Olefsky J M, Kolterman O G
Am J Med. 1981 Jan;70(1):151-68. doi: 10.1016/0002-9343(81)90422-8.
Insulin resistance is a characteristic feature of both obesity and noninsulin-dependent diabetes mellitus. In general, the causes of insulin resistance can be placed into three categories: (1) abnormal beta cell secretory products, (2) circulating insulin antagonists, and (3) target tissue defects in insulin action. In obesity and in noninsulin-dependent diabetes mellitus, the cause of the insulin resistance resides at the level of the target tissue. However, the specific mechanisms underlying these insulin-resistant states are heterogeneous. Mechanisms of insulin resistance can be evaluated by constructing in vivo dose-response curves using the euglycemic glucose clamp technique. If dose-response curves are shifted to the right with no impairment in maximal insulin action, then this is termed a decrease in "insulin sensitivity" and is consistent with a pure defect in insulin receptors. If a decrease in maximal insulin action exists, then this is termed a decrease in "insulin responsiveness" and is consistent with a postreceptor defect in insulin action. In obese patients, cellular insulin receptors are decreased and the magnitude of this decrease is inversely related to the degree of hyperinsulinemia. In those patients with only moderate hyperinsulinemia, the insulin resistance is not severe. In these patients, the in vivo dose-response curve between plasma insulin levels and glucose disposal demonstrates a rightward shift with no change in maximal insulin responsiveness. Thus, in this situation, insulin resistance is due to decreased insulin receptors only. In obese patients with more severe insulin resistance, decreased maximal insulin responsiveness is also seen indicating a combined receptor and postreceptor defect. In patients with non-insulin-dependent diabetes mellitus, the same phenomenon is observed; i.e., those patients with mild insulin resistance have decreased insulin sensitivity due to decreased insulin receptors whereas those with severe insulin resistance have decreased insulin sensitivity and decreased insulin responsiveness due to a combined receptor and postreceptor defect. When the spectrum of patients is examined, a continuum of defects exists. In patients with mild insulin resistance, decreased insulin receptors are the only abnormality; in patients with severe insulin resistance, decreased numbers of insulin receptors and the postreceptor defect in insulin action coexist, but the postreceptor defect is the predominant abnormality. Between these extremes the relative roles of receptor defects and postreceptor defects vary, but the general trend is that as insulin resistance worsens, the postreceptor defect becomes more prominant.
胰岛素抵抗是肥胖症和非胰岛素依赖型糖尿病的一个特征性表现。一般来说，胰岛素抵抗的原因可分为三类：（1）β细胞分泌产物异常；（2）循环中的胰岛素拮抗剂；（3）胰岛素作用的靶组织缺陷。在肥胖症和非胰岛素依赖型糖尿病中，胰岛素抵抗的原因在于靶组织水平。然而，这些胰岛素抵抗状态背后的具体机制是多种多样的。胰岛素抵抗的机制可以通过使用正常血糖葡萄糖钳夹技术构建体内剂量反应曲线来评估。如果剂量反应曲线向右移动而最大胰岛素作用没有受损，那么这被称为“胰岛素敏感性”降低，并且与胰岛素受体的单纯缺陷一致。如果存在最大胰岛素作用降低，那么这被称为“胰岛素反应性”降低，并且与胰岛素作用的受体后缺陷一致。在肥胖患者中，细胞胰岛素受体减少，这种减少的程度与高胰岛素血症的程度呈负相关。在那些只有中度高胰岛素血症的患者中，胰岛素抵抗并不严重。在这些患者中，血浆胰岛素水平与葡萄糖代谢之间的体内剂量反应曲线显示向右移动，而最大胰岛素反应性没有变化。因此，在这种情况下，胰岛素抵抗仅归因于胰岛素受体减少。在具有更严重胰岛素抵抗的肥胖患者中，也可见最大胰岛素反应性降低，表明存在受体和受体后联合缺陷。在非胰岛素依赖型糖尿病患者中，观察到相同的现象；即，那些轻度胰岛素抵抗的患者由于胰岛素受体减少而胰岛素敏感性降低，而那些严重胰岛素抵抗的患者由于受体和受体后联合缺陷而胰岛素敏感性和胰岛素反应性降低。当检查患者群体时，存在一系列连续不断的缺陷。在轻度胰岛素抵抗的患者中，胰岛素受体减少是唯一的异常；在严重胰岛素抵抗的患者中，胰岛素受体数量减少和胰岛素作用的受体后缺陷并存，但受体后缺陷是主要异常。在这些极端情况之间，受体缺陷和受体后缺陷的相对作用各不相同，但总体趋势是随着胰岛素抵抗加重，受体后缺陷变得更加突出。
