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p27 Regulates the Transition of ß-Cells From Quiescence to Proliferation

From the Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California

Address correspondence and reprint requests to Anil Bhushan, Larry Hillblom Islet Research Center, University of California, Los Angeles, 900A Weyburn Pl., Los Angeles, CA 90095. E-mail: abhushan{at}mednet.ucla.edu

Abbreviations: BrdU, 5-bromo-2'-deoxyuridine; CKI, cyclin kinase inhibitor; pRb, phosphorylate retinoblastoma; STZ, streptozotocin

Diabetes results from an inadequate mass of functional ß-cells. Such inadequacy could result from loss of ß-cells due to an immune assault or the inability to compensate for insulin resistance. Thus, mechanisms that regulate the number of ß-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 ß-cells formed before birth. We show that p27 accumulates in terminally differentiated ß-cells during embryogenesis. Disabling p27 allows newly differentiated ß-cells that are normally quiescent during embryogenesis to reenter the cell cycle and proliferate. As a consequence, excess ß-cells are generated in the p27^–/– mice, doubling their ß-cell mass at birth. The early postnatal expansion of ß-cell mass was unaffected in p27^–/– mice, indicating that the main function of p27 is to maintain the quiescent state of newly differentiated ß-cells generated during embryogenesis. The expanded ß-cell mass was accompanied by increased insulin secretion; however, the p27^–/– mice were glucose intolerant, as these mice were insulin insensitive. To assess the role of p27 to affect regeneration of ß-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, ß-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 ß-cell mass and an important target for facilitating ß-cell regeneration in therapies for diabetes.

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