title: Glucose and aging control the quiescence period that follows pancreatic beta cell replication.
abstract: Pancreatic beta cell proliferation has emerged as the principal mechanism for homeostatic maintenance of beta cell mass during adult life. This underscores the importance of understanding the mechanisms of beta cell replication and suggests novel approaches for regenerative therapy to treat diabetes. Here we use an in vivo pulse-chase labeling assay to investigate the replication dynamics of adult mouse beta cells. We find that replicated beta cells are able to re-enter the cell division cycle shortly after mitosis and regain their normal proliferative potential after a short quiescence period of several days. This quiescence period is lengthened with advanced age, but shortened during injury-driven beta cell regeneration and following treatment with a pharmacological activator of glucokinase, providing strong evidence that metabolic demand is a key determinant of cell cycle re-entry. Lastly, we show that cyclin D2, a crucial factor in beta cell replication, is downregulated during cell division, and is slowly upregulated post-mitosis by a glucose-sensitive mechanism. These results demonstrate that beta cells quickly regain their capacity to re-enter the cell cycle post-mitosis and implicate glucose control of cyclin D2 expression in the regulation of this process.
authors.affiliation: Department of Developmental Biology and Cancer Research and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Salpeter
authors.forename: Allon M
authors.initials: AM
authors.lastname: Klein
authors.forename: Danwei
authors.initials: D
authors.lastname: Huangfu
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
mesh_terms: D000375:Aging; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence; D056742:Cyclin D2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice
chemical_list: D056742:Cyclin D2; D005947:Glucose
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