Mice with beta cell overexpression of glycogen synthase kinase-3β have reduced beta cell mass and proliferation

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 GSK3 beta would lead to alterations in islet beta cell mass and/or function. Methods Transgenic mice overexpressing a constitutively active form of human GSK3 beta (S9A) under the control of the rat insulin promoter (RIP-GSK3 beta CA) were created. Studies using mouse insulinoma cells (MIN6) were conducted to investigate the regulation of GSK3 beta activity and its impact on pancreas/duodenum homeobox protein-1 (PDX-1) levels. Results We demonstrated that phosphorylation of GSK3 beta was decreased, indicating increased GSK3 beta activity in two animal models of diabetes, Lepr(-/-) mice and Ins2(Akita/+) mice. In MIN6 cells, the activity of GSK3 beta was regulated by glucose, in a fashion largely dependent on phosphatidylinositol 3-kinase. RIP-GSK3 beta CA 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 GSK3 beta 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.