Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I
Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I
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DOI：
10.1038/sj.gt.3301333
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发表时间：
2000-12-01
期刊：
影响因子：
5.1
通讯作者：
Robbins, P
中科院分区：
文献类型：
--
作者：
Giannoukakis, N;Mi, Z;Robbins, P
白细胞介素-1 β是一种有效的促炎细胞因子，已显示其抑制胰岛β细胞功能以及以一氧化氮依赖性方式激活Fas介导的细胞凋亡。此外，这种细胞因子在募集淋巴细胞方面是有效的，所述淋巴细胞在IDDM发作时介导β细胞破坏。胰岛素样生长因子I（IGF-I）已显示在体外阻断IL-1 β作用。我们假设胰岛素样生长因子I基因转移到完整的人胰岛可以防止IL-1 β诱导的β细胞功能障碍和Fas触发的细胞凋亡激活的敏感性。用编码IGF-1以及β-半乳糖苷酶和增强型绿色荧光蛋白的腺病毒载体感染完整的人胰岛作为对照。人IGF-I的腺病毒基因转移在体外阻止了IL-1 β介导的人胰岛一氧化氮的产生，以及通过葡萄糖刺激的胰岛素产生确定的β细胞功能的抑制。此外，IGF-I基因转移阻止了IL-1 β诱导的Fas介导的细胞凋亡。这些结果表明，从培养的胰岛中局部产生的IGF-I可能有利于维持β细胞功能，并促进胰岛移植前后的胰岛存活，作为I型糖尿病的潜在治疗方法。
Interleukin-1 beta is a potent pro-inflammatory cytokine that has been shown to inhibit islet beta cell function as well as to activate Fas-mediated apoptosis in a nitric oxide-dependent manner. Furthermore, this cytokine is effective in recruiting lymphocytes that mediate beta cell destruction in IDDM onset. The insulin-like growth factor I (IGF-I) has been shown to block IL-1 beta actions in vitro. We hypothesized that gene transfer of the insulin-like growth factor I to intact human islets could prevent IL-1 beta -induced beta cell dysfunction and sensitization to Fas-triggered apoptosis activation. intact human islets were infected with adenoviral vectors encoding IGF-I as well as beta -galactosidase and enhanced green fluorescent protein as controls. Adenoviral gene transfer of human IGF-I prevented IL-1 beta -mediated nitric oxide production from human islets in vitro as well as the suppression of beta cell function as determined by glucose-stimulated insulin production. Moreover, IGF-I gene transfer prevented IL-1 beta -induced, Fas-mediated apoptosis. These results suggest that locally produced IGF-I from cultured islets may be beneficial in maintaining beta cell function and promoting islet survival before and following islet transplantation as a potential therapy for type I diabetes.