Survey of the human pancreatic beta-cell G1/S proteome reveals a potential therapeutic role for cdk-6 and cyclin D1 in enhancing human beta-cell replication and function in vivo

Diabetes. 2009 Apr;58(4):882-93. doi: 10.2337/db08-0631. Epub 2009 Jan 9.


Objectives: To comprehensively inventory the proteins that control the G1/S cell cycle checkpoint in the human islet and compare them with those in the murine islet, to determine whether these might therapeutically enhance human beta-cell replication, to determine whether human beta-cell replication can be demonstrated in an in vivo model, and to enhance human beta-cell function in vivo.

Research design and methods: Thirty-four G1/S regulatory proteins were examined in human islets. Effects of adenoviruses expressing cdk-6, cdk-4, and cyclin D1 on proliferation in human beta-cells were studied in both in vitro and in vivo models.

Results: Multiple differences between murine and human islets occur, most strikingly the presence of cdk-6 in human beta-cells versus its low abundance in the murine islet. Cdk-6 and cyclin D1 in vitro led to marked activation of retinoblastoma protein phosphorylation and cell cycle progression with no induction of cell death. Human islets transduced with cdk-6 and cyclin D1 were transplanted into diabetic NOD-SCID mice and markedly outperformed native human islets in vivo, maintaining glucose control for the entire 6 weeks of the study.

Conclusions: The human G1/S proteome is described for the first time. Human islets are unlike their rodent counterparts in that they contain easily measurable cdk-6. Cdk-6 overexpression, alone or in combination with cyclin D1, strikingly stimulates human beta-cell replication, both in vitro as well as in vivo, without inducing cell death or loss of function. Using this model, human beta-cell replication can be induced and studied in vivo.

Publication types

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

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Division
  • Cyclin D1 / genetics
  • Cyclin D1 / physiology*
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclin-Dependent Kinase 6 / physiology*
  • DNA Primers
  • G1 Phase / genetics*
  • Gene Expression Regulation
  • Glucose / pharmacology
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / enzymology
  • Insulin-Secreting Cells / physiology*
  • Insulin-Secreting Cells / transplantation
  • Kinetics
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phosphorylation
  • Proteome*
  • Retinoblastoma Protein / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • S Phase / genetics*
  • Species Specificity


  • DNA Primers
  • Insulin
  • Proteome
  • Retinoblastoma Protein
  • Cyclin D1
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6
  • Glucose