Skp2 is required for incretin hormone-mediated β-cell proliferation

Mol Endocrinol. 2011 Dec;25(12):2134-43. doi: 10.1210/me.2011-1119. Epub 2011 Oct 6.


The glucoincretin hormone glucagon-like peptide-1 (GLP-1) and its analog exendin-4 (Ex-4) promote β-cell growth and expansion. Here we report an essential role for Skp2, a substrate recognition component of SCF (Skp, Cullin, F-box) ubiquitin ligase, in promoting glucoincretin-induced β-cell proliferation by regulating the cellular abundance of p27. In vitro, GLP-1 treatment increases Skp2 levels, which accelerates p27 degradation, whereas in vivo, loss of Skp2 prevents glucoincretin-induced β-cell proliferation. Using inhibitors of phosphatidylinositol 3-kinase and Irs2 silencing RNA, we also show that the effects of GLP-1 in facilitating Skp2-dependent p27 degradation are mediated via the Irs2-phosphatidylinositol-3 kinase pathway. Finally, we show that down-regulation of p27 occurs in islets from aged mice and humans, although in these islets, age-dependent accumulation of p16(Ink4a) prevent glucoincretin-induced β-cell proliferation; however, ductal cell proliferation is maintained. Taken together, these data highlight a critical role for Skp2 in glucoincretin-induced β-cell proliferation.

Publication types

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

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Animals
  • Cell Proliferation*
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Exenatide
  • Gene Knockdown Techniques
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide 1 / physiology*
  • Humans
  • Incretins / pharmacology
  • Incretins / physiology*
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Peptides / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proteolysis
  • RNA Interference
  • S-Phase Kinase-Associated Proteins / metabolism*
  • Signal Transduction
  • Venoms / pharmacology


  • IRS2 protein, human
  • Incretins
  • Insulin Receptor Substrate Proteins
  • Peptides
  • S-Phase Kinase-Associated Proteins
  • Venoms
  • Cyclin-Dependent Kinase Inhibitor p27
  • Glucagon-Like Peptide 1
  • Exenatide
  • Phosphatidylinositol 3-Kinases