p27 Regulates the transition of beta-cells from quiescence to proliferation

Diabetes. 2006 Nov;55(11):2950-6. doi: 10.2337/db06-0249.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / physiology
  • Cell Differentiation / physiology*
  • DNA Primers
  • Diabetes Mellitus, Experimental / genetics*
  • Fasting
  • Genetic Predisposition to Disease
  • Genotype
  • Glucose Intolerance / genetics
  • Insulin / blood
  • Insulin-Secreting Cells / cytology*
  • Mice
  • Mice, Knockout
  • Polymerase Chain Reaction
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / physiology*

Substances

  • Blood Glucose
  • DNA Primers
  • Insulin
  • Proliferating Cell Nuclear Antigen
  • p27 antigen