Inhibition of Gsk3β activity improves β-cell function in c-KitWv/+ male mice.
Inhibition of Gsk3β activity improves β-cell function in c-KitWv/+ male mice.
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DOI：
10.1038/labinvest.2011.200
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发表时间：
2012-04
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影响因子：
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先前的研究表明，干细胞标志物c-Kit参与葡萄糖稳态。我们最近报道，c-KitWv/+雄性小鼠在8周龄时显示糖尿病发作;然而，c-Kit调节β细胞增殖和功能的机制尚不清楚。本研究的目的是检查c-KitWv/+突变诱导的β细胞功能障碍是否与c-KitWv/+雄性小鼠中磷酸化Akt/Gsk 3 β通路的下调相关。使用免疫荧光和蛋白质印迹法在C57 BL/6 J/KitWv/+（c-KitWv/+）和野生型（c-Kit+/+）小鼠中检查组织学和细胞信号传导。对c-KitWv/+和c-Kit+/+小鼠给予Gsk 3 β抑制剂1-azakenpaullone（1-AKP）2周，从而检查葡萄糖代谢的变化并进行形态学分析。与c-Kit+/+小鼠相比，c-KitWv/+小鼠胰岛中磷酸化Akt显著降低（P <0.05）沿着磷酸化Gsk 3 β降低（P<0.05），cyclin D1蛋白水平降低（P<0.01）。然而，接受1-AKP治疗的c-KitWv/+小鼠表现出正常的空腹血糖和显著改善的葡萄糖耐量。1-AKP处理的c-KitWv/+小鼠还显示胰岛中β-连环蛋白、细胞周期蛋白D1和Pdx-1水平增加，表明Gsk 3 β活性的抑制导致β-细胞增殖和胰岛素分泌增加。这些数据表明，c-KitWv/+雄性小鼠的Akt/Gsk 3 β信号通路发生了改变，通过降低Pdx-1和细胞周期蛋白D1水平导致β细胞功能障碍。抑制Gsk 3 β可以通过改善糖耐量和β细胞功能来预防糖尿病的发生。
Previous studies have shown that the stem cell marker, c-Kit, is involved in glucose homeostasis. We recently reported that c-KitWv/+ male mice displayed onset of diabetes at 8 weeks of age; however, the mechanisms by which c-Kit regulates β-cell proliferation and function are unknown. The purpose of the present study is to examine if c-KitWv/+ mutation-induced β-cell dysfunction is associated with down-regulation of the phospho-Akt/Gsk3β pathway in c-KitWv/+ male mice. Histology and cell signaling were examined in C57BL/6J/KitWv/+ (c-KitWv/+) and wild-type (c-Kit+/+) mice using immunofluorescence and western blotting approaches. The Gsk3β inhibitor, 1-azakenpaullone (1-AKP), was administered to c-KitWv/+ and c-Kit+/+ mice for 2 weeks, whereby alterations in glucose metabolism were examined and morphometric analyses were performed. A significant reduction in phosphorylated Akt was observed in the islets of c-KitWv/+ mice (P<0.05) along with a decrease in phosphorylated Gsk3β (P<0.05), and cyclin D1 protein level (P<0.01) when compared to c-Kit+/+ mice. However, c-KitWv/+ mice that received 1-AKP treatment demonstrated normal fasting blood glucose with significantly improved glucose tolerance. 1-AKP treated c-KitWv/+ mice also showed increased β-catenin, cyclin D1 and Pdx-1 levels in islets demonstrating that inhibition of Gsk3β activity led to increased β-cell proliferation and insulin secretion. These data suggest that c-KitWv/+ male mice had alterations in the Akt/Gsk3β signaling pathway, which lead to β-cell dysfunction by decreasing Pdx-1 and cyclin D1 levels. Inhibition of Gsk3β could prevent the onset of diabetes by improving glucose tolerance and β-cell function.
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DOI：
10.1152/ajpendo.00172.2007
发表时间：
2007-08-01
影响因子：
5.1
作者：
Li, Jinming;Quirt, Jaclyn;Wang, Rennian
通讯作者：
Wang, Rennian
影响因子：
3.5
作者：
Le Bacquer, Olivier;Shu, Luan;Maedler, Kathrin
通讯作者：
Maedler, Kathrin
影响因子：
5.2
作者：
Jiang, Jianjie;Au, Melinda;Majumdar, Anish S.
通讯作者：
Majumdar, Anish S.
影响因子：
15.9
作者：
Johnson, JD;Ahmed, NT;Polonsky, KS
通讯作者：
Polonsky, KS
影响因子：
4.1
作者：
Krishnamurthy, Mansa;Li, Jinming;Al-Masri, Maia;Wang, Rennian
通讯作者：
Wang, Rennian