p27 regulates the transition of β-cells from quiescence to proliferation

被引:77
作者
Georgia, Senta [1 ]
Bhushan, Anil [1 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Larry Hillblom Islet Res Ctr, Los Angeles, CA 90095 USA
关键词
D O I
10.2337/db06-0249
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Diabetes results from an inadequate mass of functional beta-cells. Such inadequacy could result from loss of P-cells due to an immune assault or the inability to compensate for insulin resistance. Thus, mechanisms that regulate the number of beta-cells will be key to understanding both the pathogenesis of diabetes and for developing therapies. In this study, we show that cell cycle regulator p27 plays a crucial role in establishing the number of beta-cells formed before birth. We show that p27 accumulates in terminally differentiated beta-cells during embryogenesis. Disabling p27 allows newly differentiated beta-cells that are normally quiescent during embryogenesis to reenter the cell cycle and proliferate. As a consequence, excess beta-cells are generated in the p27(-/-) mice, doubling their beta-cell mass at birth. The early postnatal expansion of beta-cell mass was unaffected in p27(-/-) mice, indicating that the main function of p27 is to maintain the quiescent state of newly differentiated beta-cells generated during embryogenesis. The expanded beta-cell mass was accompanied by increased insulin secretion; how ever, the p27(-/-) mice were glucose intolerant, as these mice were insulin insensitive. To assess the role of p27 to affect regeneration of beta-cells in models of diabetes, p27(-/-) mice were injected with streptozotocin (STZ). In contrast to control mice that displayed elevated blood glucose levels, p27(-/-) mice showed decreased susceptibility to develop STZ-induced diabetes. Furthermore, beta-cells retained the ability to reenter the cell cycle at a far greater frequency in p27(-/-) mice after developing STZ-induced diabetes compared with wild-type littermates. These data indicate that p27 is a key regulator in establishing beta-cell mass and an important target for facilitating beta-cell regeneration in therapies for diabetes.
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收藏
页码:2950 / 2956
页数:7
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