The human glucagon-like peptide-1 analogue liraglutide regulates pancreatic beta-cell proliferation and apoptosis via an AMPK/mTOR/P70S6K signaling pathway
The human glucagon-like peptide-1 analogue liraglutide regulates pancreatic beta-cell proliferation and apoptosis via an AMPK/mTOR/P70S6K signaling pathway
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人胰高血糖素样肽 1 类似物利拉鲁肽通过 AMPK/mTOR/P70S6K 信号通路调节胰腺 β 细胞增殖和凋亡
DOI：
10.1016/j.peptides.2012.10.006
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发表时间：
2013-01-01
期刊：
影响因子：
3
通讯作者：
Li, Chun-Lin
中科院分区：
文献类型：
--
作者：
Miao, Xin-Yu;Gu, Zhao-Yan;Li, Chun-Lin
胰高血糖素样肽-1（GLP-1）是治疗糖尿病的有效药物，已被证明可通过多种途径保护胰腺β细胞。近年来的研究表明，AMP活化蛋白激酶（AMPK）作为一种代谢调节因子，通过调节哺乳动物雷帕霉素靶蛋白（mTOR）信号通路来协调β细胞蛋白质的合成。本研究的目的是探索利拉鲁肽（一种人GLP-1类似物）是否通过AMPK/mTOR信号传导保护β细胞。我们使用细胞计数试剂盒-8评估了INS-1 β细胞系的增殖，并使用ATP测定试剂盒检查了GLP-1对细胞ATP水平的影响。Western blotting检测mTOR通路蛋白表达水平，流式细胞术检测糖脂毒性诱导的细胞凋亡。在存在11.1或30 mmol/L葡萄糖的情况下，利拉鲁肽在100 nmol/L的最佳浓度下可增加β细胞活力。利拉鲁肽（100 nmol/L）激活INS-1细胞中的mTOR及其下游效应物70-kDa核糖体蛋白56激酶和eIF 4 E结合蛋白-1。这种作用被通路阻断剂减弱：AMPK激活剂AICAR和mTOR抑制剂雷帕霉素。此外，利拉鲁肽对β细胞增殖的影响被AICAR和雷帕霉素抑制。利拉鲁肽增加细胞ATP水平。此外，利拉鲁肽可保护β细胞免受糖脂毒性诱导的细胞凋亡。这种反应也被雷帕霉素治疗所阻止。这些结果表明，GLP-1受体激动剂利拉鲁肽对β细胞增殖的增强作用至少部分由AMPK/mTOR信号传导介导。利拉鲁肽还通过激活mTOR预防β细胞糖脂毒性。(C)2012 Elsevier Inc. All rights reserved.
Glucagon-like peptide-1 (GLP-1), an effective therapeutic agent for the treatment of diabetes, has been proven to protect pancreatic beta cells through many pathways. Recent evidence demonstrates that AMP-activated protein kinase (AMPK), as a metabolic regulator, coordinates beta-cell protein synthesis through regulation of the mammalian target of rapamycin (mTOR) signaling pathway. The purpose of the present study was to explore whether liraglutide, a human GLP-1 analogue, protects beta cells via AMPK/mTOR signaling. We evaluated INS-1 beta-cell line proliferation using the Cell Counting Kit-8, and examined the effect of GLP-1 on cellular ATP levels using an ATP assay kit. mTOR pathway protein expression levels were tested by Western blotting and glucolipotoxicity-induced cell apoptosis was evaluated by flow cytometry. Liraglutide increased beta-cell viability at an optimum concentration of 100 nmol/L in the presence of 11.1 or 30 mmol/L glucose. Liraglutide (100 nmol/L) activated mTOR and its downstream effectors, 70-kDa ribosomal protein 56 kinase and elF4E-binding protein-1, in INS-1 cells. This effect was abated by pathway blockers: the AMPK activator AICAR and the mTOR inhibitor rapamycin. Furthermore, the effect of liraglutide on beta-cell proliferation was inhibited by AICAR and rapamycin. Liraglutide increased cellular ATP levels. In addition, liraglutide protected beta cells from glucolipotoxicity-induced apoptosis. This response was also prevented by rapamycin treatment. These results suggest that the enhancement of beta-cell proliferation by that GLP-1 receptor agonist liraglutide is mediated, at least in part, by AMPK/mTOR signaling. Liraglutide also prevents beta-cell glucolipotoxicity by activating mTOR. (C) 2012 Elsevier Inc. All rights reserved.