CARBENOXOLONE INCREASES HEPATIC INSULIN SENSITIVITY IN MAN - A NOVEL ROLE FOR 11-OXOSTEROID REDUCTASE IN ENHANCING GLUCOCORTICOID RECEPTOR ACTIVATION
CARBENOXOLONE INCREASES HEPATIC INSULIN SENSITIVITY IN MAN - A NOVEL ROLE FOR 11-OXOSTEROID REDUCTASE IN ENHANCING GLUCOCORTICOID RECEPTOR ACTIVATION
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DOI：
10.1210/jc.80.11.3155
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发表时间：
1995-11-01
影响因子：
5.8
通讯作者：
EDWARDS, CRW
中科院分区：
文献类型：
--
作者：
WALKER, BR;CONNACHER, AA;EDWARDS, CRW
在肾脏中，11 β-羟类固醇脱氢酶将皮质醇转化为可的松，保护盐皮质激素受体免受皮质醇的侵害。在肝脏中，该酶的不同亚型有利于11 β-还原酶将可的松转化为皮质醇。我们已经通过用甘珀酸抑制肝脏11 β-还原酶并观察对胰岛素敏感性的影响来验证肝脏11 β-还原酶增强肝脏中糖皮质激素受体活化的假设。7名健康男性参加了一项双盲随机交叉研究，其中口服甘珀酸（每8小时100 mg）或安慰剂给药7天。然后进行正常血糖高胰岛素钳夹研究，包括测量前臂葡萄糖摄取。甘珀酸增加全身胰岛素敏感性（葡萄糖输注速率的M值，安慰剂组为41.1 +/- 2.4 μ mol/kg min。44.6甘珀酸+/- 2.3; P < 0.03），但对前臂胰岛素敏感性没有影响。我们推断，甘珀酸，通过抑制肝脏11 β-还原酶和降低肝内皮质醇浓度，增加肝脏胰岛素敏感性和减少葡萄糖的产生。因此，血浆可的松提供了一个无活性的库，可以在11 β-还原酶表达的位点转化为活性糖皮质激素，异常的肝脏11 β-还原酶活性可能在胰岛素抵抗综合征中很重要，并且肝脏11 β-还原酶的操作可能有助于治疗胰岛素抵抗。
In the kidney, conversion of cortisol to cortisone by the enzyme 11 beta-hydroxysteroid dehydrogenase protects mineralocorticoid receptors from cortisol. In the liver, a different isoform of the enzyme favors 11 beta-reductase conversion of cortisone to cortisol. We have tested the hypothesis that hepatic 11 beta-reductase enhances glucocorticoid receptor activation in the liver by inhibiting the enzyme with carbenoxolone and observing effects on insulin sensitivity. Seven healthy males took part in a double blind randomized cross-over study in which oral carbenoxolone (100 mg every 8 h) or placebo was administered for 7 days. Euglycemic hyperinsulinemic clamp studies were then performed, including measurement of forearm glucose uptake. Carbenoxolone increased whole body insulin sensitivity (M values for dextrose infusion rates, 41.1 +/- 2.4 mu mol/kg min for placebo us. 44.6 +/- 2.3 for carbenoxolone; P < 0.03), but had no effect on forearm insulin sensitivity. We infer that carbenoxolone, by inhibiting hepatic 11 beta-reductase and reducing intrahepatic cortisol concentration, increases hepatic insulin sensitivity and decreases glucose production. Thus, plasma cortisone provides an inactive pool that can be converted to active glucocorticoids at sites where 11 beta-reductase is expressed, abnormal hepatic 11 beta-reductase activity might be important in syndromes of insulin resistance, and manipulation of hepatic 11 beta-reductase may be useful in treating insulin resistance.