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Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells

Shiwani Tiwari1, Chris Roel1, Mansoor Tanwir2

  • 1Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Scientific Reports
|July 7, 2016
PubMed

Insights

Type 2 diabetes (T2D) is linked to reduced human beta-cell proliferation. Skp2 protein enhances beta-cell expansion and regeneration in T2D by targeting c-Myc, offering a potential therapeutic strategy.

Area of Science:

  • Endocrinology
  • Cell Biology
  • Molecular Medicine

Background:

  • Type 2 diabetes (T2D) is characterized by insulin resistance and diminished functional beta-cell mass.
  • Reduced beta-cell mass in T2D may result from developmental issues, impaired adaptive expansion, or beta-cell death/de-differentiation.

Purpose of the Study:

  • To investigate the hypothesis that human beta-cells from T2D donors exhibit a reduced proliferative response to mitogens.
  • To explore the role of cell cycle regulators in T2D beta-cell dysfunction and identify potential targets for beta-cell regeneration.

Main Methods:

  • Assessed the proliferative response of human beta-cells from T2D and non-diabetic donors to specific mitogens (cdk6 and cyclin D3).
  • Investigated the role of the cell cycle inhibitor p27(kip1) and the E3 ubiquitin ligase Skp2 in regulating beta-cell proliferation.
  • Utilized adenoviral delivery for gene manipulation and measured beta-cell expansion and proliferation rates.

Main Results:

  • Human beta-cells from T2D donors showed a significantly impaired proliferative response to cdk6 and cyclin D3.
  • Increased nuclear abundance of p27(kip1) was observed in T2D beta-cells, and its overexpression inhibited proliferation in non-diabetic beta-cells.
  • Skp2 overexpression, unlike p27(kip1) silencing, effectively promoted human beta-cell expansion and significantly enhanced T2D beta-cell proliferation.
  • c-Myc was identified as a key Skp2 target essential for initiating cell cycle entry and promoting beta-cell expansion and regeneration.

Conclusions:

  • The impaired proliferative capacity of beta-cells contributes to the pathogenesis of T2D.
  • Skp2 plays a critical role in beta-cell expansion and regeneration, potentially through c-Myc regulation.
  • Targeting the Skp2-c-Myc pathway represents a promising strategy for regenerating beta-cells in T2D.

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