A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells

Cell Cycle. 2014;13(24):3948-57. doi: 10.4161/15384101.2014.952176.


The putative induction of adult β-cell regeneration represents a promising approach for the treatment of type 1 diabetes. Toward this ultimate goal, it is essential to develop an inducible model mimicking the long-lasting disease progression. In the current study, we have established a novel β-cell ablation mouse model, in which the β-cell mass progressively declines, as seen in type 1 diabetes. The model is based on the β-cell specific genetic ablation of the transcription initiation factor 1A, TIF-IA, essential for RNA Polymerase I activity (TIF-IA(Δ/Δ)). Using this approach, we induced a slow apoptotic response that eventually leads to a protracted β-cell death. In this model, we observed β-cell regeneration that resulted in a complete recovery of the β-cell mass and normoglycemia. In addition, we showed that adaptive proliferation of remaining β-cells is the prominent mechanism acting to compensate for the massive β-cell loss in young but also aged mice. Interestingly, at any age, we also detected β-like cells expressing the glucagon hormone, suggesting a transition between α- and β-cell identities or vice versa. Taken together, the TIF-IA(Δ/Δ) mouse model can be used to investigate the potential therapeutic approaches for type 1 diabetes targeting β-cell regeneration.

Keywords: Ngn3, Neurogenin 3; Pax4, Paired box gene 4; Pdx1, Pancreatic and duodenal homeobox 1; RIP, Rat Insulin Promoter; TIF-IA; TIF-IA, Transcription Initiation Factor 1A; diabetes; insulin; islet of Langerhans; pancreatic β-cell; rDNA, ribosomal DNA; regeneration; β-cell proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Cell Transdifferentiation
  • Disease Models, Animal
  • Insulin / blood
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Pol1 Transcription Initiation Complex Proteins / genetics
  • Pol1 Transcription Initiation Complex Proteins / metabolism
  • Regeneration*
  • Tamoxifen / toxicity


  • Blood Glucose
  • Insulin
  • Pol1 Transcription Initiation Complex Proteins
  • Rrn3 protein, mouse
  • Tamoxifen