p27 Regulates the transition of beta-cells from quiescence to proliferation.
Diabetes results from an inadequate mass of functional beta-cells. Such inadequacy could result from loss of beta-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; however, 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.
Georgia
Senta
S
Larry Hillblom Islet Research Center, University of California, Los Angeles, 900A Weyburn Pl., Los Angeles, CA 90095, USA.
Bhushan
Anil
A
D000818:Animals; D001786:Blood Glucose / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D005215:Fasting; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000502:physiology*
D001786:Blood Glucose; D017931:DNA Primers; D007328:Insulin; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen