| First Author | Feng ZC | Year | 2012 |
| Journal | Lab Invest | Volume | 92 |
| Issue | 4 | Pages | 543-55 |
| PubMed ID | 22249311 | Mgi Jnum | J:181933 |
| Mgi Id | MGI:5314448 | Doi | 10.1038/labinvest.2011.200 |
| Citation | Feng ZC, et al. (2012) Inhibition of Gsk3beta activity improves beta-cell function in c-Kit(Wv/+) male mice. Lab Invest 92(4):543-55 |
| abstractText | Previous studies have shown that the stem cell marker, c-Kit, is involved in glucose homeostasis. We recently reported that c-Kit(Wv/+) male mice displayed the onset of diabetes at 8 weeks of age; however, the mechanisms by which c-Kit regulates beta-cell proliferation and function are unknown. The purpose of this study is to examine if c-Kit(Wv/+) mutation-induced beta-cell dysfunction is associated with downregulation of the phospho-Akt/Gsk3beta pathway in c-Kit(Wv/+) male mice. Histology and cell signaling were examined in C57BL/6J/Kit(Wv/+) (c-Kit(Wv/+)) and wild-type (c-Kit(+/+)) mice using immunofluorescence and western blotting approaches. The Gsk3beta inhibitor, 1-azakenpaullone (1-AKP), was administered to c-Kit(Wv/+) 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-Kit(Wv/+) mice (P<0.05) along with a decrease in phosphorylated Gsk3beta (P<0.05), and cyclin D1 protein level (P<0.01) when compared with c-Kit(+/+) mice. However, c-Kit(Wv/+) mice that received 1-AKP treatment demonstrated normal fasting blood glucose with significantly improved glucose tolerance. 1-AKP-treated c-Kit(Wv/+) mice also showed increased beta-catenin, cyclin D1 and Pdx-1 levels in islets, demonstrating that inhibition of Gsk3beta activity led to increased beta-cell proliferation and insulin secretion. These data suggest that c-Kit(Wv/+) male mice had alterations in the Akt/Gsk3beta signaling pathway, which lead to beta-cell dysfunction by decreasing Pdx-1 and cyclin D1 levels. Inhibition of Gsk3beta could prevent the onset of diabetes by improving glucose tolerance and beta-cell function. |
