Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle - Implications for glucose toxicity
Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle - Implications for glucose toxicity
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DOI：
10.1172/jci118349
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发表时间：
1995-12-01
影响因子：
15.9
通讯作者：
Garvey, WT
中科院分区：
文献类型：
--
作者：
Baron, AD;Zhu, JS;Garvey, WT
葡萄糖胺（Glmn）是葡萄糖代谢通过己糖胺途径的产物，通过损害胰岛素诱导的GLUT - 4葡萄糖转运蛋白向质膜的易位，在离体脂肪细胞中引起胰岛素抵抗。我们假设Glmn在骨骼肌中通过类似的机制引起体内胰岛素抵抗。我们对清醒的雄性Sprague-Dawley大鼠进行了正糖高胰岛素钳夹（12 mu/kg/min + h -3-3-葡萄糖），注射和不注射Glmn的速率为0.1至6.5 mg/kg/min，在正糖钳夹4小时后，将后臀肌肉速冻并均质，通过差速离心分离膜，并在不连续的蔗糖梯度（25、30和35%蔗糖）上分离，膜蛋白被溶解并免疫印迹。葡萄糖吸收(GU)最大限度地减少了33 + / - 1%,P < 0.001,明显Glmn剂量减少50%的最大古0.1毫克/公斤/分钟或1/70th顾摩尔的基础上,控制半乳糖胺和mannosamine注入对顾没有影响,相对于基线,胰岛素引起过剩增加了2.6倍4膜分数(f)的25%,P < 0.01, 40%减少35%,P < 0.05,但没有影响过剩4 f在30%,P = NS,添加Glmn胰岛素引起的减少41%的过剩4 f 25%, P < 0.05, f, 29%下降30%和预防减少过剩4 f在35%,30% f膜受到第二次分离,vith 27和30%蔗糖梯度,胰岛素动员过剩4离30% f P < 0.05,但不是27%的f,相比之下,Glmn减少过剩4 f在27%,P < 0.05,但不是30%的f,因此,Glmn似乎改变insulin-insensitive过剩的易位4池,在25,30或35%的情况下，Glmn的联合输注不会改变肌层标记物5′-核苷酸酶，Na+/K(+) atp酶和磷脂蛋白的富集，因此，Glmn完全阻断胰岛素诱导的GLUT 4的运动，Glmn是体内胰岛素抵抗的有效诱导剂，通过引起（至少部分）GLUT 4易位和/或运输固有的缺陷，这些数据支持Glmn引起葡萄糖诱导的胰岛素抵抗（葡萄糖毒性）的潜在作用。
Glucosamine (Glmn), a product of glucose metabolism via the hexosamine pathway, causes insulin resistance in isolated adipocytes by impairing insulin-induced GLUT 4 glucose transporter translocation to the plasma membrane, We hypothesized that Glmn causes insulin resistance in vivo by a similar mechanism in skeletal muscle, We performed euglycemic hyperinsulinemic clamps (12 mu/kg/min + H-3-3-glucose) in awake male Sprague-Dawley rats with and without Glmn infusion at rates ranging from 0.1 to 6.5 mg/kg/min, After 4 h of euglycemic clamping, hindquarter muscles were quick-frozen and homogenized, and membranes were subfractionated by differential centrifugation and separated on a discontinuous sucrose gradient (25, 30, and 35% sucrose), Membrane proteins were solubilized and immunoblotted for GLUT 4, With Glmn, glucose uptake (GU) was maximally reduced by 33 +/- 1%, P < 0.001, The apparent Glmn dose to reduce maximal GU by 50% was 0.1 mg/kg/min or 1/70th the rate of GU on a molar basis, Control galactosamine and mannosamine infusions had no effect on GU, Relative to baseline, insulin caused a 2.6-fold increase in GLUT 4 in the 25% membrane fraction (f), P < 0.01, and a 40% reduction in the 35%f, P < 0.05, but had no effect on GLUT 4 in the 30%f, P = NS, Addition of Glmn to insulin caused a 41% reduction of GLUT 4 in the 25%f, P < 0.05, a 29% fall in the 30%f, and prevented the reduction of GLUT 4 in the 35%f, The 30%f membranes were subjected to a second separation,vith a 27 and 30% sucrose gradient, Insulin mobilized GLUT 4 away from the 30%f, P < 0.05, but not the 27%f, In contrast, Glmn reduced GLUT 4 in the 27%f, P < 0.05, but not the 30%f, Thus, Glmn appears to alter translocation of an insulin-insensitive GLUT 4 pool, Coinfusion of Glmn did not alter enrichment of the sarcolemmal markers 5'-nucleotidase, Na+/K(+)ATPase, and phospholemman in either 25, 30, or 35%f, Thus, Glmn completely blocked movement of GLUT 4 induced by insulin, Glmn is a potent inducer of insulin resistance in vivo by causing (at least in part) a defect intrinsic to GLUT 4 translocation and/or trafficking, These data support a potential role for Glmn to cause glucose-induced insulin resistance (glucose toxicity).