Beta cell mass is dynamic, changing throughout the life of the organism in response to metabolic alterations and demands. Increases in beta cell mass are thought to occur via both replication of existing beta cells and beta cell neogenesis from stem cell progenitors. Diabetes results from an absolute (Type 1) or relative (Type 2) inadequate functional beta cell mass. Thus, genes and pathways involved in maintaining or altering beta cell mass are candidates for being affected in diabetic individuals. Functional analysis of these genes may lead to new therapeutic strategies for increasing existing beta cell mass in diabetic patients and/or facilitate the production of beta cells in vitro from embryonic or stem cells. The Foxm1b transcription factor is highly expressed in proliferating cells and activates cell cycle genes. Liver-specific Foxm1b inactivation impairs liver regeneration following partial hepatectomy. These results prompted us to examine whether Foxm1b functions similarly in pancreas and/or beta cell regeneration and compensation. We found that Foxm1b is highly expressed in embryonic and neonatal endocrine cells, when many of cells are proliferating. Using a Cre-lox strategy, we made mice with a pancreas-specific Foxm1b deletion to examine its role in pancreas regeneration following partial pancreatectomy. Mice lacking Foxm1b in their entire pancreas were glucose intolerant at 6 weeks of age and overtly diabetic by 9 weeks of age, suggesting a role for Foxm1b in normal beta cell function. Examination of mutant pancreata revealed a gradual loss of beta cell mass between 4 and 9 weeks of age. We hypothesize that Foxm1b is essential to maintain normal beta cell mass and regulate betaa cell turnover. We predict that Foxm1b is critical for pancreas and beta cell regeneration and for beta cell compensation. To test these hypotheses we will inactivate Foxm1b in the entire pancreas, or exclusively in pancreatic endocrine cells. A thorough understanding of Foxm1b regulation of beta cell mass may lead to strategies for maintaining beta cell mass and enhancing beta cell proliferation in diabetics.
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