Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation
Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation
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DOI：
10.1074/jbc.m706105200
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发表时间：
2008-03-28
影响因子：
4.8
通讯作者：
Habener, Joel F.
中科院分区：
文献类型：
--
作者：
Liu, Zhengyu;Habener, Joel F.
促胰岛素激素GLP-1(胰升糖素样肽-1)是一种保存或恢复胰岛β细胞团的新型治疗剂。我们报道了GLP-1及其激动剂exendin-4(Exd4)能在胰岛和INS-1细胞中诱导Wnt信号。基础和GLP-1激动剂诱导的β细胞增殖需要激活的Wnt信号。细胞增殖的决定因素细胞周期蛋白D1和c-Myc被exd4上调。基本的内源性Wnt信号活性依赖于Wnt卷曲的受体和蛋白激酶Akt和GSK3β，而不依赖于cAMP依赖的蛋白激酶。相反，GLP-1激动剂通过GLP-1受体介导的Akt和不依赖GSK3β的β细胞激活来增强Wnt信号。通过对β-连环蛋白或显性负性TCF7L2的小干扰RNA抑制Wnt信号，可以减少基础和exd4诱导的β细胞增殖。WNT信号似乎介导了GLP-1诱导的β细胞增殖，增加了糖尿病新疗法的可能性。
The insulinotropic hormone GLP-1 (glucagon-like peptide-1) is a new therapeutic agent that preserves or restores pancreatic beta cell mass. We report that GLP-1 and its agonist, exendin-4 (Exd4), induce Wnt signaling in pancreatic beta cells, both isolated islets, and in INS-1 cells. Basal and GLP-1 agonist-induced proliferation of beta cells requires active Wnt signaling. Cyclin D1 and c-Myc, determinants of cell proliferation, are up-regulated by Exd4. Basal endogenous Wnt signaling activity depends on Wnt frizzled receptors and the protein kinases Akt and GSK3 beta but not cAMP-dependent protein kinase. In contrast, GLP-1 agonists enhance Wnt signaling via GLP-1 receptor-mediated activation of Akt and beta cell independent of GSK3 beta. Inhibition of Wnt signaling by small interfering RNAs to beta-catenin or a dominant-negative TCF7L2 decreases both basal and Exd4-induced beta cell proliferation. Wnt signaling appears to mediate GLP-1-induced beta cell proliferation raising possibilities for novel treatments of diabetes.