Inhibition of GSK3 promotes replication and survival of pancreatic beta cells
Inhibition of GSK3 promotes replication and survival of pancreatic beta cells
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DOI：
10.1074/jbc.m609637200
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发表时间：
2007-04-20
影响因子：
4.8
通讯作者：
Austen, Matthias
中科院分区：
文献类型：
--
作者：
Mussmann, Rainer;Geese, Marcus;Austen, Matthias
最近的发展表明，再生β细胞的功能和质量在糖尿病患者是可能的。相对于目前无法提供最佳血糖控制的糖尿病治疗，再生方法可能是一种替代治疗选择。在这里，我们报道了小分子抑制剂或RNA干扰对GSK3的失活刺激了INS-1E大鼠胰岛素瘤细胞的复制。特异性和有效的GSK3抑制剂也减轻了高浓度葡萄糖和饱和脂肪酸棕榈酸酯对INS-1E细胞的毒性作用。此外，用结构多样的小分子GSK3抑制剂处理离体大鼠胰岛，与对照组相比，β细胞复制率提高了2-3倍。我们认为GSK3是β细胞复制和存活的调节因子。此外，我们的研究结果表明，GSK3的特异性抑制剂可能在β细胞再生治疗中具有实际应用。
Recent developments indicate that the regeneration of beta cell function and mass in patients with diabetes is possible. A regenerative approach may represent an alternative treatment option relative to current diabetes therapies that fail to provide optimal glycemic control. Here we report that the inactivation of GSK3 by small molecule inhibitors or RNA interference stimulates replication of INS-1E rat insulinoma cells. Specific and potent GSK3 inhibitors also alleviate the toxic effects of high concentrations of glucose and the saturated fatty acid palmitate on INS-1E cells. Furthermore, treatment of isolated rat islets with structurally diverse small molecule GSK3 inhibitors increases the rate beta cell replication by 2-3-fold relative to controls. We propose that GSK3 is a regulator of beta cell replication and survival. Moreover, our results suggest that specific inhibitors of GSK3 may have practical applications in beta cell regenerative therapies.