| Pancreatic beta-cells adapt to changing physiologic states marked by increased systemic insulin demand. However, the signal pathways that govern facultative proliferation and compensatory gene expression in beta-cells are not well understood. In this thesis, I show that calcineurin and its target Nuclear Factor of Activated T-cells (NFAT) control beta-cell proliferation and insulin production in vivo. Mice with beta-cell-specific conditional deletion of Calcineurin b1 (betaCnb1KO mice) developed age-dependent diabetes characterized by decreased beta-cell proliferation and mass, reduced pancreatic insulin content and impaired insulin secretion. In contrast, conditional activation of NFATc1 in adult beta-cells increased proliferation and beta-cell mass and directly stimulated expression of insulin and other characteristic beta-cell factors. Expression of activated NFATc1 in the beta-cells of betaCnb1KO mice rescued diabetes mellitus and restored serum insulin levels. Thus, our loss- and gain-of-function studies show that calcineurin/NFAT signaling in vivo is crucial for maintaining growth and hallmark endocrine functions of pancreatic beta-cells. |
