Increased glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 1 expression in hepatocytes may contribute to the phenotype of type 2 diabetes in db/db mice
Increased glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 1 expression in hepatocytes may contribute to the phenotype of type 2 diabetes in db/db mice
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DOI：
10.2337/diabetes.54.1.32
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发表时间：
2005-01-01
期刊：
影响因子：
7.7
通讯作者：
Friedman, TC
中科院分区：
文献类型：
--
作者：
Liu, YJ;Nakagawa, Y;Friedman, TC
过量的组织糖皮质激素作用可能会导致与 2 型糖尿病相关的高血糖和胰岛素抵抗，但相关机制尚不清楚。 1 型 11β-羟基类固醇脱氢酶 (11β-HSD1) 将无活性的 11-脱氢皮质酮转化为活性皮质酮，从而放大糖皮质激素受体介导的组织糖皮质激素作用，特别是在肝脏中。为了研究组织糖皮质激素在 2 型糖尿病中的作用，我们分析了 db/db 小鼠（2 型糖尿病模型）肝细胞中糖皮质激素受体和 11β-HSD1 的表达及其体内和体外内源激素的调节。我们观察到 db/db 小鼠和 db/+ 对照肝脏中糖皮质激素受体和 11β-HSD1 的表达与胰岛素敏感性和 PEPCK mRNA 表达之间呈正相关。 db/db 小鼠肝脏中糖皮质激素受体和 11β-HSD1 表达的增加与皮质酮、胰岛素和血糖循环水平的升高相关。用糖皮质激素拮抗剂 RU486 治疗 db/db 小鼠，逆转了肝脏内糖皮质激素受体和 11β-HSD1 表达的增加，并减弱了 2 型糖尿病的表型。向 db/db 小鼠原代肝细胞中添加皮质酮可激活糖皮质激素受体、11β-HSD1 和 PEPCK 的表达，而这些作用被 RU486 消除。原代肝细胞与浓度增加的葡萄糖一起孵育导致糖皮质激素受体和11β-HSD1表达呈剂量依赖性增加，而胰岛素不影响原代肝细胞中11β-HSD1和糖皮质激素受体的表达。这些发现表明，肝脏内糖皮质激素受体的激活和 11β-HSD1 的表达可能有助于 db/db 小鼠患上 2 型糖尿病。
Excess tissue glucocorticoid action may contribute to the hyperglycemia and insulin resistance associated with type 2 diabetes, but the associated mechanisms are poorly understood. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive 11-dehydrocorticosterone into active corticosterone, thus amplifying glucocorticoid receptor-mediated tissue glucocorticoid action, particularly in the liver. To examine the role of tissue glucocorticoid action in type 2 diabetes, we analyzed expression of glucocorticoid receptor and 11beta-HSD1 and their regulation by endogenous hormones in vivo and in vitro in hepatocytes from db/db mice (a model of type 2 diabetes). We observed positive relations between expression of both glucocorticoid receptor and 11beta-HSD1 in liver and insulin sensitivity and expression of PEPCK mRNA in db/db mice and db/+ controls. Increased expression of glucocorticoid receptor and 11beta-HSD1 in the liver of db/db mice was correlated with elevated circulating levels of corticosterone, insulin, and blood glu-cose. Treatment of db/db mice with glucocorticoid antagonist RU486 reversed the increases in the expression of glucocorticoid receptor and 11beta-HSD1 within the liver and attenuated the phenotype of type 2 diabetes. Addition of corticosterone to db/db mouse primary hepatocytes activated expression of glucocorticoid receptor, 11beta-HSD1, and PEPCK, and these effects were abolished by RU486. Incubation of primary hepatocytes with increasing concentrations of glucose caused dose-dependent increases in glucocorticoid receptor and 11beta-HSD1 expression, whereas insulin did not affect the expression of 11beta-HSD1 and glucocorticoid receptor in primary hepatocytes. These findings suggest that activation of glucocorticoid receptor and 11beta-HSD1 expression within the liver may contribute to the development of type 2 diabetes in db/db mice.