Regulated and reversible induction of adult human β-cell replication

Diabetes. 2012 Feb;61(2):418-24. doi: 10.2337/db11-0580. Epub 2011 Dec 30.


Induction of proliferation in adult human β-cells is challenging. It can be accomplished by introduction of cell cycle molecules such as cyclin-dependent kinase 6 (cdk6) and cyclin D1, but their continuous overexpression raises oncogenic concerns. We attempted to mimic normal, transient, perinatal human β-cell proliferation by delivering these molecules in a regulated and reversible manner. Adult cadaveric islets were transduced with doxycycline (Dox)-inducible adenoviruses expressing cdk6 or cyclin D1. End points were cdk6/cyclin D1 expression and human β-cell proliferation, survival, and function. Increasing doses of Dox led to marked dose- and time-related increases in cdk6 and cyclin D1, accompanied by a 20-fold increase in β-cell proliferation. Notably, Dox withdrawal resulted in a reversal of both cdk6 and cyclin D1 expression as well as β-cell proliferation. Re-exposure to Dox reinduced both cdk/cyclin expression and proliferation. β-Cell function and survival were not adversely affected. The adenoviral tetracycline (tet)-on system has not been used previously to drive human β-cell proliferation. Human β-cells can be induced to proliferate or arrest in a regulated, reversible manner, temporally and quantitatively mimicking the transient perinatal physiological proliferation that occurs in human β-cells.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Adult
  • Cell Proliferation / drug effects
  • Cyclin D1 / genetics
  • Cyclin D1 / physiology
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclin-Dependent Kinase 6 / physiology
  • Doxycycline / pharmacology
  • Humans
  • Insulin-Secreting Cells / physiology*


  • CCND1 protein, human
  • Cyclin D1
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6
  • Doxycycline