β cell replication is the primary mechanism for maintaining postnatal β cell mass
Senta Georgia, Anil Bhushan
Senta Georgia, Anil Bhushan
Published October 1, 2004
Citation Information: J Clin Invest. 2004;114(7):963-968. https://doi.org/10.1172/JCI22098.
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Article Metabolism

β cell replication is the primary mechanism for maintaining postnatal β cell mass

Abstract

The endocrine pancreas undergoes major remodeling during neonatal development when replication of differentiated β cells is the major mechanism by which β cell mass is regulated. The molecular mechanisms that govern the replication of terminally differentiated β cells are unclear. We show that during neonatal development, cyclin D2 expression in the endocrine pancreas coincides with the replication of endocrine cells and a massive increase in islet mass. Using cyclin D2–/– mice, we demonstrate that cyclin D2 is required for the replication of endocrine cells but is expendable for exocrine and ductal cell replication. As a result, 14-day-old cyclin D2–/– mice display dramatically smaller islets and a 4-fold reduction in β cell mass in comparison to their WT littermates. Consistent with these morphological findings, the cyclin D2–/– mice are glucose intolerant. These results suggest that cyclin D2 plays a key role in regulating the transition of β cells from quiescence to replication and may provide a target for the development of therapeutic strategies to induce expansion and/or regeneration of β cells.

Authors

Senta Georgia, Anil Bhushan

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Incorporation of BrdU during postnatal pancreatic development of WT and ...
Incorporation of BrdU during postnatal pancreatic development of WT and cyclin D2–/– mice. BrdU was injected in 4- and 7-day-old mice 2 hours before being sacrificed. (A and B) Sections from pancreata costained with anti_insulin and anti_BrdU Ab’s. (A) In P4 WT mice, a fraction of β cells that incorporate BrdU are evident during the first week of postnatal development. Quantification of 20 representative islets showed that 9.2% of β cells incorporated BrdU in P4 WT mice. Arrow indicates an example of an islet with BrdU-positive β cells. (B) In cyclin D2–/– littermates, β cells that incorporated BrdU are not observed. Arrows indicate islets in cyclin D2–/– that do not contain BrdU-positive β cells. (C and D) Sections from pancreas costained with anti_glucagon and anti_BrdU Ab’s. (C) Glucagon-positive cells incorporate BrdU in the WT pancreas. Arrow indicates an example of an islet with a BrdU-positive α cell. (D) No glucagon-positive cells that incorporate BrdU are observed. (E and F) Sections from pancreas costained with anti_amylase and anti_BrdU Ab’s. BrdU incorporation is similar in exocrine and ductal tissue of the pancreata from WT (E) and cyclin D2–/– mice (F).