Philippe J, Halban P A, Gjinovci A, Duckworth W C, Estreicher J, Renold A E
J Clin Invest. 1981 Mar;67(3):673-80. doi: 10.1172/JCI110082.
The role of the insulin-receptor compartment in the pharmacokinetics of intravenously injected insulin in rats was studied. Since streptozotocin-diabetes in rats results in increased insulin binding to tissues in vitro, insulin pharmacokinetics in streptozotocin-diabetic rats were compared to controls, using semisynthetic [(3)H]insulin as the tracer. The initial distribution volume for [(3)H]insulin was elevated by 60% in diabetic rats. By contrast, no difference in initial distribution volume for [(14)C]inulin was observed, and the absolute values were lower than those found for [(3)H]insulin. The metabolic clearance rate of [(3)H]insulin was elevated by 44% in diabetic rats. That these differences were the result of increased binding of insulin to a specific receptor compartment in diabetic rats was shown by three additional experiments. The first involved receptor saturation by injection of 10 U native insulin 2 min before the tracer injection, resulting in identical [(3)H]insulin disappearance rates in the two groups of rats. The second consisted of displacing [(3)H]insulin from receptors by injecting 10 U unlabeled insulin 6 min after the tracer injection. Displacement of intact [(3)H]insulin from receptors and subsequent reappearance in the circulation occurred in both control and diabetic animals; however, such displacement was 25% greater in the diabetic rats. Finally, treatment of diabetic rats with insulin for 8 d normalized [(3)H]insulin clearance even though the tracer was injected at a time when the animals were again hyperglycemic and hypoinsulinemic. This suggests that down-regulation of insulin receptors had occurred during insulin therapy. These results confirm that a specific compartment for insulin exists (the insulin-receptor compartment) and that this compartment plays an important role in insulin clearance.
研究了胰岛素受体区室在大鼠静脉注射胰岛素药代动力学中的作用。由于大鼠链脲佐菌素诱导的糖尿病会导致体外胰岛素与组织的结合增加，因此使用半合成的[(3)H]胰岛素作为示踪剂，比较了链脲佐菌素诱导的糖尿病大鼠与对照大鼠的胰岛素药代动力学。糖尿病大鼠中[(3)H]胰岛素的初始分布容积升高了60%。相比之下，未观察到[(14)C]菊粉的初始分布容积有差异，且其绝对值低于[(3)H]胰岛素的初始分布容积。糖尿病大鼠中[(3)H]胰岛素的代谢清除率提高了44%。另外三个实验表明，这些差异是糖尿病大鼠中胰岛素与特定受体区室结合增加的结果。第一个实验是在注射示踪剂前2分钟注射10 U天然胰岛素使受体饱和，结果两组大鼠中[(3)H]胰岛素的消失率相同。第二个实验是在注射示踪剂6分钟后注射10 U未标记胰岛素，将[(3)H]胰岛素从受体上置换下来。完整的[(3)H]胰岛素从受体上被置换下来并随后重新出现在循环中的情况在对照动物和糖尿病动物中均有发生；然而，糖尿病大鼠中的这种置换作用比对照大鼠大25%。最后，用胰岛素治疗糖尿病大鼠8天可使[(3)H]胰岛素清除率恢复正常，尽管示踪剂是在动物再次出现高血糖和低胰岛素血症时注射的。这表明在胰岛素治疗期间发生了胰岛素受体的下调。这些结果证实存在一个胰岛素的特定区室（胰岛素受体区室），并且该区室在胰岛素清除中起重要作用。
