronically increased glucose flux or exposure to glucosamine disrupts this process, which may negatively impact the fusion of GLUT4-containing vesicles with the plasma membrane.

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