The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.
The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.
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DOI：
10.1016/j.cmet.2017.02.008
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发表时间：
2017-04-04
期刊：
影响因子：
29
通讯作者：
Sandoval DA
中科院分区：
文献类型：
--
作者：
Chambers AP;Sorrell JE;Haller A;Roelofs K;Hutch CR;Kim KS;Gutierrez-Aguilar R;Li B;Drucker DJ;D'Alessio DA;Seeley RJ;Sandoval DA
胰高血糖素样肽1（GLP-1）是正常葡萄糖调节所必需的，并且已经广泛假定该功能反映了从肠内分泌L细胞释放的GLP-1的作用。为了测试GLP-1的肠源与胰腺源对于葡萄糖生理调节的相对重要性，我们向具有前胰高血糖素原基因（Gcg）的组织特异性再活化的小鼠施用GLP-1 R拮抗剂毒蜥外泌肽9-39（Ex 9）。Ex 9使野生型小鼠的葡萄糖耐量受损，但对Gcg缺失或GLP-1 R KO小鼠无影响，表明Ex 9是真正的特异性GLP-1 R拮抗剂。出乎意料的是，Ex-9对肠Gcg恢复的小鼠的血糖没有影响。相比之下，Gcg的胰腺再活化完全恢复了Ex 9损害口服和IP葡萄糖耐量的作用。这些发现提示了一种替代模型，其中胰岛GLP-1在调节葡萄糖稳态中也起重要作用。GLP-1对于正常的葡萄糖调节是必需的，并且已经广泛地假定该功能是从肠内分泌L细胞释放的肽的作用。来自Chambers等人的数据挑战了这一教条，并发现胰腺产生的GLP-1是必需的，而胰腺产生的GLP-1是葡萄糖调节所必需的。
Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L-cells. To test the relative importance of intestinal vs. pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin 9–39 (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg null or GLP-1R KO mice suggesting that Ex9 is a true and specific GLP-1R antagonist. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and IP glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis. GLP-1 is necessary for normal gluco-regulation, and it has been widely presumed that this function is the action of peptide released from enteroendocrine L-cells. The data from Chambers et al. challenge this dogma and find that intestinally produced GLP-1 is dispensable while pancreatic production of GLP-1 is necessary for gluco-regulation.