Amelioration of diabetes by imatinib mesylate (Gleevec®):: role of β-cell NF-κB activation and anti-apoptotic preconditioning
Amelioration of diabetes by imatinib mesylate (Gleevec®):: role of β-cell NF-κB activation and anti-apoptotic preconditioning
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DOI：
10.1096/fj.06-6910com
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发表时间：
2007-02-01
期刊：
影响因子：
4.8
通讯作者：
Welsh, Nils
中科院分区：
文献类型：
--
作者：
Hagerkvist, Robert;Sandler, Stellan;Welsh, Nils
最近有报道称，酪氨酸激酶抑制剂甲磺酸伊马替尼（Gleevec（R））可能通过降低胰岛素抵抗来改善2型糖尿病。然而，由于2型和I型糖尿病的特征都是β细胞功能障碍和死亡，我们研究了伊马替尼是否通过维持β细胞功能来对抗糖尿病。我们观察到，伊马替尼抵消糖尿病在两种动物模型，链脲佐菌素注射小鼠和非肥胖糖尿病小鼠，这是由部分保存的P细胞群。此外，伊马替尼在体外暴露于NO、细胞因子和链脲佐菌素时减少了人β细胞的死亡。通过siRNA介导的c-Ab 1 mRNA敲低来模拟伊马替尼效应。伊马替尼通过促进类似于缺血预处理的状态来增强β细胞存活，如NF-κ B活化、增加NO和活性氧产生以及线粒体内膜去极化所证明的。伊马替尼在NF-κ B抑制剂存在下不抑制胰岛细胞死亡，表明NF-κ B活化是伊马替尼抗凋亡作用的必要步骤。我们的结论是，伊马替尼介导的P细胞存活，这可能有助于在糖尿病中观察到的有益效果。
It was recently reported that tyrosine kinase inhibitor imatinib mesylate (Gleevec (R)) improves Type 2 diabetes, possibly by decreasing insulin resistance. However, as both Type 2 and Type I diabetes are characterized by beta-cell dysfunction and death, we investigated whether imatinib counteracts diabetes by maintaining beta-cell function. We observed that imatinib counteracted diabetes in two animal models, the streptozotocin-injected mouse and the nonobese diabetes mouse, and that this was paralleled by a partial preservation of the P-cell mass. In addition, imatinib decreased the death of human beta-cells in vitro when exposed to NO, cytokines, and streptozotocin. The imatinib effect was mimicked by siRNA-mediated knockdown of c-Ab1 mRNA. Imatinib enhanced beta-cell survival by promoting a state similar to ischemic preconditioning, as evidenced by NF-kappa B activation, increased NO and reactive oxygen species production, and depolarization of the inner mitochondrial membrane. Imatinib did not suppress islet cell death in the presence of an NF-kappa B inhibitor, suggesting that NF-kappa B activation is a necessary step in the antiapoptotic action of imatinib. We conclude that imatinib mediates P-cell survival and that this could contribute to the beneficial effects observed in diabetes.