Antisense oligonucleotides targeted against glucocorticoid receptor reduce hepatic glucose production and ameliorate hyperglycemia in diabetic mice
Antisense oligonucleotides targeted against glucocorticoid receptor reduce hepatic glucose production and ameliorate hyperglycemia in diabetic mice
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DOI：
10.1016/j.metabol.2005.01.030
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发表时间：
2005-07-01
影响因子：
9.8
通讯作者：
Demarest, K
中科院分区：
文献类型：
--
作者：
Liang, Y;Osborne, MC;Demarest, K
特异性阻断肝脏中糖皮质激素受体（GCCR）的作用而不影响下丘脑-垂体-肾上腺轴可能是治疗2型糖尿病的一种新的药物途径。在本研究中，我们应用针对GCCR的反义寡核苷酸（ASO-GCCR）来降低肝脏GCCR的表达，并观察其对ob/ob和db/db小鼠糖尿病综合征的影响。ASO-GCCR（25 mg/kg IP，每周两次）的3周治疗方案显著降低了肝脏GCCR信使RNA和蛋白质表达，而下丘脑、垂体或肾上腺中的GCCR信使RNA表达无变化。与对照组相比，ASO-GCCR治疗使ob/ob和db/db小鼠的血糖水平分别降低了45%和23%。与对照小鼠相比，ASO-GCCR处理的小鼠在正常血糖-高胰岛素钳夹期间还显示出胰岛素介导的对肝脏葡萄糖产生的抑制显著增强，以及磷酸烯醇式丙酮酸羧激酶和葡萄糖6-磷酸酶活性显著降低。ASO-GCCR处理在钳夹期间不改变外周胰岛素敏感性。经ASO-GCCR处理的ob/ob小鼠血浆皮质酮和促肾上腺皮质激素水平与对照组相比无显著差异。接受类似ASO-GCCR治疗方案的瘦小鼠在血糖水平、口服葡萄糖耐量试验或胰岛素耐量试验中没有表现出变化。我们的结果表明，通过ASO-GCCR治疗选择性抑制肝脏中GCCR表达减少了肝脏葡萄糖产生并改善了糖尿病条件下的血糖控制。(c)2005年爱思唯尔公司All rights reserved.
Specific blockade of glucocorticoid receptor (GCCR) action in the liver without affecting the hypothalamus-pituitary-adrenal axis could be a novel pharmaceutical approach to treat type 2 diabetes. In the present study, we applied an antisense oligonucleotide (ASO) against GCCR (ASO-GCCR) to reduce the expression of liver GCCR and examined its impact on the diabetic syndrome in ob/ob and db/db mice. A 3-week treatment regimen of ASO-GCCR (25 mg/kg IP, twice per week) markedly reduced liver GCCR messenger RNA and protein expression with no alteration of GCCR messenger RNA expression in the hypothalamus, pituitary, or adrenal gland. The ASO-GCCR treatment lowered blood glucose levels by 45% and 23% in ob/ob and db/db mice, respectively, compared with those observed in the control group. The ASO-GCCR-treated mice also showed significant enhancement of insulin-mediated inhibition of hepatic glucose production during a euglycemic-hyperinsulinemic clamp as well as marked reduction of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity compared with control mice. The ASO-GCCR treatment did not change peripheral insulin sensitivity during the clamp. The ob/ob mice treated with ASO-GCCR had no significant difference in the plasma corticosterone and corticotropin levels compared with control mice. Lean mice receiving a similar treatment regimen of ASO-GCCR exhibited no change in blood glucose levels, oral glucose tolerance tests, or insulin tolerance tests. Our results demonstrate that selective inhibition of GCCR expression in the liver by the ASO-GCCR treatment reduced hepatic glucose production and improved blood glucose control under diabetic conditions. (c) 2005 Elsevier Inc. All rights reserved.