title: Glucosamine induces rapid desensitization of glucose transport in isolated adipocytes by increasing GlcN-6-P levels.
abstract: We have examined the hypothesis that glucosamine (GlcN) can rapidly induce insulin resistance through an allosteric mechanism. When insulin-treated adipocytes were exposed to 2mM GlcN, glucose uptake was rapidly reduced by approximately 60% with a T(1/2) of 2 min. We also observed an increase in intracellular GlcN-6-P (at 5 min) from undetectable levels to approximately 260 nmol/g. Continued GlcN treatment resulted in additional accumulation of GlcN-6-P (>1200 nmol/g at 2h), but caused no further decrease in glucose uptake. Although the acute inhibitory action of GlcN could be completely reversed by removing extracellular GlcN, a slow and progressive decrease in insulin-stimulated glucose transport was observed with longer treatment times (T(1/2) of 45 min, 62% loss by 5h). From these data, we conclude that: (1) GlcN elevates intracellular GlcN-6-P levels within minutes, resulting in desensitization of the glucose transport system through allosteric inhibition of hexokinase; (2) prolonged treatment elevates GlcN-6-P to levels that cannot be effectively lowered by cell washing; and (3) residual levels of GlcN-6-P continue to allosterically inhibit glucose uptake, resulting in a slower rate of desensitization that is temporally similar to glucose-induced desensitization, but mechanistically different.
authors.affiliation: Hexos Inc., Woodinville, WA 98072, USA. Hexos@comcast.net
authors.forename: Stephen
authors.initials: S
authors.lastname: Marshall
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Okuyama
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D005947:Glucose / Q000493:pharmacokinetics*; D019298:Glucose-6-Phosphate / Q000031:analogs & derivatives* / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007328:Insulin; C001293:glucosamine 6-phosphate; D019298:Glucose-6-Phosphate; D005947:Glucose; D005944:Glucosamine