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Differential Effects of p27 in Regulation of ß-Cell Mass During Development, Neonatal Period, and Adult Life

¹ Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri
² Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Address correspondence and reprint requests to Ernesto Bernal-Mizrachi, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8127, St. Louis, MO 63110. E-mail: ebernal{at}wustl.edu

Abbreviations: BrdU, bromodeoxyuridine; cdk, cyclin-dependent kinase; CKI, cell cycle inhibitor; INK4, inhibitor of kinase 4

ß-Cell cycle progression and proliferation are critical to maintain ß-cell mass in adult mice. Of the cell cycle inhibitors, p27Kip1 is thought to be the primary modulator of the proliferative status in most cell types. p27 plays a role in ß-cell adaptation in genetic models of insulin resistance. To study the role of p27 in ß-cells during physiological conditions and at different stages of ß-cell differentiation, we studied mice deficient of or overexpressing p27. Experiments in p27-deficient mice showed improved glucose tolerance and hyperinsulinemia. These changes were associated with increased islet mass and proliferation. The experiments overexpressing p27 in ß-cells were performed using a doxycycline-inducible model. Interestingly, overexpression of p27 for 16 weeks in ß-cells from adult mice had no effect on glucose tolerance, ß-cell mass, or proliferation. In contrast, induction of p27 expression during ß-cell development or early neonatal period resulted in severe glucose intolerance and reduced ß-cell mass by decreased proliferation. These changes were reversible upon discontinuation of doxycycline. These experiments suggest that p27 is a critical molecule for ß-cell proliferation during ß-cell development and early postnatal life but not for maintenance of adult mass.

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