Karlsson F A, Van Obberghen E, Grunfeld C, Kahn C R
Proc Natl Acad Sci U S A. 1979 Feb;76(2):809-13. doi: 10.1073/pnas.76.2.809.
We have used an adipocyte-like cell line, the 3T3-L1 fatty fibroblasts, to compare acute and chronic effects of autoantibodies directed against the insulin receptor. Acute exposure of the cells in tissue culture to the antibodies resulted in a blockade of insulin binding and stimulation of 2-deoxy-glucose transport and glucose oxidation. Maximal acute effects were reached within 30-120 min. Subsequently, the stimulatory response decayed and, after 6 hr in the continuous presence of the antibodies, basal glucose metabolism had returned to the level observed with unexposed cells and a state of severe insulin resistance prevailed. In contrast to the decay of bioresponse, no change in insulin binding was detectable over the same time period. The mechanism of desensitization seemed to involve events early after insulin binding to receptor because cells exposed to antibody for prolonged periods of time, although unresponsive to insulin and antireceptor antibodies, responded normally to both spermine and vitamin K(5), agents that stimulate glucose metabolism independently of the insulin receptor. These data suggest that prolonged or continuous occupancy of the insulin receptor by a ligand, in this case antireceptor antibodies, does not produce a continuous biological response. Instead, there is desensitization at some early step in the pathway for insulin action. These observations have important implications with respect to the mechanism of insulin action and to other situations in which there is long-term exposure of cells to antibodies that react with membrane components.
我们使用了一种脂肪细胞样细胞系，即3T3-L1脂肪成纤维细胞，来比较针对胰岛素受体的自身抗体的急性和慢性效应。在组织培养中，细胞急性暴露于这些抗体导致胰岛素结合受阻，同时刺激2-脱氧葡萄糖转运和葡萄糖氧化。在30 - 120分钟内达到最大急性效应。随后，刺激反应衰减，在抗体持续存在6小时后，基础葡萄糖代谢恢复到未暴露细胞所观察到的水平，并且出现严重胰岛素抵抗状态。与生物反应的衰减相反，在同一时间段内未检测到胰岛素结合的变化。脱敏机制似乎涉及胰岛素与受体结合后的早期事件，因为长时间暴露于抗体的细胞，虽然对胰岛素和抗受体抗体无反应，但对精胺和维生素K(5)（这两种独立于胰岛素受体刺激葡萄糖代谢的物质）反应正常。这些数据表明，配体（在这种情况下是抗受体抗体）对胰岛素受体的长时间或持续占据不会产生持续的生物学反应。相反，在胰岛素作用途径的某个早期步骤存在脱敏现象。这些观察结果对于胰岛素作用机制以及细胞长期暴露于与膜成分反应的抗体的其他情况具有重要意义。
