3 cell mass is dynamic, changing throughout the life of the organism in response to metabolic alterations and demands. Increases in 3 cell mass are thought to occur via both replication of existing 3 cells and 3 cell neogenesis from stem cell progenitors. Diabetes results from an absolute (Type 1) or relative (Type 2) inadequate functional 3 cell mass. Thus, genes and pathways involved in maintaining or altering 3 cell mass are candidates for being affected in diabetic individuals. Functional analysis of these genes may lead to new therapeutic strategies for increasing existing 3 cell mass in diabetic patients and/or facilitate the production of 3 cells in vitro from embryonic or stem cells. The Foxml transcription factor is highly expressed in proliferating cells and activates cell cycle genes. Liver-specific Foxml inactivation impairs liver regeneration following partial hepatectomy. These results prompted us to examine whether Foxml functions similarly in pancreas and/or 3 cell regeneration and compensation. We found that Foxml 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 Foxml deletion to examine its role in pancreas regeneration following partial pancreatectomy. Mice lacking Foxml in their entire pancreas were glucose intolerant at 6 weeks of age and overtly diabetic by 9 weeks of age, suggesting an unexpected role for Foxml in normal 3 cell function. Examination of mutant pancreata revealed a gradual loss of 3 cell mass between 4 and 9 weeks of age. We hypothesize that Foxml is essential to maintain normal 3 cell mass and regulate 3 cell turnover. We predict that Foxml is critical for pancreas and 3 cell regeneration and for 3 cell compensation. To test these hypotheses we will inactivate Foxml in the entire pancreas, or exclusively in pancreatic endocrine cells. We will test the requirement for Foxml in different models of b cell mass expansion including pregnancy and high fat diet/insulin resistance. A thorough understanding of Foxml regulation of 3 cell mass may lead to strategies for maintaining 3 cell mass and enhancing 3 cell proliferation in diabetics.
