Hepatic glucagon receptor binding and glucose-lowening in vivo by peptidyl and non-peptidyl glucagon receptor antagonists
Hepatic glucagon receptor binding and glucose-lowening in vivo by peptidyl and non-peptidyl glucagon receptor antagonists
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DOI：
10.1016/j.ejphar.2004.08.023
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发表时间：
2004-10-06
影响因子：
5
通讯作者：
Jiang, GQ
中科院分区：
文献类型：
--
作者：
Dallas-Yang, Q;Shen, XL;Jiang, GQ
胰高血糖素受体拮抗剂作为治疗2型糖尿病的潜在治疗剂已被积极寻求。肽基和非肽基胰高血糖素受体拮抗剂已显示在动物和人类中阻断胰高血糖素诱导的血糖升高。拮抗剂和胰高血糖素受体如何在体内相互作用尚未报道，这是当前研究的主题。使用标记的胰高血糖素作为放射性示踪剂，我们在表达人胰高血糖素受体代替内源性小鼠胰高血糖素受体的小鼠（hGCGR小鼠）中开发了一种体内胰高血糖素受体占有率测定法。使用该测定法，我们首先表明胰高血糖素受体主要在肝脏中表达，在肾脏中表达的程度要小得多，并且在小鼠的几个其他组织/器官中低于检测。我们随后表明，以2 mg/kg体重（mg/pk）腹膜内（i. p.）给药，肽基胰高血糖素受体拮抗剂des-His-胰高血糖素与大约78%的肝胰高血糖素受体结合，并阻断外源性胰高血糖素诱导的小鼠血糖升高。最后，我们还表明，在10和30 mg/kg经口给药（p.o.），化合物A是一种非肽基小分子胰高血糖素受体拮抗剂，占据了肝胰高血糖素受体的65-70%，并显著降低了小鼠中外源性胰高血糖素诱导的血糖升高。然而，在3 mg/kg时，化合物A仅占据肝脏胰高血糖素受体的39%，并且不影响小鼠中外源性胰高血糖素诱导的血糖升高。总之，结果证实了先前的报告，即胰高血糖素受体主要存在于肝脏中，并提供了肽基和非肽基胰高血糖素受体拮抗剂在体内与肝胰高血糖素受体结合的第一个直接证据，并且至少60%的受体占有率与拮抗剂在体内的降糖功效相关。(C)2004 Elsevier B. V.保留所有权利。
Glucagon receptor antagonists have been actively pursued as potential therapeutics for the treatment of type 2 diabetes. Peptidyl and non-peptidyl glucagon receptor antagonists have been shown to block glucagon-induced blood glucose elevation in both animals and humans. How the antagonists and the glucagon receptor interact in vivo has not been reported and is the subject of the current study. Using labeled glucagon as a radiotracer, we developed an in vivo glucagon receptor occupancy assay in mice expressing a human glucagon receptor in place of the endogenous mouse glucagon receptor (hGCGR mice). Using this assay, we first showed that the glucagon receptor is expressed predominantly in liver, to a much lesser extent in kidney, and is below detection in several other tissues/organs in the mice. We subsequently showed that, at 2 mg/kg body weight (mg/pk) dosed intraperitoneally (i.p.), peptidyl glucagon receptor antagonist des-His-glucagon binds to similar to78% of the hepatic glucagon receptor and blocks an exogenous glucagon-induced blood glucose elevation in the mice. Finally, we also showed that, at 10 and 30 mg/kg dosed orally (p.o.), compound A, a non-peptidyl small molecule glucagon receptor antagonist, occupied 65-70% of the hepatic glucagon receptor, and significantly diminished exogenous glucagon-induced blood glucose elevation in the mice. At 3 mg/kg, however, compound A occupied only similar to39% of the hepatic glucagon receptor and did not affect exogenous glucagon-induced blood glucose elevation in the mice. Taken together, the results confirmed previous reports that glucagon receptors are present predominantly in the liver, and provide the first direct evidence that peptidyl and non-peptidyl glucagon receptor antagonists bind to the hepatic glucagon receptor in vivo, and that at least 60% receptor occupancy correlates with the glucose lowering efficacy by the antagonists in vivo. (C) 2004 Elsevier B.V. All rights reserved.