Pre-Exposure to Glucosamine Induces Insulin Resistance of Glucose Transport and Glycogen Synthesis in Isolated Rat Skeletal Muscles: Study of Mechanisms in Muscle and in Rat-1 Fibroblasts Overexpressing the Human Insulin Receptor
Pre-Exposure to Glucosamine Induces Insulin Resistance of Glucose Transport and Glycogen Synthesis in Isolated Rat Skeletal Muscles: Study of Mechanisms in Muscle and in Rat-1 Fibroblasts Overexpressing the Human Insulin Receptor
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DOI：
10.2337/diab.42.9.1333
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发表时间：
1993-09
期刊：
影响因子：
7.7
通讯作者：
Kathrine A Robinson;D. Sens;M. Buse
中科院分区：
文献类型：
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作者：
Kathrine A Robinson;D. Sens;M. Buse
葡萄糖通过己糖胺生物合成途径的增加与葡萄糖诱导的胰岛素抵抗培养脂肪细胞的葡萄糖转运有关。由于氨基葡萄糖和葡萄糖都以氨基葡萄糖-6-磷酸的形式进入这一途径，我们在分离的大鼠横隔膜和高表达人胰岛素受体的成纤维细胞(hir-细胞)中检测了氨基葡萄糖预培养的效果。在肌肉中，预先暴露于氨基葡萄糖以时间和剂量依赖的方式抑制随后的基础，并在更大程度上抑制胰岛素刺激的葡萄糖运输，并取消胰岛素对糖原合成的刺激。氨基葡萄糖预处理不影响胰岛素受体数目、胰岛素受体酪氨酸激酶的原位和溶解后的激活以及葡萄糖转运体的总库(GLUT4)，并激活糖原合成酶。在表达GLUT1而不表达GLUT4的HIR细胞中，氨基葡萄糖不影响葡萄糖的基础转运和胰岛素刺激的葡萄糖转运，但明显抑制糖原合成。胰岛素刺激的蛋白激酶(MAP和S6)的激活不受影响，糖原合成酶的分数速度和表观总活性在氨基葡萄糖处理的HIR细胞中增加。在脉冲标记研究中，在追赶过程中加入氨基葡萄糖延长了胰岛素前受体对受体的加工，并改变了前受体和加工的α亚基的电泳率，与糖基化改变一致。氨基葡萄糖引起的葡萄糖转运的胰岛素抵抗似乎仅限于表达GLUT4的细胞，即骨骼肌和脂肪细胞；这可能反映了GLUT4到质膜的转运受损。氨基葡萄糖引起的UDP糖的失衡，即UDP-N-乙酰己糖胺的增加和UDP-葡萄糖的减少，可能改变关键蛋白质的糖基化，限制葡萄糖进入糖原的流量。
Increased routing of glucose through the hexosamine-biosynthetic pathway has been implicated in the development of glucose-induced insulin resistance of glucose transport in cultured adipocytes. Because both glucosamine and glucose enter this pathway as glucosamine-6-phosphate, we examined the effects of preincubation with glucosamine in isolated rat diaphragms and in fibroblasts overexpressing the human insulin receptor (HIR-cells). In muscles, pre-exposure to glucosamine inhibited subsequent basal and, to a greater extent, insulin-stimulated glucose transport in a time- and dose-dependent manner and abolished the stimulation by insulin of glycogen synthesis. Insulin receptor number, activation of the insulin receptor tyrosine kinase in situ and after solubilization, and the total pool of glucose transporters (GLUT4) were unaffected, and glycogen synthase was activated by glucosamine pretreatment. In HIR-cells, which express GLUT1 and not GLUT4, basal and insulin-stimulated glucose transport were unaffected by glucosamine, but glycogen synthesis was markedly inhibited. Insulin-stimulated activation of protein kinases (MAP and S6) was unaffected, and the fractional velocity and apparent total activity of glycogen synthase was increased in glucosamine-treated HIR-cells. In pulse-labeling studies, addition of glucosamine during the chase prolonged processing of insulin proreceptors to receptors and altered the electrophoretic mobility of proreceptors and processed α-subunits, consistent with altered glycosylation. Glucosamine-induced insulin resistance of glucose transport appears to be restricted to GLUT4-expressing cells, i.e., skeletal muscle and adipocytes; it may reflect impaired translocation of GLUT4 to the plasmalemma. The glucosamine-induced imbalance in UDP sugars, i.e., increased UDP-N-acetylhexosamines and decreased UDP-glucose, may alter glycosylation of critical proteins and limit the flux of glucose into glycogen.