GIP and GLP-1 as incretin hormones: Lessons from single and double incretin receptor knockout mice
GIP and GLP-1 as incretin hormones: Lessons from single and double incretin receptor knockout mice
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DOI：
10.1016/j.regpep.2004.07.019
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发表时间：
2005-06-15
影响因子：
--
通讯作者：
Drucker, DJ
中科院分区：
文献类型：
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作者：
Hansotia, T;Drucker, DJ
葡萄糖依赖性促胰岛素多肽(GIP)和胰高血糖素样肽-1(GLP-1)是肠道来源的胰岛素，在营养摄入时分泌。这两种胰岛素通过调节β细胞的增殖、新生和凋亡，增强了依赖葡萄糖的胰岛素的分泌，增加了β细胞的质量。相反，GLP-1，而不是GIP，可以抑制胃排空、胰高血糖素分泌和食物摄入。此外，2型糖尿病患者对GIP的作用表现出相对的抵抗力，但对GLP-1R激动剂没有影响。通过建立和分析INS受体基因敲除小鼠，研究了这两种INS的生理意义。消除GIPR(-/-)或GLP-1R(-/-)小鼠的胰岛素受体作用只会对葡萄糖稳态造成轻微的损害。同样，双胰岛素受体基因敲除(DIRKO)小鼠表现出正常体重和正常水平的血浆胰高血糖素以及对外源性胰岛素的降糖反应。然而，在DIRKO小鼠中，葡萄糖刺激的胰岛素分泌在口服葡萄糖刺激后显著减少，但在DIRKO小鼠中没有。DPP-IV抑制剂的降糖作用在DIRKO小鼠中消失。因此，胰岛素受体信号对血糖稳态具有重要的生理作用，是开发治疗2型糖尿病药物的一个有吸引力的药理靶点。(C)2004爱思唯尔B.V.保留所有权利。
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretins secreted in response to nutrient ingestion. Both incretins potentiate glucose-dependent insulin secretion and enhance beta-cell mass through regulation of beta-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. Furthermore, human subjects with Type 2 diabetes exhibit relative resistance to the actions of GIP, but not GLP-1R agonists. The physiological importance of both incretins has been investigated through generation and analysis of incretin receptor knockout mice. Elimination of incretin receptor action in GIPR(-/-) or GLP-1R(-/-) mice produces only modest impairment in glucose homeostasis. Similarly, double incretin receptor knockout (DIRKO) mice exhibit normal body weight and normal levels of plasma glucagon and hypoglycemic responses to exogenous insulin. However, glucose-stimulated insulin secretion is significantly decreased following oral but not intraperitoneal glucose challenge in DIRKO mice and the glucose lowering actions of dipeptidyl peptidase-IV (DPP-IV) inhibitors are extinguished in DIRKO mice. Hence, incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes. (c) 2004 Elsevier B.V. All rights reserved.