Augmented Stat5 Signaling Bypasses Multiple Impediments to Lactogen-Mediated Proliferation in Human β-Cells

Diabetes. 2015 Nov;64(11):3784-97. doi: 10.2337/db15-0083. Epub 2015 Jul 9.


Pregnancy in rodents is associated with a two- to threefold increase in β-cell mass, which is attributable to large increases in β-cell proliferation, complimented by increases in β-cell size, survival, and function and mediated mainly by the lactogenic hormones prolactin (PRL) and placental lactogens. In humans, however, β-cell mass does not increase as dramatically during pregnancy, and PRL fails to activate proliferation in human islets in vitro. To determine why, we explored the human PRL-prolactin receptor (hPRLR)-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5)-cyclin-cdk signaling cascade in human β-cells. Surprisingly, adult human β-cells express little or no PRLR. As expected, restoration of the hPRLR in human β-cells rescued JAK2-STAT5 signaling in response to PRL. However, rescuing hPRLR-STAT5 signaling nevertheless failed to confer proliferative ability on adult human β-cells in response to PRL. Surprisingly, mouse (but not human) Stat5a overexpression led to upregulation of cyclins D1-3 and cdk4, as well as their nuclear translocation, all of which are associated with β-cell cycle entry. Collectively, the findings show that human β-cells fail to proliferate in response to PRL for multiple reasons, one of which is a paucity of functional PRL receptors, and that murine Stat5 overexpression is able to bypass these impediments.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology*
  • Cyclin D / genetics
  • Cyclin D / metabolism
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Phosphorylation / drug effects
  • Prolactin / pharmacology*
  • Receptors, Prolactin / genetics
  • Receptors, Prolactin / metabolism*
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Up-Regulation


  • Cyclin D
  • Receptors, Prolactin
  • STAT5 Transcription Factor
  • Prolactin
  • Cyclin-Dependent Kinase 4