Enhanced peripheral glucose utilization in transgenic mice expressing the human GLUT4 gene.
Enhanced peripheral glucose utilization in transgenic mice expressing the human GLUT4 gene.
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DOI：
10.1016/s0021-9258(18)43974-9
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发表时间：
1994-11
期刊：
影响因子：
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通讯作者：
J. Treadway;D M Hargrove;N. A. Nardone;R. K. McPherson;J F Russo;A J Milici;H A Stukenbrok;E. Gibbs;R W Stevenson;J. E. Pessin
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文献类型：
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作者：
J. Treadway;D M Hargrove;N. A. Nardone;R. K. McPherson;J F Russo;A J Milici;H A Stukenbrok;E. Gibbs;R W Stevenson;J. E. Pessin
与非转基因对照相比，转基因小鼠的肌肉和脂肪组织中的人GLUT 4蛋白表达降低血浆胰岛素和葡萄糖水平，并改善葡萄糖耐量（Liu，M. L.，Gibbs，E. M.，McCoid，S. C.的方法，Milici，A. J.，Stukenbrok，H.一、麦克弗森河K.，特雷德韦，J.L.，和Pessin，J.E.等人（1993）Proc. Acad. Sci. U.S.A.90，11346-11350）。我们通过测定体内葡萄糖稳态和代谢谱，研究了hGLUT 4转基因小鼠血糖控制改善的基础。葡萄糖周转实验表明，相对于对照组，hGLUT 4小鼠的全身葡萄糖清除率高1.4倍（p < 0.05），而尽管葡萄糖水平低26%（p < 0.05），但肝脏葡萄糖产生相似。在正常血糖-高胰岛素钳夹过程中，hGLUT 4小鼠的葡萄糖输注速率比对照组高2倍（p < 0.05），骨骼肌和心脏糖原含量增加3-5倍（p < 0.05）。hGLUT 4小鼠外周葡萄糖清除率的增加与比目鱼肌中基础和胰岛素刺激的葡萄糖转运率的增加（25-32%）（p < 0.01）以及肌质膜相关GLUT 4蛋白的增加相关。与对照相比，喂食的hGLUT 4小鼠显示出血浆葡萄糖和胰岛素水平降低20-30%（p < 0.05）和胰高血糖素水平升高43%（p < 0.001）。由于低胰岛素血症诱导的脂解，甘油三酯、游离脂肪酸和β-羟基丁酸酯在hGLUT 4小鼠中升高43-63%（p < 0.05）。与对照组相比，hGLUT 4小鼠的游离脂肪酸和β-羟基丁酸水平在禁食后进一步增加，骨骼肌糖原水平显著降低。数据表明hGLUT 4的高水平表达增加体内全身葡萄糖清除和肌肉葡萄糖利用，并且还导致禁食期间显著的代偿性脂解和肌肉糖原分解。
Human GLUT4 protein expression in muscle and adipose tissues of transgenic mice decreases plasma insulin and glucose levels and improves glucose tolerance compared with nontransgenic controls (Liu, M.-L., Gibbs, E. M., McCoid, S. C., Milici, A. J., Stukenbrok, H. A., McPherson, R. K., Treadway, J. L., and Pessin, J. E. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 11346-11350). We examined the basis of improved glycemic control in hGLUT4 transgenic mice by determining glucose homeostasis and metabolic profiles in vivo. Glucose turnover experiments indicated a 1.4-fold greater systemic glucose clearance in hGLUT4 mice relative to controls (p < 0.05), whereas hepatic glucose production was similar despite 26% lower (p < 0.05) glucose levels. Glucose infusion rate during an euglycemic-hyperinsulinemic clamp was 2-fold greater (p < 0.05) in hGLUT4 mice versus controls, and skeletal muscle and heart glycogen content were increased 3-5-fold (p < 0.05). The increased peripheral glucose clearance in hGLUT4 mice was associated with increased (25-32%) basal and insulin-stimulated glucose transport rate in soleus muscle (p < 0.01), and increased muscle plasma membrane-associated GLUT4 protein. Fed hGLUT4 mice displayed 20-30% lower plasma glucose and insulin levels (p < 0.05) and 43% elevated glucagon levels (p < 0.001) compared with controls. Triglycerides, free fatty acids, and beta-hydroxy-butyrate were elevated 43-63% (p < 0.05) in hGLUT4 mice due to hypoinsulinemia-induced lipolysis. Free fatty acids and beta-hydroxybutyrate levels in hGLUT4 mice increased further upon fasting, and skeletal muscle glycogen levels decreased markedly compared with controls. The data demonstrate that high level expression of hGLUT4 increases systemic glucose clearance and muscle glucose utilization in vivo and also results in marked compensatory lipolysis and muscle glycogenolysis during a fast.