SATURABLE TRANSPORT OF INSULIN FROM PLASMA INTO THE CENTRAL-NERVOUS-SYSTEM OF DOGS IN-VIVO - A MECHANISM FOR REGULATED INSULIN DELIVERY TO THE BRAIN
SATURABLE TRANSPORT OF INSULIN FROM PLASMA INTO THE CENTRAL-NERVOUS-SYSTEM OF DOGS IN-VIVO - A MECHANISM FOR REGULATED INSULIN DELIVERY TO THE BRAIN
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DOI：
10.1172/jci116773
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发表时间：
1993-10-01
影响因子：
15.9
通讯作者：
SCHWARTZ, MW
中科院分区：
文献类型：
--
作者：
BAURA, GD;FOSTER, DM;SCHWARTZ, MW
通过作用于中枢神经系统，循环胰岛素可以调节食物摄入和体重。我们以前已经表明，从血浆到脑脊液（CSF）的胰岛素摄取动力学可以最好地解释通过一个中间室。为了确定进入该隔室的转运动力学是否与胰岛素受体介导的转运过程一致，我们对禁食过夜的麻醉狗在宽范围的血浆胰岛素水平（69- 5，064 μ U/ml）（n = 10）下进行正常血糖静脉内胰岛素输注90分钟。在8小时内收集血浆和CSF样品用于测定免疫反应性胰岛素水平，并且使用具有三个组分（血浆->中间室-> CSF）的房室模型分析胰岛素从血浆摄取到CSF中的动力学。通过在血浆和CSF胰岛素水平快速变化期间频繁采样，我们能够精确估计三个参数（平均标准差14%），这些参数表征了胰岛素从血浆、通过中间室并进入CSF的摄取（k1 k2）;胰岛素进入CSF和胰岛素从中间室的清除（k2 + k3）;以及胰岛素从CSF的清除（k4）。在生理血浆胰岛素水平（80+/-7.4 muU/ml）下，k1 k2测定为10.7 × 10（-6）+/-1.3 × 10（-6）min-2。然而，随着血浆水平的增加，k1 k2逐渐降低，在超生理水平（5,064 μ U/ml）时降低了7倍。该饱和曲线的表观K（M）为742 μ U/ml（约5 nM）。相比之下，胰岛素从中间室和CSF中清除的速率常数不随血浆胰岛素变化（k2 + k3 = 0.011+/-0.0019 min-1和k4 = 0.046+/-0.021 min-1）。我们的结论是，血浆胰岛素进入中枢神经系统的传递是饱和的，并可能促进胰岛素受体介导的运输过程。
By acting in the central nervous system, circulating insulin may regulate food intake and body weight. We have previously shown that the kinetics of insulin uptake from plasma into cerebrospinal fluid (CSF) can best be explained by passage through an intermediate compartment. To determine if transport kinetics into this compartment were consistent with an insulin receptor-mediated transport process, we subjected overnight fasted, anesthetized dogs to euglycemic intravenous insulin infusions for 90 min over a wide range of plasma insulin levels (69-5,064 muU/ml) (n = 10). Plasma and CSF samples were collected over 8 h for determination of immunoreactive insulin levels, and the kinetics of insulin uptake from plasma into CSF were analyzed using a compartmental model with three components (plasma --> intermediate compartment --> CSF). By sampling frequently during rapid changes of plasma and CSF insulin levels, we were able to precisely estimate three parameters (average standard deviation 14%) characterizing the uptake of insulin from plasma, through the intermediate compartment and into CSF (k1k2); insulin entry into CSF and insulin clearance from the intermediate compartment (k2 + k3); and insulin clearance from CSF (k4). At physiologic plasma insulin levels (80+/-7.4 muU/ml), k1k2 was determined to be 10.7 X 10(-6)+/-1.3 x 10(-6) min-2. With increasing plasma levels, however, k1k2 decreased progressively, being reduced sevenfold at supraphysiologic levels (5,064 muU/ml). The apparent K(M) of this saturation curve was 742 muU/ml (approximately 5 nM). In contrast, the rate constants for insulin removal from the intermediate compartment and from CSF did not vary with plasma insulin (k2 + k3 = 0.011+/-0.0019 min-1 and k4 = 0.046+/-0.021 min-1). We conclude that delivery of plasma insulin into the central nervous system is saturable, and is likely facilitated by an insulin-receptor mediated transport process.