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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 the 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 this study is to examine if c-KitWv/+ mutation-induced β-cell dysfunction is associated with downregulation of the phospho-Akt/Gsk3β pathway in c-KitWv/+ male mice. Histology and cell signaling were examined in C57BL/6J/KitWv/+ (c-Kit Wv/+) 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 with 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. © 2012 USCAP, Inc All rights reserved.