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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Expression of cyclin D1 and D3 in WT and cyclin D2–/– mice during postna...
Expression of cyclin D1 and D3 in WT and cyclin D2–/– mice during postnatal development. (A and B) Sections from pancreata of 4-day-old WT and cyclin D2–/– mice were stained with anti_cyclin D3 and anti_insulin Ab’s. (A) In P4 WT mice, cyclin D3 expression is observed in exocrine and ductal tissue but is not observed in the endocrine pancreas. Arrow indicates islet lacking cyclin D3 expression. (B) In cyclin D2–/– littermates, cyclin D3 expression is observed in exocrine and ductal tissue (arrowhead) but not observed in the β cells. (C) Sections from pancreata of 4-day-old cyclin D2–/– mice were stained with anti_cyclin D1 and anti_insulin Ab’s. Cyclin D1 expression is not observed in the β cells in cyclin D2–/– mice. (D_F) Sections from pancreata of 14-day-old WT and cyclin D2–/– mice are stained with anti_cyclin D1, anti_glucagon (D and E), and anti_insulin (F) Ab’s. (D) Cyclin D1 is not expressed in the pancreas from WT P14 mice. (E) Cyclin D1 expression is observed within islets in pancreata from cyclin D2–/– littermates. Arrow indicates cyclin D1 expression within an islet of P14 cyclin D2–/– pancreas. (F) Cyclin D1 expression is observed in the nuclei of insulin-positive cells. Arrow indicates cyclin D1 expression in a β cell of P14 cyclin D2–/– pancreas.