Dexamethasone induces posttranslational degradation of GLUT2 and inhibition of insulin secretion in isolated pancreatic beta cells - Comparison with the effects of fatty acids
Dexamethasone induces posttranslational degradation of GLUT2 and inhibition of insulin secretion in isolated pancreatic beta cells - Comparison with the effects of fatty acids
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DOI：
10.1074/jbc.272.6.3216
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发表时间：
1997-02-07
影响因子：
4.8
通讯作者：
Thorens, B
中科院分区：
文献类型：
--
作者：
Gremlich, S;Roduit, R;Thorens, B
在糖尿病啮齿动物的葡萄糖无反应胰腺β细胞中，GLUT 2表达强烈降低。这种降低的表达是由于不同于胰岛素或葡萄糖的循环因子，在这里，我们评估了棕榈酸和合成的糖皮质激素去甲肾上腺素对体外培养的大鼠胰岛GLUT 2表达的影响。棕榈酸诱导GLUT 2 mRNA水平降低40%，但对蛋白表达无一致影响，相反，地塞米松对GLUT 2 mRNA无影响，但使GLUT 2蛋白降低约65%。地塞米松的作用在高葡萄糖浓度下更明显，并被糖皮质激素拮抗剂RU-486抑制。生物合成标记实验表明，GLUTS翻译率仅受地塞米松的影响最小，但其半衰期减少了50%，表明糖皮质激素激活了翻译后降解机制。由于Na+/K+-ATP酶的α亚基不受影响，因此这种降解机制并不影响所有膜蛋白，棕榈酸和/或地塞米松处理强烈降低了葡萄糖诱导的胰岛素分泌。在棕榈酸的存在下，胰岛素含量降低（类似于55%），但在地塞米松的存在下增加（类似于180%）。我们得出结论，升高的脂肪酸和糖皮质激素的组合可以诱导糖尿病β细胞中观察到的两个共同特征，GLUT 2表达降低和葡萄糖诱导的胰岛素分泌丧失。
GLUT2 expression is strongly decreased in glucose-unresponsive pancreatic beta cells of diabetic rodents. This decreased expression is due to circulating factors distinct from insulin or glucose, Here we evaluated the effect of palmitic acid and the synthetic glucocorticoid desamethasone on GLUT2 expression by in vitro cultured rat pancreatic islets. Palmitic acid induced a 40% decrease in GLUT2 mRNA levels with, however, no consistent effect on protein expression, Dexamethasone, in contrast, had no effect on GLUT2 mRNA, but decreased GLUT2 protein by about 65%. The effect of dexamethasone was more pronounced at high glucose concentrations and was inhibited by the glucocorticoid antagonist RU-486. Biosynthetic labeling experiments revealed that GLUTS translation rate was only minimally affected by dexamethasone, but that its half-life was decreased by 50%, indicating that glucocorticoids activated a posttranslational degradation mechanism. This degradation mechanism was not affecting all membrane proteins, since the alpha subunit of the Na+/K+-ATPase was unaffected, Glucose-induced insulin secretion was strongly decreased by treatment with palmitic acid and/or dexamethasone. The insulin content was decreased (similar to 55 percent) in the presence of palmitic acid, but increased (similar to 180%) in the presence of dexamethasone. We conclude that a combination of elevated fatty acids and glucocorticoids can induce two common features observed in diabetic beta cells, decreased GLUT2 expression, and loss of glucose-induced insulin secretion.