Glucosamine-induced insulin resistance is coupled to O-linked glycosylation of Munc18c.
Evidence suggests that glucosamine inhibits distal components regulating insulin-stimulated GLUT4 translocation to the plasma membrane. Here we assessed whether key membrane docking and fusion events were targeted. Consistent with a plasma membrane-localized effect, 3T3-L1 adipocytes exposed to glucosamine displayed an increase in cell-surface O-linked glycosylation and a simultaneously impaired mobilization of GLUT4 by insulin. Analysis of syntaxin 4 and SNAP23, plasma membrane-localized target receptor proteins (t-SNAREs) for the GLUT4 vesicle, showed that they were not cell-surface targets of O-linked glycosylation. However, the syntaxin 4 binding protein, Munc18c, was targeted by O-linked glycosylation. This occurred concomitantly with a block in insulin-stimulated association of syntaxin 4 with its cognate GLUT4 vesicle receptor protein (v-SNARE), VAMP2. In conclusion, our data suggest that the mechanism by which glucosamine inhibits insulin-stimulated GLUT4 translocation involves modification of Munc18c.
Chen
Guoli
G
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, IN 46202-5120, USA.
Liu
Ping
P
Thurmond
Debbie C
DC
Elmendorf
Jeffrey S
JS
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005944:Glucosamine / Q000494:pharmacology*; D051275:Glucose Transporter Type 4; D006031:Glycosylation; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D051938:Munc18 Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D050765:Qa-SNARE Proteins; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; D050683:R-SNARE Proteins; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050600:SNARE Proteins; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D051938:Munc18 Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D050765:Qa-SNARE Proteins; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; D050683:R-SNARE Proteins; D011994:Recombinant Proteins; C100493:SNAP23 protein, human; D050600:SNARE Proteins; C495693:Slc2a4 protein, mouse; C107017:Snap23 protein, mouse; C497943:Stxbp3 protein, mouse; D033921:Vesicular Transport Proteins; D005944:Glucosamine