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Cyclin D2 is sufficient to drive β cell self-renewal and regeneration.

  • Author(s): Tschen, Shuen-Ing;
  • Zeng, Chun;
  • Field, Loren;
  • Dhawan, Sangeeta;
  • Bhushan, Anil;
  • Georgia, Senta
  • et al.
Abstract

Diabetes results from an inadequate mass of functional β cells, due to either β cell loss caused by autoimmune destruction (type I diabetes) or β cell failure in response to insulin resistance (type II diabetes). Elucidating the mechanisms that regulate β cell mass may be key to developing new techniques that foster β cell regeneration as a cellular therapy to treat diabetes. While previous studies concluded that cyclin D2 is required for postnatal β cell self-renewal in mice, it is not clear if cyclin D2 is sufficient to drive β cell self-renewal. Using transgenic mice that overexpress cyclin D2 specifically in β cells, we show that cyclin D2 overexpression increases β cell self-renewal post-weaning and results in increased β cell mass. β cells that overexpress cyclin D2 are responsive to glucose stimulation, suggesting they are functionally mature. β cells that overexpress cyclin D2 demonstrate an enhanced regenerative capacity after injury induced by streptozotocin toxicity. To understand if cyclin D2 overexpression is sufficient to drive β cell self-renewal, we generated a novel mouse model where cyclin D2 is only expressed in β cells of cyclin D2-/- mice. Transgenic overexpression of cyclin D2 in cyclin D2-/- β cells was sufficient to restore β cell mass, maintain normoglycaemia, and improve regenerative capacity when compared with cyclin D2-/- littermates. Taken together, our results indicate that cyclin D2 is sufficient to regulate β cell self-renewal and that manipulation of its expression could be used to enhance β cell regeneration.

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