Tsao T S, Burcelin R, Katz E B, Huang L, Charron M J
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Diabetes. 1996 Jan;45(1):28-36. doi: 10.2337/diab.45.1.28.
Dysregulation of GLUT4, the insulin-responsive glucose transporter, is associated with insulin resistance in skeletal muscle. Although skeletal muscle is the major target of insulin action, muscle GLUT4 has not been linked causally to whole-body insulin sensitivity and regulation of glucose homeostasis. To address this, we generated a line of transgenic mice that overexpresses GLUT4 in skeletal muscle. We demonstrate that restricted overexpression of GLUT4 in fast-twitch skeletal muscles of myosin light chain (MLC)-GLUT4 transgenic mice induces a 2.5-fold increase in insulin-stimulated 2-deoxyglucose uptake in transgene-overexpressing cells. Consequently, glycogen content is increased in the fast-twitch skeletal muscles under insulin action (5.75 +/- 1.02 vs. 3.24 +/- 0.26 mg/g). This indicates that insulin-stimulated glucose transport is partly rate-limiting for glycogen synthesis. At the whole-body level, insulin-stimulated glucose turnover is increased 2.5-fold in unconscious MLC-GLUT4 mice. Plasma glucose and insulin levels in MLC-GLUT4 mice are altered as a result of increased insulin action. In 2- to 3-month-old MLC-GLUT4 mice, fasting insulin levels are decreased (0.43 +/- 0.05 vs. 0.74 +/- 0.10 microgram/l), whereas normal fasting glycemia is maintained. Conversely, 7- to 9-month-old MLC-GLUT4 mice exhibit decreased fasting glycemia (5.75 +/- 0.73 vs. 8.11 +/- 0.57 mmol/l) with normal insulin levels. Fasting plasma lactate levels are elevated in both age groups (50-100%). Additionally lipid metabolism is affected by skeletal muscle GLUT4 overexpression. This is indicated by changes in plasma free fatty acid and beta-hydroxybutyrate levels. These studies underscore the importance of GLUT4 in the regulation of glucose homeostasis and its interaction with lipid metabolism.
胰岛素反应性葡萄糖转运蛋白GLUT4的失调与骨骼肌中的胰岛素抵抗有关。虽然骨骼肌是胰岛素作用的主要靶器官，但肌肉中的GLUT4与全身胰岛素敏感性和葡萄糖稳态调节之间尚未建立因果联系。为了解决这个问题，我们培育了一种在骨骼肌中过表达GLUT4的转基因小鼠品系。我们证明，在肌球蛋白轻链（MLC）-GLUT4转基因小鼠的快肌骨骼肌中特异性过表达GLUT4，可使转基因过表达细胞中胰岛素刺激的2-脱氧葡萄糖摄取增加2.5倍。因此，在胰岛素作用下，快肌骨骼肌中的糖原含量增加（5.75±1.02对3.24±0.26毫克/克）。这表明胰岛素刺激的葡萄糖转运在一定程度上是糖原合成的限速因素。在全身水平上，无意识的MLC-GLUT4小鼠中胰岛素刺激的葡萄糖周转率增加了2.5倍。由于胰岛素作用增强，MLC-GLUT4小鼠的血浆葡萄糖和胰岛素水平发生了改变。在2至3月龄的MLC-GLUT4小鼠中，空腹胰岛素水平降低（0.43±0.05对0.74±0.10微克/升），而空腹血糖维持正常。相反，7至9月龄的MLC-GLUT4小鼠空腹血糖降低（5.75±0.73对8.11±0.57毫摩尔/升），胰岛素水平正常。两个年龄组的空腹血浆乳酸水平均升高（50-100%）。此外，骨骼肌GLUT4过表达会影响脂质代谢。血浆游离脂肪酸和β-羟基丁酸水平的变化表明了这一点。这些研究强调了GLUT4在葡萄糖稳态调节及其与脂质代谢相互作用中的重要性。
