title: Inhibition of Gsk3β activity improves β-cell function in c-KitWv/+ male mice.
abstract: 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 β-cell proliferation and function are unknown. The purpose of this study is to examine if c-Kit(Wv/+) mutation-induced β-cell dysfunction is associated with downregulation of the phospho-Akt/Gsk3β 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 Gsk3β 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 Gsk3β (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 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-Kit(Wv/+) 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.
authors.affiliation: Children's Health Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Feng
authors.forename: Lisa
authors.initials: L
authors.lastname: Donnelly
authors.forename: Jinming
authors.initials: J
authors.lastname: Li
authors.forename: Mansa
authors.initials: M
authors.lastname: Krishnamurthy
authors.forename: Matthew
authors.initials: M
authors.lastname: Riopel
authors.forename: Rennian
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001552:Benzazepines; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins / Q000378:metabolism; D007211:Indoles; D051473:Maf Transcription Factors, Large / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D001552:Benzazepines; C495267:CTNNB1 protein, mouse; C530105:Ccnd1 protein, mouse; D018398:Homeodomain Proteins; D007211:Indoles; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D015534:Trans-Activators; D051176:beta Catenin; C119620:kenpaullone; C084010:pancreatic and duodenal homeobox 1 protein; D019938:Cyclin D1; D019009:Proto-Oncogene Proteins c-kit; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3