St-Denis J F, Cushman S W
Experimental Diabetes, Metabolism, and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Basic Clin Physiol Pharmacol. 1998;9(2-4):153-65. doi: 10.1515/jbcpp.1998.9.2-4.153.
Insulin stimulates glucose transport in skeletal muscle, heart, and adipose tissue by promoting the appearance of GLUT4, the major glucose transporter isoform present in these tissues, on the cell surface. This is achieved by differentially modulating GLUT4 exocytosis and endocytosis, between a specialized intracellular compartment and the plasma membrane. Ligands which activate the heterotrimeric GTP-binding proteins Gs and Gi appear to modulate insulin-stimulated glucose transport through effects on the fusion of docked GLUT4-containing vesicles with the plasma membrane. In insulin resistance states, reduced cellular GLUT4 levels in adipose cells fully account for the decreased glucose transport response to insulin in these cells. In contrast, although insulin-stimulated GLUT4 translocation is also impaired in muscle, total cellular levels of GLUT4 are not altered. The defect in muscle has been attributed to a GLUT4 trafficking problem and thus studies of this mechanism could provide clues as to the nature of the impairment. The movement of GLUT4-containing vesicles from an intracellular storage site to the plasma membrane and the fusion of docked GLUT4-containing vesicles with the plasma membrane are conceptually similar to some secretory processes. A general hypothesis called the SNARE hypothesis (soluble NSF attachment protein receptors where NSF stands for N-ethylmaleimide-sensitive fusion protein) postulates that the specificity of secretory vesicle targeting is generated by complexes that form between membrane proteins on the transport vesicle (v-SNARE's) and membrane proteins located on the target membrane (t-SNARE's). Several v- and t-SNARE's have been identified in adipose cells and muscle. VAMP2 and VAMP3/cellubrevin (v-SNARE's) have been shown to interact with the t-SNARE's syntaxin 4 and SNAP-23. The cytosolic protein NSF has the characteristic of binding to the v-/t-SNARE complex through its interaction with alpha-SNAP, another soluble factor. Furthermore, recent studies have demonstrated that VAMP2/3, syntaxin 4, SNAP-23, and NSF are functionally involved in insulin-stimulated GLUT4 translocation in adipose cells and thus are likely to be involved in the Gs- and Gi-mediated modulation of the glucose transport response to insulin as well. This review summarizes recent advances on the normal mechanism of GLUT4 translocation and discusses how this process could be affected in insulin resistant states such as type II diabetes.
胰岛素通过促使主要的葡萄糖转运体亚型GLUT4出现在细胞表面，从而刺激骨骼肌、心脏和脂肪组织中的葡萄糖转运。这一过程是通过在一个特殊的细胞内区室和质膜之间差异性地调节GLUT4的胞吐作用和内吞作用来实现的。激活异三聚体GTP结合蛋白Gs和Gi的配体似乎通过影响停靠的含GLUT4囊泡与质膜的融合来调节胰岛素刺激的葡萄糖转运。在胰岛素抵抗状态下，脂肪细胞中细胞GLUT4水平的降低完全可以解释这些细胞中对胰岛素的葡萄糖转运反应的下降。相比之下，虽然胰岛素刺激的GLUT4转位在肌肉中也受损，但细胞中GLUT4的总水平并未改变。肌肉中的缺陷归因于GLUT4的运输问题，因此对这一机制的研究可能为损伤的本质提供线索。含GLUT4囊泡从细胞内储存位点向质膜的移动以及停靠的含GLUT4囊泡与质膜的融合在概念上与一些分泌过程相似。一个被称为SNARE假说（可溶性NSF附着蛋白受体，其中NSF代表N-乙基马来酰亚胺敏感融合蛋白）的普遍假说是，分泌囊泡靶向的特异性是由运输囊泡上的膜蛋白（v-SNARE）和位于靶膜上的膜蛋白（t-SNARE）之间形成的复合物产生的。在脂肪细胞和肌肉中已经鉴定出了几种v-SNARE和t-SNARE。VAMP2和VAMP3/细胞ubrevin（v-SNARE）已被证明与t-SNARE syntaxin 4和SNAP-23相互作用。胞质蛋白NSF具有通过与另一种可溶性因子α-SNAP相互作用而与v-/t-SNARE复合物结合的特性。此外，最近的研究表明，VAMP2/3、syntaxin 4、SNAP-23和NSF在脂肪细胞中胰岛素刺激的GLUT4转位中发挥功能作用，因此也可能参与Gs和Gi介导的对胰岛素葡萄糖转运反应的调节。这篇综述总结了GLUT4转位正常机制的最新进展，并讨论了在II型糖尿病等胰岛素抵抗状态下这一过程可能如何受到影响。
