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
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
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DOI：
10.2337/diabetes.48.2.310
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发表时间：
1999-02-01
期刊：
影响因子：
7.7
通讯作者：
Kahn, BB
中科院分区：
文献类型：
--
作者：
Kim, YB;Zhu, JS;Kahn, BB
葡萄糖胺是葡萄糖通过己糖胺生物合成途径的代谢产物，通过损害胰岛素诱导的 GLUT4 易位到质膜，有效诱导骨骼肌中的胰岛素抵抗。磷酸肌醇 (PI) 3-激酶的激活对于胰岛素刺激的 GLUT4 易位是必需的，丝氨酸/苏氨酸激酶 Akt/蛋白激酶 B (PKB) 是 PI 3-激酶某些作用的下游介质。为了确定葡萄糖胺诱导的胰岛素抵抗是否可能是由于信号传导受损所致，我测量了胰岛素受体底物 (IRS)-1 和胰岛素受体酪氨酸磷酸化；与 IRS-1、IRS-2 和磷酸酪氨酸相关的 PI 3-激酶活性；注射葡萄糖胺(6.0 mg.kg(-1).min(-1))或生理盐水2小时后大鼠骨骼肌Akt活性和磷酸化。在清醒大鼠中进行的正常血糖-高胰岛素钳夹研究（12 mU.kg(-1).min(-1) 胰岛素）表明；葡萄糖胺输注导致胰岛素抵抗快速诱导，葡萄糖输注率降低33%（P < 0.01）。在注射盐水和葡萄糖胺的大鼠中，仅在盐水（基础）、胰岛素推注（10 U/kg）后1分钟或胰岛素钳夹2小时后收获组织。在胰岛素刺激1分钟后，IRS-1和胰岛素受体的磷酸化在注射盐水的大鼠中增加6至8倍，在注射葡萄糖胺的大鼠中增加7至10倍。在注射盐水的大鼠中，1 分钟的胰岛素刺激使与 IRS-1、IRS-2 或磷酸酪氨酸相关的 PI 3 激酶活性分别增加了 7.6 倍、6.4 倍和 10 倍。在注射葡萄糖胺的大鼠中，用胰岛素治疗 1 分钟，与 IRS-1 相关的 PI 3 激酶活性降低了 28% (P < 0.01)，与磷酸酪氨酸相关的活性降低了 43% (P < 0.01)。在注射盐水和注射葡萄糖胺的大鼠中，胰岛素 1 分钟刺激的 Akt/PKB 活性类似于 5 倍；胰岛素诱导的 Akt/PKB 过度磷酸化在各组之间没有差异。单独输注葡萄糖胺对胰岛素受体或IRS-I的酪氨酸磷酸化或对PI 3-激酶或Akt/PKB活性的刺激没有影响。然而，2 小时的胰岛素钳夹降低了与 IRS-1、IRS-2 或磷酸酪氨酸相关的 PI 3 激酶活性，
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, me 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.kg(-1).min(-1)) or saline. Euglycemic-hyperinsulinemic clamp studies (12 mU.kg(-1).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 similar to 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-I 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