Le Marchand-Brustel Y, Jeanrenaud B, Freychet P
Am J Physiol. 1978 Apr;234(4):E348-58. doi: 10.1152/ajpendo.1978.234.4.E348.
To get some insight into the mechanisms of insulin resistance in obesity, insulin binding and biological effects were investigated in soleus muscles isolated from normal and obese mice. Basal and insulin-stimulated 2-deoxyglucose uptake were measured at the steady state of insulin binding. The results were consistent with the concept of spare receptors, i.e., maximal insulin effect was achieved when only about 20% of total receptors was occupied. When similar studies were applied to muscles of gold thioglucose obese or genetically obese (ob/ob) mice, and compared to lean controls: a) insulin binding was decreased; b) the insulin dose-response curve of 2-deoxyglucose uptake was shifted to the right; c) maximally insulin-stimulated 2-deoxyglucose uptake, glycolysis, and glycogen synthesis were markedly decreased. Insulin binding and effects returned toward normal after a 40-h fast in obese mice. These results point to two loci for the insulin resistance of skeletal muscle in obesity: 1) a decrease in the number of insulin receptors, which results in a diminished insulin sensitivity; and 2) one or more alterations beyond receptor that are responsible for the decreased responsiveness of the tissue to insulin and appear to play a major role in the insulin resistance of muscle in obesity.
为深入了解肥胖症中胰岛素抵抗的机制，对从正常小鼠和肥胖小鼠分离出的比目鱼肌中的胰岛素结合及生物学效应进行了研究。在胰岛素结合的稳定状态下测量基础状态及胰岛素刺激后的2-脱氧葡萄糖摄取。结果与备用受体的概念相符，即当仅约20%的总受体被占据时，可实现最大胰岛素效应。当将类似研究应用于金硫葡萄糖肥胖小鼠或遗传性肥胖（ob/ob）小鼠的肌肉，并与瘦对照进行比较时：a）胰岛素结合减少；b）2-脱氧葡萄糖摄取的胰岛素剂量反应曲线右移；c）最大胰岛素刺激的2-脱氧葡萄糖摄取、糖酵解和糖原合成显著减少。肥胖小鼠禁食40小时后，胰岛素结合及效应恢复正常。这些结果表明肥胖症中骨骼肌胰岛素抵抗存在两个位点：1）胰岛素受体数量减少，导致胰岛素敏感性降低；2）受体之外的一个或多个改变，这些改变导致组织对胰岛素的反应性降低，并且似乎在肥胖症中肌肉的胰岛素抵抗中起主要作用。
