Glycogen synthase kinase-3 and mammalian target of rapamycin pathways contribute to DNA synthesis, cell cycle progression, and proliferation in human islets.
Glycogen synthase kinase-3 and mammalian target of rapamycin pathways contribute to DNA synthesis, cell cycle progression, and proliferation in human islets.
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DOI：
10.2337/db07-1208
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发表时间：
2009-03
期刊：
影响因子：
7.7
通讯作者：
McDaniel ML
中科院分区：
文献类型：
--
作者：
Liu H;Remedi MS;Pappan KL;Kwon G;Rohatgi N;Marshall CA;McDaniel ML
目的：我们以前的研究表明，哺乳动物雷帕霉素靶标(MTOR)信号的营养调节促进了啮齿动物胰岛的再生过程，但在人类胰岛中很少。我们的目标是通过使用治疗药物来扩展这些发现，以确定糖原合成酶激酶-3(GSK-3)/β-连环蛋白和mTOR信号的调节是否是对与1型和2型糖尿病相关的人类β细胞团产生积极影响所必需的关键成分。研究设计和方法：原代成年人和大鼠的胰岛用GSK-3抑制剂LiCl和高效的1-氮杂苯丙酮(1-AKP)处理，并用营养素处理。检测β-细胞的DNA合成、细胞周期进程和增殖情况。测定胰岛素分泌和含量，Western印迹分析GSK-3和mTOR信号转导元件。结果：人胰岛经氯化锂或1-碱性磷酸酶处理4天后，β-细胞的DNA合成、细胞周期进程和增殖均显著增加，对雷帕霉素表现出不同程度的敏感性。中等浓度的葡萄糖(8 mmoL/L)联合GSK-3抑制对人β-细胞的BrdU掺入和Ki-67表达有显著的协同作用。负责细胞增殖的β-连环蛋白的核转位对雷帕霉素特别敏感。结论：GSK-3抑制和mTOR营养激活相结合有助于促进人β细胞的DNA合成、细胞周期进展和增殖。寻找适当调节GSK-3和mTOR信号的治疗药物可能为促进人胰岛的生长和增殖提供一种可行和有效的方法。
OBJECTIVE—Our previous studies demonstrated that nutrient regulation of mammalian target of rapamycin (mTOR) signaling promotes regenerative processes in rodent islets but rarely in human islets. Our objective was to extend these findings by using therapeutic agents to determine whether the regulation of glycogen synthase kinase-3 (GSK-3)/β-catenin and mTOR signaling represent key components necessary for effecting a positive impact on human β-cell mass relevant to type 1 and 2 diabetes. RESEARCH DESIGN AND METHODS—Primary adult human and rat islets were treated with the GSK-3 inhibitors, LiCl and the highly potent 1-azakenpaullone (1-Akp), and with nutrients. DNA synthesis, cell cycle progression, and proliferation of β-cells were assessed. Measurement of insulin secretion and content and Western blot analysis of GSK-3 and mTOR signaling components were performed. RESULTS—Human islets treated for 4 days with LiCl or 1-Akp exhibited significant increases in DNA synthesis, cell cycle progression, and proliferation of β-cells that displayed varying degrees of sensitivity to rapamycin. Intermediate glucose (8 mmol/l) produced a striking degree of synergism in combination with GSK-3 inhibition to enhance bromodeoxyuridine (BrdU) incorporation and Ki-67 expression in human β-cells. Nuclear translocation of β-catenin responsible for cell proliferation was found to be particularly sensitive to rapamycin. CONCLUSIONS—A combination of GSK-3 inhibition and nutrient activation of mTOR contributes to enhanced DNA synthesis, cell cycle progression, and proliferation of human β-cells. Identification of therapeutic agents that appropriately regulate GSK-3 and mTOR signaling may provide a feasible and available approach to enhance human islet growth and proliferation.
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