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首页> 外文期刊>The journal of clinical investigation >Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis
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Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

机译：小鼠体内胰高血糖素和GLP-1受体的双重消除揭示了肠降血糖素轴的可塑性

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Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor ( Gcgr ) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr~(–/–) mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr~(–/–) mice by generating Gcgr~(–/–)Glp1r~(–/–) mice. Although insulin sensitivity was similar in all genotypes, fasting glucose was increased in Gcgr~(–/–)Glp1r~(–/–) mice. Elimination of the Glp1r normalized gastric emptying and impaired intraperitoneal glucose tolerance in Gcgr~(–/–) mice. Unexpectedly, deletion of Glp1r in Gcgr~(–/–) mice did not alter the improved oral glucose tolerance and increased insulin secretion characteristic of that genotype. Although Gcgr~(–/–)Glp1r~(–/–) islets exhibited increased sensitivity to the incretin glucose-dependent insulinotropic polypeptide (GIP), mice lacking both Glp1r and the GIP receptor ( Gipr ) maintained preservation of the enteroinsular axis following reduction of Gcgr signaling. Moreover, Gcgr~(–/–)Glp1r~(–/–) islets expressed increased levels of the cholecystokinin A receptor ( Cckar ) and G protein–coupled receptor 119 ( Gpr119 ) mRNA transcripts, and Gcgr~(–/–)Glp1r~(–/–) mice exhibited increased sensitivity to exogenous CCK and the GPR119 agonist {"type":"entrez-nucleotide","attrs":{"text":"AR231453","term_id":"27272544","term_text":"AR231453"}}AR231453. Our data reveal extensive functional plasticity in the enteroinsular axis via induction of compensatory mechanisms that control nutrient-dependent regulation of insulin secretion.
机译：胰高血糖素分泌紊乱加剧了糖尿病的症状，已知降低的胰高血糖素作用可改善葡萄糖稳态。在小鼠中，胰高血糖素受体（Gcgr）的基因缺失导致促胰岛素激素胰高血糖素样肽1（GLP-1）水平升高，这可能有助于在Gcgr〜（– / –）小鼠中观察到葡萄糖稳态的改变。 。在这里，我们通过产生Gcgr〜（– / –）Glp1r〜（– / –）小鼠来评估GLP-1受体（GLP-1R）信号传导对Gcgr〜（– / –）小鼠表型的贡献。尽管所有基因型的胰岛素敏感性相似，但Gcgr〜（– / –）Glp1r〜（– / –）小鼠的空腹血糖升高。在Gcgr〜（– / –）小鼠中，消除了Glp1r可使胃排空正常化，并损害腹膜内葡萄糖耐量。出乎意料的是，删除Gcgr〜（– / –）小鼠中的Glp1r不会改变该基因型的口服葡萄糖耐量改善和胰岛素分泌特征增加。尽管Gcgr〜（– / –）Glp1r〜（– / –）胰岛对肠降血糖素葡萄糖依赖性促胰岛素多肽（GIP）的敏感性增加，但是缺乏Glp1r和GIP受体（Gipr）的小鼠在还原后仍保持肠小肠轴Gcgr信号传递。此外，Gcgr〜（– / –）Glp1r〜（– / –）胰岛表达的胆囊收缩素A受体（Cckar）和G蛋白偶联受体119（Gpr119）mRNA转录水平以及Gcgr〜（– / –）Glp1r 〜（– / –）小鼠对外源CCK和GPR119激动剂{“ type”：“ entrez-nucleotide”，“ attrs”：{“ text”：“ AR231453”，“ term_id”：“ 27272544”，“ term_text“：” AR231453“}} AR231453。我们的数据通过诱导补偿机制控制胰岛素分泌的营养依赖性调节，揭示了肠小肠轴广泛的功能可塑性。

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