10334307

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2

Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin-induced GLUT4 translocation to the plasma membrane. Activation of phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4 translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a downstream mediator of some actions of PI 3-kinase. To determine whether glucosamine-induced insulin resistance could be due to impaired signaling, we measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline. Euglycemic-hyperinsulinemic clamp studies (12 mU x kg(-1) x min(-1) insulin) in awake rats showed that glucosamine infusion resulted in rapid induction of insulin resistance, with a 33% decrease in glucose infusion rate (P < 0.01). Tissues were harvested after saline alone (basal), 1 min after an insulin bolus (10 U/kg), or after 2 h of insulin clamp in saline- and glucosamine-infused rats. After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine-infused rats. In saline-infused rats, 1 min of insulin stimulation increased PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and 10-fold, respectively. In glucosamine-infused rats treated for 1 min with insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01) and that associated with phosphotyrosine was reduced 43% (P < 0.01). Insulin for 1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not different between groups. Glucosamine infusion alone had no effect on tyrosine phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase or Akt/PKB activity. However, 2 h of insulin clamp reduced PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min of insulin. No effect of glucosamine was seen on these signaling events when compared with 2 h of insulin clamp without glucosamine. Our data show that 1) glucosamine infusion in rats is associated with an impairment in the early activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin-resistant state does not involve alterations in the activation of Akt/PKB, and 3) prolonged insulin infusion under clamp conditions results in a blunting of the PI 3-kinase response to insulin.

eng

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MEDLINE

0012-1797

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310-20

pubmed-meshheading:10334307-Animals, pubmed-meshheading:10334307-Enzyme Activation, pubmed-meshheading:10334307-Glucosamine, pubmed-meshheading:10334307-Glucose, pubmed-meshheading:10334307-Glucose Clamp Technique, pubmed-meshheading:10334307-Hyperinsulinism, pubmed-meshheading:10334307-Insulin, pubmed-meshheading:10334307-Insulin Receptor Substrate Proteins, pubmed-meshheading:10334307-Male, pubmed-meshheading:10334307-Muscle, Skeletal, pubmed-meshheading:10334307-Phosphatidylinositol 3-Kinases, pubmed-meshheading:10334307-Phosphoproteins, pubmed-meshheading:10334307-Phosphorylation, pubmed-meshheading:10334307-Protein-Serine-Threonine Kinases, pubmed-meshheading:10334307-Proto-Oncogene Proteins, pubmed-meshheading:10334307-Proto-Oncogene Proteins c-akt, pubmed-meshheading:10334307-Rats, pubmed-meshheading:10334307-Rats, Sprague-Dawley, pubmed-meshheading:10334307-Receptor, Insulin, pubmed-meshheading:10334307-Time Factors, pubmed-meshheading:10334307-Tyrosine

Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't