Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs
Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs
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DOI：
10.2337/diabetes.45.1.86
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发表时间：
1996-01-01
期刊：
影响因子：
7.7
通讯作者：
Schwartz, MW
中科院分区：
文献类型：
--
作者：
Baura, GD;Foster, DM;Schwartz, MW
我们先前已经证明，血浆胰岛素向中枢神经系统(CNS)的转运是由一种饱和机制介导的，这种机制与胰岛素与血脑屏障胰岛素受体结合并随后通过微血管内皮细胞转运一致。由于糖皮质激素在外周和中枢神经系统都拮抗胰岛素受体介导的作用，我们假设糖皮质激素也会损害CNS胰岛素的转运，9只犬在对照组和大剂量口服地塞米松(12 mg/d)7d后进行研究，采集血浆和脑脊液样本8h以上，测定正常血糖静脉注射胰岛素90min(血浆胰岛素水平相当于700pmol/L)期间免疫活性胰岛素水平。根据这些数据，使用一个由三个组分(血浆-->；中间隔室，假设为脑间质液-gt；脑脊液)组成的数学模型来确定中枢神经系统胰岛素摄取和清除的动力学。地塞米松使基础胰岛素水平从24+/-6升至42+/-30 pmoL/L(P<；0.005)，基础血糖水平从5.0+/-0.7升至5.3/-1.0 mm ol/L(P<；0.05)。Dex还将表征中枢神经系统胰岛素转运的模型速率常数从5.3x10(-6)+/-4.0x10(-6)降至2.7x10(-6)+1.2x10(-6)min(-2)(P<或等于0.001)。由于糖皮质激素可以减少脑脊液的转运，我们还假设地塞米松会降低与脑脊液胰岛素清除相关的模型速率常数。不出所料，地塞米松治疗期间脑脊液胰岛素清除的模型速率常数从0.038+/-0.013下降到0.020+/-0.088分钟(-1)(P小于或等于0.0005)。我们得出结论，地塞米松损害了中枢胰岛素的转运，这一发现支持了我们的假设，即胰岛素受体参与了中枢胰岛素的转运过程，这一过程可能受到调节。此外，由于增加了脑胰岛素的转运，减少了食物摄入量和身体肥胖。这一观察提供了糖皮质激素过量导致身体肥胖增加的潜在机制。
We have previously Shown that transport of plasma insulin into the central nervous system (CNS) is mediated by a saturable mechanism consistent with insulin binding to blood-brain barrier insulin receptors and subsequent transcytosis through microvessel endothelial cells, Since glucocorticoids antagonize insulin receptor-mediated actions both peripherally and in the CNS, we hypothesized that glucocorticoids also impair CNS insulin transport, Nine dogs were studied both in the control condition and after 7 days of high-dose oral dexamethasone (DEX) administration (12 mg/day) by obtaining plasma and cerebrospinal fluid (CSF) samples over 8 h for determination of immunoreactive insulin levels during a 90-min euglycemic intravenous insulin infusion (plasma insulin similar to 700 pmol/l). From these data, the kinetics of CNS insulin uptake and removal were determined using a mathematical model with three components (plasma --> intermediate compartment, hypothesized to be brain interstitial fluid --> CSF). DEX increased basal insulin levels 75% from 24 +/- 6 to 42 +/- 30 pmol/l (P < 0.005) and slightly increased basal glucose levels from 5.0 +/- 0.7 to 5.3 +/- 1.0 mmol/l (P < 0.05). DEX also lowered the model rate constant characterizing CNS insulin transport by 49% from 5.3 x 10(-6) +/- 4.0 x 10(-6) to 2.7 x 10(-6) + 1.2 x 10(-6) min(-2) (P less than or equal to 0.001). As glucocorticoids are known to reduce CSF turnover, we also hypothesized that the model rate constant associated with CSF insulin removal would be decreased by DEX, As expected, the model rate constant for CSF insulin removal decreased 47% from 0.038 +/- 0.013 to 0.020 +/- 0.088 min(-1) (P less than or equal to 0.0005) during DEX treatment, We conclude that DEX impairs CNS insulin transport, This finding supports our hypothesis that insulin receptors participate in the CNS insulin transport process and that this process may be subject to regulation, Moreover, since increasing brain insulin transport reduces food intake and body adiposity, this observation provides a potential mechanism by which glucocorticoid excess leads to increased body adiposity.