Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors
Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors
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DOI：
10.2337/diabetes.53.5.1326
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发表时间：
2004-05-01
期刊：
影响因子：
7.7
通讯作者：
Drucker, DJ
中科院分区：
文献类型：
--
作者：
Hansotia, T;Baggio, LL;Drucker, DJ
葡萄糖依赖型促胰岛素多肽(GIP)和胰升糖素样肽1(GLP-1)是肠道来源的胰岛素，可促进营养摄入后的葡萄糖清除。在GIPR(-/-)或GLP-1R(-/-)小鼠中消除胰岛素受体的作用只会对葡萄糖稳态造成轻微的损害，可能是由于代偿性上调了剩余的胰岛素。我们现在已经研究了双胰岛素受体基因敲除(DIRKO)小鼠的葡萄糖稳态。DIRKO小鼠体重正常，在外源性给予GIP或GLP-1R激动剂exendin-4后未能表现出改善的血糖反应。在DIRKO小鼠中，血浆胰高血糖素和外源性胰岛素的降糖反应是正常的。与GIPR(-/-)或GLP-1R(-/-)小鼠相比，口服葡萄糖刺激后DIRKO小鼠的血糖漂移异常增加，葡萄糖刺激的胰岛素分泌水平下降，但未见明显变化。同样，葡萄糖刺激的胰岛素分泌和对Forskolin的反应在灌流的DIRKO胰岛中保存得很好。虽然二肽基肽酶-IV(DPP-IV)抑制剂valine pyrrolidide(Val-PYR)和SYR106124在野生型和单一INS受体基因敲除小鼠中降低血糖和升高血浆胰岛素，但DPP-IV抑制剂在DIRKO小鼠中的降糖作用被消除。这些发现表明，即使完全缺乏两种胰岛素受体，葡萄糖刺激的胰岛素分泌仍保持不变，并且它们描绘了胰岛素受体作为DPP-IV抑制剂急性糖调节作用的关键下游靶点的关键作用。
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived incretins that potentiate glucose clearance following nutrient ingestion. Elimination of incretin receptor action in GIPR(-/-) or GLP-1R(-/-) mice produces only modest impairment in glucose homeostasis, perhaps due to compensatory upregulation of the remaining incretin. We have now studied glucose homeostasis in double incretin receptor knockout (DIRKO) mice. DIRKO mice exhibit normal body weight and fail to exhibit an improved glycemic response after exogenous administration of GIP or the GLP-1R agonist exendin-4. Plasma glucagon and the hypoglycemic response to exogenous insulin were normal in DIRKO mice. Glycemic excursion was abnormally increased and levels of glucose-stimulated insulin secretion were decreased following oral but not intraperitoneal glucose challenge in DIRKO compared with GIPR(-/-) or GLP-1R(-/-) mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin in wildtype and single incretin receptor knockout mice, the glucose-lowering actions of DPP-IV inhibitors were eliminated in DIRKO mice. These findings demonstrate that glucose-stimulated insulin secretion is maintained despite complete absence of both incretin receptors, and they delineate a critical role for incretin receptors as essential downstream targets for the acute glucoregulatory actions of DPP-IV inhibitors.