Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice

Nat Med. 2005 Feb;11(2):175-82. doi: 10.1038/nm1187. Epub 2005 Jan 30.

Abstract

The protein p27(Kip1) regulates cell cycle progression in mammals by inhibiting the activity of cyclin-dependent kinases (CDKs). Here we show that p27(Kip1) progressively accumulates in the nucleus of pancreatic beta cells in mice that lack either insulin receptor substrate 2 (Irs2(-/-)) or the long form of the leptin receptor (Lepr(-/-) or db/db). Deletion of the gene encoding p27(Kip1) (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation. Thus, p27(Kip1) contributes to beta-cell failure during the development of type 2 diabetes in Irs2(-/-) and Lepr(-/-) mice and represents a potential new target for the treatment of this condition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27
  • Diabetes Mellitus, Type 2 / metabolism*
  • Disease Models, Animal
  • Enzyme Inhibitors / metabolism*
  • Hyperglycemia / metabolism
  • Hyperinsulinism / metabolism*
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism
  • Leptin / genetics
  • Leptin / metabolism
  • Mice
  • Mice, Knockout
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Leptin
  • Signal Transduction / physiology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs2 protein, mouse
  • Leptin
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Receptors, Leptin
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Insulin-Like Growth Factor I
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt