Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5′-adenosine monophosphate-dependent protein kinase A- and a phosphatidylinositol 3-kinase-dependent pathway
Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5′-adenosine monophosphate-dependent protein kinase A- and a phosphatidylinositol 3-kinase-dependent pathway
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DOI：
10.1210/en.2002-220897
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发表时间：
2003-04-01
期刊：
影响因子：
4.8
通讯作者：
Perfetti, R
中科院分区：
文献类型：
--
作者：
Hui, HX;Nourparvar, A;Perfetti, R
胰升糖素样肽-1(GLP-1)受体的激活在胰岛β细胞的功能活动和胰岛细胞团的扩张中起着重要作用。胰岛细胞团的持续重塑在体内由增殖和凋亡刺激介导，以确保对不断变化的胰岛素需求的动态反应。本研究旨在研究GLP-1在细胞受到促凋亡刺激时的生物学活性。我们已经证明，GLP-1受体的激活抑制了过氧化氢诱导的小鼠胰岛素瘤细胞系MIN6的凋亡。GLP-1减少DNA片段化，提高细胞存活率。这是通过增加抗凋亡蛋白Bcl2和Bclxl的表达来实现的。GLP-1还可阻止依赖H_2O_2的聚腺苷二磷酸核糖聚合酶的切割。通过DNA片段化和多聚ADP核糖聚合酶检测以及对Bcl2和Bclxl蛋白水平的检测，发现RP-cAMP抑制GLP-1依赖的cAMP增加可阻断GLP-1的抗凋亡作用。使用抑制剂PD098059和LY294002研究蛋白激酶PI-3激酶(PI3K)和MAPK的作用表明，在H_2O_2暴露的细胞中，需要激活PI3K而不是MAPK来防止促凋亡事件。本研究提供了GLP-1通过cAMP和PI3K依赖的信号通路介导的抗细胞凋亡作用的证据。
The activation of the glucagon-like peptide-1 (GLP-1) receptor has been shown to have an important role in the functional activity of islet beta-cells and in the expansion of the islet cell mass. Constant remodeling of islet cell mass is mediated in vivo by proliferative and apoptotic stimuli to ensure a dynamic response to a changing demand for insulin. The present study was undertaken to investigate the biological activity of GLP-1 when cells were challenged by a proapoptotic stimulus. We have shown that activation of the GLP-1 receptor inhibits H2O2-induced apoptosis in a cultured mouse insulinoma cell line, termed MIN6. GLP-1 reduced DNA fragmentation and improved cell survival. This was mediated by an increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. GLP-1 also prevented the H2O2-dependent cleavage of poly-(ADP-ribose)-polymerase. Inhibition of the GLP-1-dependent increase of cAMP by Rp-cAMP blocked the antiapoptotic action of GLP-1, as determined by DNA fragmentation and poly-(ADP-ribose)-polymerase assays and by detection of Bcl-2 and Bcl-xL protein levels. Investigation of the role of the protein kinases, PI-3 kinase (PI3K) and MAPK, by use of the inhibitors PD098059 and LY294002 demonstrated that the activation of PI3K, but not MAPK, was required to prevent proapoptotic events in cells exposed to H2O2. The present study provides evidence that GLP-1 has an antiapoptotic action mediated by a cAMP- and PI3K-dependent signaling pathway.