Houdali B, Nguyen V, Ammon H P T, Haap M, Schechinger W, Machicao F, Rett K, Häring H-U, Schleicher E D
Department of Endocrinology, Metabolism and Pathobiochemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany.
Diabetologia. 2002 Mar;45(3):356-68. doi: 10.1007/s00125-001-0754-9.
AIMS/HYPOTHESIS: Previous studies on diabetic patients have shown that hyperglycaemia increases glucose uptake in an apparently insulin-independent manner. However, the molecular mechanism has not been clarified.
We studied rats receiving continuous glucose infusion to address this question. In this animal model, rats accommodate systemic glucose oversupply and rapidly develop insulin resistance.
Glucose infusion increased both plasma glucose and insulin concentrations to peak after one day. In spite of continuous glucose infusion normoglycaemia was reached after 5 days while insulin concentrations remained higher. Focusing our studies in day 2 (hyperglycaemia/hyperinsulinaemia) and day 5 (normoglycaemia/hyperinsulinaemia) we found, particularly in day 5, that the early steps of the insulin signalling cascade in skeletal muscle of glucose-infused rats were not more activated when compared to control animals as assessed by a comparable phosphorylation of the insulin receptor, IRS-1 and PKB and by an unaltered IRS-1-associated Ptd(Ins) 3' kinase activity. Continuous glucose infusion induced GLUT4 protein expression and translocation to the plasma membrane while neither expression nor translocation of GLUT1 was affected. Translocation of PKC- betaI, - betaII (> threefold) and -alpha, -theta (to a lesser extent) to the plasma membrane was significantly induced after 2 days but not after 5 days of glucose infusion when normoglycaemia was reached.
CONCLUSIONS/INTERPRETATION: Our data support the hypothesis that continuous glucose infusion induces translocation of GLUT4 while the early steps of the insulin signalling cascade were not increased. These effects could be mediated by activation of PKC.
目的/假设：先前针对糖尿病患者的研究表明，高血糖以明显不依赖胰岛素的方式增加葡萄糖摄取。然而，其分子机制尚未阐明。
我们通过研究持续输注葡萄糖的大鼠来解决这个问题。在这个动物模型中，大鼠适应全身葡萄糖供应过多并迅速发展为胰岛素抵抗。
葡萄糖输注使血浆葡萄糖和胰岛素浓度在一天后均升至峰值。尽管持续输注葡萄糖，但5天后血糖恢复正常，而胰岛素浓度仍较高。我们将研究重点放在第2天（高血糖/高胰岛素血症）和第5天（正常血糖/高胰岛素血症），发现特别是在第5天，与对照动物相比，输注葡萄糖的大鼠骨骼肌中胰岛素信号级联反应的早期步骤并未因胰岛素受体、IRS-1和蛋白激酶B的磷酸化水平相当以及IRS-1相关的磷脂酰肌醇-3激酶活性未改变而被更多激活。持续输注葡萄糖诱导了葡萄糖转运蛋白4（GLUT4）的蛋白表达并使其转位至质膜，而葡萄糖转运蛋白1（GLUT1）的表达和转位均未受影响。葡萄糖输注2天后，蛋白激酶C-βI、-βII（超过三倍）以及-α、-θ（程度较轻）转位至质膜的现象显著诱导，但在达到正常血糖的第5天葡萄糖输注后未出现这种情况。
结论/解读：我们的数据支持这样的假设，即持续输注葡萄糖诱导了GLUT4的转位，而胰岛素信号级联反应的早期步骤并未增强。这些效应可能由蛋白激酶C的激活介导。
