Normal hepatic glucose production in the absence of GLUT2 reveals an alternative pathway for glucose release from hepatocytes
Normal hepatic glucose production in the absence of GLUT2 reveals an alternative pathway for glucose release from hepatocytes
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DOI：
10.1073/pnas.95.21.12317
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发表时间：
1998-10-13
影响因子：
11.1
通讯作者：
Thorens, B
中科院分区：
文献类型：
--
作者：
Guillam, MT;Burcelin, R;Thorens, B
肝脏产生葡萄糖是一种主要的生理功能，这是防止餐后和空腹状态下发生低血糖所必需的。肝细胞释放葡萄糖的机制尚未被详细研究，而是被认为依赖于通过葡萄糖转运蛋白GLUT2的促进扩散。在这里，我们证明了在没有GLUT2的情况下，其他转运蛋白亚型在肝脏中没有过表达，只有轻微的促进跨肝细胞质膜的扩散被检测到。然而，肝脏葡萄糖输出率正常。这表现为：(1)腹腔注射的高血糖反应。(Ii)体内葡萄糖周转率的测量；(Iii)从分离的肝细胞释放新合成葡萄糖的速率。因此，这些观察结果表明，肝脏葡萄糖输出存在另一种途径。用[C-14]-丙酮酸脉冲标记法定量测定[C-14]葡萄糖的新合成和释放，我们证明该途径对低温(12℃)敏感，它不被细胞松弛素B或细胞内交通抑制剂布雷菲尔丁A和莫能菌素抑制，但被黄体酮(一种胆固醇和小窝从内质网到质膜的运输的抑制剂)阻断。因此，我们的观察表明，肝脏葡萄糖的释放不需要GLUT2的存在，也不需要任何质膜葡萄糖促进扩散的机制。这意味着可能存在一种未知的葡萄糖释放途径，这种途径可能基于膜运输机制。
Glucose production by liver is a major physiological function, which is required to prevent development of hypoglycemia in the postprandial and fasted states. The mechanism of glucose release from hepatocytes has not been studied in detail but was assumed instead to depend on facilitated diffusion through the glucose transporter GLUT2, Here, we demonstrate that in the absence of GLUT2 no other transporter isoforms were overexpressed in liver and only marginally significant facilitated diffusion across the hepatocyte plasma membrane was detectable. However, the rate of hepatic glucose output was normal. This was evidenced by (i) the hyperglycemic response to i.p. glucagon injection; (ii) the in vivo measurement of glucose turnover rate; and (iii) the rate of release of neosynthesized glucose from isolated hepatocytes. These observations therefore indicated the existence of an alternative pathway for hepatic glucose output. Using a [C-14]-pyruvate pulse-labeling protocol to quantitate neosynthesis and release of [C-14]glucose, we demonstrated that this pathway was sensitive to low temperature (12 degrees C), It was not inhibited by cytochalasin B nor by the intracellular traffic inhibitors brefeldin A and monensin but was blocked by progesterone, an inhibitor of cholesterol and caveolae traffic from the endoplasmic reticulum to the plasma membrane. Our observations thus demonstrate that hepatic glucose release does not require the presence of GLUT2 nor of any plasma membrane glucose facilitative diffusion mechanism. This implies the existence of an as yet unsuspected pathway for glucose release that may be based on a membrane traffic mechanism.