Hansen P A, Han D H, Marshall B A, Nolte L A, Chen M M, Mueckler M, Holloszy J O
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Biol Chem. 1998 Oct 2;273(40):26157-63. doi: 10.1074/jbc.273.40.26157.
A high fat diet causes resistance of skeletal muscle glucose transport to insulin and contractions. We tested the hypothesis that fat feeding causes a change in plasma membrane composition that interferes with functioning of glucose transporters and/or insulin receptors. Epitrochlearis muscles of rats fed a high (50% of calories) fat diet for 8 weeks showed approximately 50% decreases in insulin- and contraction-stimulated 3-O-methylglucose transport. Similar decreases in stimulated glucose transport activity occurred in muscles of wild-type mice with 4 weeks of fat feeding. In contrast, GLUT1 overexpressing muscles of transgenic mice fed a high fat diet showed no decreases in their high rates of glucose transport, providing evidence against impaired glucose transporter function. Insulin-stimulated system A amino acid transport, insulin receptor (IR) tyrosine kinase activity, and insulin-stimulated IR and IRS-1 tyrosine phosphorylation were all normal in muscles of rats fed the high fat diet for 8 weeks. However, after 30 weeks on the high fat diet, there was a significant reduction in insulin-stimulated tyrosine phosphorylation in muscle. The increases in GLUT4 at the cell surface induced by insulin or muscle contractions, measured with the 3H-labeled 2-N-4-(1-azi-2,2, 2-trifluoroethyl)-benzoyl-1,3-bis-(D-mannose-4-yloxy)-2-propyla min e photolabel, were 26-36% smaller in muscles of the 8-week high fat-fed rats as compared with control rats. Our findings provide evidence that (a) impairment of muscle glucose transport by 8 weeks of high fat feeding is not due to plasma membrane composition-related reductions in glucose transporter or insulin receptor function, (b) a defect in insulin receptor signaling is a late event, not a primary cause, of the muscle insulin resistance induced by fat feeding, and (c) impaired GLUT4 translocation to the cell surface plays a major role in the decrease in stimulated glucose transport.
高脂饮食会导致骨骼肌葡萄糖转运对胰岛素和收缩产生抵抗。我们检验了这样一个假设，即高脂喂养会导致质膜成分发生变化，从而干扰葡萄糖转运体和/或胰岛素受体的功能。喂食高脂（占卡路里的50%）饮食8周的大鼠的肱三头肌，胰岛素刺激和收缩刺激的3 - O - 甲基葡萄糖转运降低了约50%。野生型小鼠喂食4周高脂饮食后，刺激的葡萄糖转运活性也出现类似降低。相比之下，喂食高脂饮食的转基因小鼠中过表达GLUT1的肌肉，其高葡萄糖转运速率并未降低，这为葡萄糖转运体功能未受损提供了证据。喂食高脂饮食8周的大鼠肌肉中，胰岛素刺激的系统A氨基酸转运、胰岛素受体（IR）酪氨酸激酶活性以及胰岛素刺激的IR和IRS - 1酪氨酸磷酸化均正常。然而，在高脂饮食30周后，肌肉中胰岛素刺激的酪氨酸磷酸化显著降低。用3H标记的2 - N - 4 -（1 - 叠氮 - 2,2,2 - 三氟乙基）- 苯甲酰基 - 1,3 - 双 -（D - 甘露糖 - 4 - 氧基）- 2 - 丙胺光标记法测量，8周高脂喂养大鼠的肌肉中，胰岛素或肌肉收缩诱导的细胞表面GLUT4增加量比对照大鼠小26 - 36%。我们的研究结果表明：（a）8周高脂喂养导致的肌肉葡萄糖转运受损并非由于质膜成分相关的葡萄糖转运体或胰岛素受体功能降低；（b）胰岛素受体信号缺陷是高脂喂养诱导的肌肉胰岛素抵抗的晚期事件，而非主要原因；（c）GLUT4向细胞表面的转位受损在刺激的葡萄糖转运减少中起主要作用。
