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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Sato, Sheryl M
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Henley, Kathryn D; Gooding, Kimberly A; Economides, Aris N et al. (2012) Inactivation of the dual Bmp/Wnt inhibitor Sostdc1 enhances pancreatic islet function. Am J Physiol Endocrinol Metab 303:E752-61
Moore, Mary Courtney; Menon, Renuka; Coate, Katie C et al. (2011) Diet-induced impaired glucose tolerance and gestational diabetes in the dog. J Appl Physiol 110:458-67
Wicksteed, Barton; Brissova, Marcela; Yan, Wenbo et al. (2010) Conditional gene targeting in mouse pancreatic ß-Cells: analysis of ectopic Cre transgene expression in the brain. Diabetes 59:3090-8
Golson, M L; Misfeldt, A Ackermann; Kopsombut, U G et al. (2010) High Fat Diet Regulation of ?-Cell Proliferation and ?-Cell Mass. Open Endocrinol J 4:
Vellanki, Ravi N; Zhang, Liling; Guney, Michelle A et al. (2010) OASIS/CREB3L1 induces expression of genes involved in extracellular matrix production but not classical endoplasmic reticulum stress response genes in pancreatic beta-cells. Endocrinology 151:4146-57
Zhang, Hongjie; Zhang, Jia; Pope, Christine F et al. (2010) Gestational diabetes mellitus resulting from impaired beta-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen. Diabetes 59:143-52
Guney, Michelle A; Gannon, Maureen (2009) Pancreas cell fate. Birth Defects Res C Embryo Today 87:232-48
Ackermann Misfeldt, Amanda; Costa, Robert H; Gannon, Maureen (2008) Beta-cell proliferation, but not neogenesis, following 60% partial pancreatectomy is impaired in the absence of FoxM1. Diabetes 57:3069-77
Ackermann, Amanda M; Gannon, Maureen (2007) Molecular regulation of pancreatic beta-cell mass development, maintenance, and expansion. J Mol Endocrinol 38:193-206