Jiménez-Chillarón Josep C, Telemaque-Potts Sabine, Gómez-Valadés Alícia G, Anderson Paul, Newgard Christopher B, Gómez-Foix Anna M
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
Metabolism. 2002 Jan;51(1):121-6. doi: 10.1053/meta.2002.29028.
Skeletal muscle has a prime role in glucose homeostasis. We have previously demonstrated that adenovirus-mediated glucokinase (GK) gene transfer to skeletal muscle of Wistar rats enhances muscle glucose uptake and whole body glucose disposal under conditions of hyperglycemia and hyperinsulinemia. In this study, we have tested whether GK gene transfer to the muscle of the Zucker Diabetic Fatty rat (ZDF), a genetic model of obesity and type 2 diabetes, could improve glycemic control and prevent the onset of hyperglycemia in obese males. We show that GK delivery results in a doubling of total gastrocnemius muscle glucose phosphorylating activity 9 weeks after gene transfer. GK-treated rats exhibited slightly reduced weight and normal insulin-sensitive glucose uptake, as assessed during an insulin tolerance test, whereas age-matched rats treated with a control virus were clearly insulin resistant. The improved glucose uptake in GK-expressing rats was associated with higher gastrocnemius lactate content, whereas glycogen and triacylglyceride (TAG) levels were unmodified. Remarkably, GK-treated rats showed increased expression of both hexokinase II (HKII) and GLUT4, in accordance with a glucose-dependent regulation of these proteins. Thus, our data show that delivery of GK, despite improving insulin-sensitive glucose disposal in muscle, is not sufficient to prevent or delay the appearance of elevated glucose and insulin levels associated with severe obesity in male ZDF animals.
骨骼肌在葡萄糖稳态中起主要作用。我们之前已经证明，腺病毒介导的葡萄糖激酶（GK）基因转移至Wistar大鼠的骨骼肌，可在高血糖和高胰岛素血症条件下增强肌肉葡萄糖摄取及全身葡萄糖代谢。在本研究中，我们测试了将GK基因转移至肥胖和2型糖尿病的遗传模型Zucker糖尿病脂肪大鼠（ZDF）的肌肉中，是否能改善血糖控制并预防肥胖雄性大鼠高血糖的发生。我们发现，基因转移9周后，GK导入使腓肠肌总葡萄糖磷酸化活性加倍。在胰岛素耐量试验中评估发现，经GK处理的大鼠体重略有降低，胰岛素敏感的葡萄糖摄取正常，而用对照病毒处理的年龄匹配大鼠明显存在胰岛素抵抗。GK表达大鼠葡萄糖摄取的改善与腓肠肌乳酸含量升高有关，而糖原和甘油三酯（TAG）水平未改变。值得注意的是，根据这些蛋白质的葡萄糖依赖性调节，经GK处理的大鼠己糖激酶II（HKII）和葡萄糖转运蛋白4（GLUT4）的表达均增加。因此，我们的数据表明，尽管GK导入改善了肌肉中胰岛素敏感的葡萄糖代谢，但不足以预防或延缓雄性ZDF动物中与严重肥胖相关的血糖和胰岛素水平升高的出现。
