Studies on molecular mechanism of etiology of diabetes mellitus

为了研究葡萄糖转运蛋白基因在糖尿病代谢状态改变中的表达调控，我们检测了不同胰岛素抵抗动物模型肝脏GLUT4和腓肠肌GLUT4的基因表达水平，包括Zucker脂肪、Wistar脂肪和链脲佐菌素(STZ)治疗的糖尿病大鼠。Northern印迹分析显示，与瘦子相比，14wk Zucker和Wistar肥胖大鼠的GLUT2mRNA水平显著升高(P&lt；0.001)，但在5wk时这两组大鼠的GLUT2基因表达水平相似。此外，STZ糖尿病大鼠治疗3wk后，GLUT2基因表达水平显著升高(P<0.01)。在所有动物模型中，正常大鼠和胰岛素抵抗大鼠的GLUT4基因表达水平均无显著差异。这些结果表明，高胰岛素血症和高血糖都不会影响肌肉中GLUT4mRNA的水平。然而，尽管存在…，肥胖和糖尿病患者肝脏中的GLUT2基因水平却升高。更多的h这一调节事件独立于循环中的胰岛素或葡萄糖浓度发生。另一方面，以往的研究表明，大鼠胰岛表达GLUT2-肝脏促进葡萄糖转运蛋白亚型，这是一种低亲和力但高葡萄糖转运能力的葡萄糖载体。这些研究表明，在大鼠胰岛中存在第二个葡萄糖转运体；然而，他们没有指出它对应于五个已知的促进性葡萄糖转运体中的哪一个。在本研究中，我们从大鼠的朗格汉斯胰岛中提取了RNA，并证实了GLUT2 mRNA的存在。此外，我们提供的数据表明，在胰岛表达的第二种亚型是GLUTI-红细胞亚型。用5.5、8.3和11.1 mM葡萄糖培养胰岛，观察其对GLUT1和GLUT2基因表达水平的影响。在11.1 mM葡萄糖中培养24 h的胰岛细胞中，GLUTI和GLUT2基因的表达水平分别是5.5 mM葡萄糖培养组的2倍和3倍。因此，先前观察到的葡萄糖引起的高血糖大鼠胰岛GLUT2基因表达水平的升高在体外可以被模拟，暗示葡萄糖调节GLUT2基因的表达。较少

In order to investigate the regulation of glucose transporter gene expression in the altered metabolic conditions of diabetes, we have measured MRNA levels encoding GLUT4 in the liver and GLUT4 in the gastrocnemius muscle from various insulin resistant animal models, including Zucker fatty, Wistar fatty, and streptozocin(STZ)-treated diabetic rats. Northern blot analysis revealed that GLUT2 MRNA levels were significantly(P<0.001)elevated in 14 wk Zucker fatty and Wistar fatty rats relative to lean littermates but were similar in these two groups at 5 wk of age. Furthermore, there was significant increase(P<0.01)in GLUT2 MRNA levels in STZ diabetic rats at 3 wk after treatment. GLUT4 MRNA levels were not significantly different between control and insulin resistant rats in all animal models. These results indicate that neither hyperinsulinemia nor hyperglycemia affects GLUT4 MRNA levels in the muscle. However, GLUT2 MRNA levels in the liver were elevated in obesity and diabetes, althoug … More h this regulatory event occurred independently from circulating insulin or glucose concentrations. On the other hand, previous studies revealed that rat islets express the GLUT2-liver facilitative glucose transporter isoform, a glucose carrier with a low affinity for glucose but a high capacity for glucose transport. These studies indicated the presence of a second glucose transporter in rat islets ; however, they did not indicate to which of the five known facilitative glucose transporters it corresponded. In this study, we isolated RNA from rat islets of Langerhans and confirmed the presence of GLUT2 MRNA. In addition, we present data indicating that the second isoform expressed in islets is the GLUTI-erythrocyte isoform. The effect of culturing islets in 5.5, 8.3 or 11.1 mM glucose on the levels of GLUT1 and GLUT2 MRNA also was examined. The levels of GLUTI and GLUT2 MRNA were two- and threefold higher, respectively, in islets cultured for 24 h in 11.1 mM glucose compared with those incubated in the presence of 5.5 mM glucose. Therefore, the previously observed increase in GLUT2 MRNA levels in the islets of rats made hyperglycemic by chronic infusion of glucose can be mimicked in vitro, implying that glucose regulates GLUT2 MRNA expression. Less