Effects of the 11β-hydroxysteroid dehydrogrenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes
Effects of the 11β-hydroxysteroid dehydrogrenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes
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DOI：
10.1210/jc.2002-021194
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发表时间：
2003-01-01
影响因子：
5.8
通讯作者：
Walker, BR
中科院分区：
文献类型：
--
作者：
Andrews, RC;Rooyackers, O;Walker, BR
11 β-羟基类固醇脱氢酶1型（11 β-HSD 1）从肝脏和脂肪组织中的无活性可的松再生皮质醇。抑制11 β-HSD 1提供了一种新的潜在疗法，以降低细胞内皮质醇浓度，从而增强2型糖尿病、肥胖症和高脂血症患者的胰岛素敏感性和肝脏脂质代谢。我们评估了这种方法使用非选择性11 β-HSD抑制剂，甘珀酸，在健康男性和瘦男性2型糖尿病患者。6名饮食控制的非肥胖糖尿病患者血红蛋白A（1c）低于8%，和6名匹配的对照参加了一个双盲，交叉比较甘珀酸（100毫克，每8小时，口服，7天）和安慰剂。他们入院过夜输注胰岛素（根据需要维持动脉化血糖5.0 mm）和[C-13（6）]葡萄糖。在0700-0730 h空腹状态下，在3小时正常血糖高胰岛素钳夹（包括生长抑素输注和生理GH和胰高血糖素水平的替代）期间，以及在胰高血糖素水平增加4倍的2小时正常血糖高胰岛素钳夹期间，测量葡萄糖动力学。数据为平均值+/- SEM。甘珀酸具有升高血压和降低血浆钾的预期效果。甘珀酸降低健康受试者的总胆固醇（5.25 +/- 0.34 vs. 4.78 +/- 0.40 mm; P < 0.01），但对其他血脂或糖尿病患者的胆固醇没有影响。甘珀酸不影响高胰岛素血症期间的葡萄糖处置率或游离脂肪酸的抑制。然而，甘珀酸降低了糖尿病患者高胰高血糖素血症期间的葡萄糖生成速率（1.90 +/- 0.2 vs 1.53 +/- 0.3 mg/kg（.）min; P < 0.05）。这归因于糖原分解减少（1.31 +/- 0.2 vs 1.01 +/- 0.2 mg/kg（.）min; P < 0.005），而不是改变肝脏的新生血管生成。这些观察结果加强了抑制2型糖尿病患者肝脏中11 β-HSD 1的潜在代谢益处。现在需要进一步研究肥胖和高脂血症。然而，临床上有用的治疗效果可能需要选择性的11 β-HSD 1抑制剂，降低脂肪内皮质醇水平，提高外周葡萄糖摄取。
11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates cortisol from inactive cortisone in liver and adipose tissue. Inhibition of 11beta-HSD1 offers a novel potential therapy to lower intracellular cortisol concentrations and thereby enhance insulin sensitivity and hepatic lipid catabolism in type 2 diabetes, obesity, and hyperlipidemia. We evaluated this approach using the nonselective 11beta-HSD inhibitor, carbenoxolone, in healthy men and lean male patients with type 2 diabetes.Six diet-controlled nonobese diabetic patients with hemoglobin A(1c) less than 8%, and six matched controls participated in a double-blind, cross-over comparison of carbenoxolone (100 mg every 8 h, orally, for 7 d) and placebo. They were admitted overnight for infusions of insulin (as required to maintain arterialized plasma glucose of 5.0 mm) and [C-13(6)]glucose. Glucose kinetics were measured in the fasted state from 0700-0730 h, during a 3-h euglycemic hyperinsulinemic clamp (including somatostatin infusion and replacement of physiological GH and glucagon levels), and during a 2-h euglycemic hyperinsulinemic clamp with a 4-fold increase in glucagon levels. Data are the mean +/- SEM.Carbenoxolone had the expected effects of raising blood pressure and lowering plasma potassium. Carbenoxolone reduced total cholesterol in healthy subjects (5.25 +/- 0.34 vs. 4.78 +/- 0.40 mm; P < 0.01), but had no effect on other serum lipids or on cholesterol in diabetic patients. Carbenoxolone did not affect the rate of glucose disposal or the suppression of free fatty acids during hyperinsulinemia. However, carbenoxolone reduced the glucose production rate during hyperglucagonemia in diabetic patients (1.90 +/- 0.2 vs. 1.53 +/- 0.3 mg/kg(.)min; P < 0.05). This was attributable to reduced glycogenolysis (1.31 +/- 0.2 vs. 1.01 +/- 0.2 mg/kg(.)min; P < 0.005) rather than altered gluconeogenesis.These observations reinforce the potential metabolic benefits of inhibiting 11beta-HSD1 in the liver of patients with type 2 diabetes. Further studies in obesity and hyperlipidemia are now warranted. However, clinically useful therapeutic effects will probably require selective 11beta-HSD1 inhibitors that lower intraadipose cortisol levels and enhance peripheral glucose uptake.