Published in:
01-04-2008 | Article
Mice with beta cell overexpression of glycogen synthase kinase-3β have reduced beta cell mass and proliferation
Published in: Diabetologia | Issue 4/2008
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Aims/hypothesis
Glycogen synthase kinase-3 (GSK3) has been implicated in the pathophysiology of several prevalent diseases, including diabetes. However, despite recent progress in our understanding of the role of GSK3 in the regulation of glucose metabolism in peripheral tissues, the involvement of GSK3 in islet beta cell growth and function in vivo is unknown. We therefore sought to determine whether over-activation of GSK3β would lead to alterations in islet beta cell mass and/or function.
Methods
Transgenic mice overexpressing a constitutively active form of human GSK3β (S9A) under the control of the rat insulin promoter (RIP-GSK3βCA) were created. Studies using mouse insulinoma cells (MIN6) were conducted to investigate the regulation of GSK3β activity and its impact on pancreas/duodenum homeobox protein-1 (PDX-1) levels.
Results
We demonstrated that phosphorylation of GSK3β was decreased, indicating increased GSK3β activity in two animal models of diabetes, Lepr
−/−
mice and Ins2
Akita/+
mice. In MIN6 cells, the activity of GSK3β was regulated by glucose, in a fashion largely dependent on phosphatidylinositol 3-kinase. RIP-GSK3βCA transgenic mice showed impaired glucose tolerance after 5 months of age. Histological studies revealed that transgenic mice had decreased beta cell mass and decreased beta cell proliferation, with a 50% decrease (p < 0.05) in the level of PDX-1.
Conclusions/interpretation
We showed direct evidence that GSK3β activity is associated with beta cell failure in diabetic mouse models and that its overactivation resulted in decreased pancreatic beta cell proliferation and mass. GSK3 modulates PDX-1 stability in both cultured insulinoma cells and islets in vivo. These results may ultimately facilitate the development of potential therapeutic interventions targeting type 2 diabetes and/or islet transplantation.