Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets
Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets
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DOI：
10.1210/en.2003-0323
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发表时间：
2003-12-01
期刊：
影响因子：
4.8
通讯作者：
Perfetti, R
中科院分区：
文献类型：
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作者：
Farilla, L;Bulotta, A;Perfetti, R
在糖尿病动物模型中，肽激素胰高血糖素样肽1（GLP-1）已被证明可增加葡萄糖依赖性胰岛素分泌，增强胰岛素基因转录，扩大胰岛细胞群，并抑制β细胞凋亡。本研究的目的是评估GLP-1是否可以改善功能和抑制新鲜分离的人胰岛细胞凋亡。在存在或不存在GLP-1（10 nM，每12 h添加一次）的情况下培养人胰岛5 d，并研究促凋亡因子（caspase-3）和抗凋亡因子（bcl-2）的活力和表达以及葡萄糖依赖性胰岛素产生。与对照组相比，我们在GLP-1处理的胰岛中观察到更好的三维胰岛形态。核凝聚，细胞凋亡的一个特征，被GLP-1抑制。GLP-1处理的胰岛中凋亡细胞数量的减少在第3天（处理培养物中6.1%凋亡细胞核对对照中15.5%; P < 0.01）和第5天（8.9%对18.9%; P < 0.01）特别明显。GLP-1的抗凋亡作用与caspase-3活性下调（P < 0.001）和bcl-2表达上调（P < 0.01）有关。在mRNA和蛋白水平观察GLP-1对细胞内bcl-2和caspase-3水平的影响。与对照组相比，在用GLP-1培养的胰岛中细胞内胰岛素含量显著增加（P < 0.001，在第5天），并且存在葡萄糖依赖性胰岛素分泌的平行GLP-1依赖性增强（P < 0.01，在第3天; P < 0.05，在第5天）。我们的研究结果提供了证据，GLP-1加入到新鲜分离的人胰岛保留形态和功能，并抑制细胞凋亡。
The peptide hormone, glucagon-like peptide 1 (GLP-1), has been shown to increase glucose-dependent insulin secretion, enhance insulin gene transcription, expand islet cell mass, and inhibit beta-cell apoptosis in animal models of diabetes. The aim of the present study was to evaluate whether GLP-1 could improve function and inhibit apoptosis in freshly isolated human islets. Human islets were cultured for 5 d in the presence, or absence, of GLP-1 ( 10 nM, added every 12 h) and studied for viability and expression of proapoptotic (caspase-3) and antiapoptotic factors (bcl-2) as well as glucose-dependent insulin production. We observed better-preserved three-dimensional islet morphology in the GLP-1-treated islets, compared with controls. Nuclear condensation, a feature of cell apoptosis, was inhibited by GLP-1. The reduction in the number of apoptotic cells in GLP-1-treated islets was particularly evident at d 3 (6.1% apoptotic nuclei in treated cultures vs. 15.5% in controls; P < 0.01) and at d 5 (8.9 vs. 18.9%; P < 0.01). The antiapoptotic effect of GLP-1 was associated with the downregulation of active caspase-3 ( P < 0.001) and the up-regulation of bcl-2 ( P < 0.01). The effect of GLP-1 on the intracellular levels of bcl-2 and caspase-3 was observed at the mRNA and protein levels. Intracellular insulin content was markedly enhanced in islets cultured with GLP-1 vs. control ( P < 0.001, at d 5), and there was a parallel GLP-1-dependent potentiation of glucose-dependent insulin secretion ( P < 0.01 at d 3; P < 0.05 at d 5). Our findings provide evidence that GLP-1 added to freshly isolated human islets preserves morphology and function and inhibits cell apoptosis.