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Notch signaling: a mediator of beta-cell de-differentiation in diabetes?

Martine I Darville1, Décio L Eizirik

  • 1Laboratory of Experimental Medicine, Université Libre de Bruxelles, Belgium. mdarvill@ulb.ac.be

Biochemical and Biophysical Research Communications
|December 13, 2005
PubMed

Insights

Cytokines induce Notch signaling in pancreatic beta-cells, potentially causing dysfunction in type 1 diabetes. Notch activation inhibits differentiated functions in dividing beta-cells but not terminally differentiated ones.

Area of Science:

  • Endocrinology
  • Immunology
  • Developmental Biology

Background:

  • Cytokines mediate pancreatic beta-cell dysfunction and death in type 1 diabetes mellitus.
  • Microarray analysis reveals altered gene expression in beta-cells exposed to inflammatory cytokines, including upregulation of the Notch signaling pathway.
  • Re-expression of developmental pathways like Notch may contribute to beta-cell loss-of-function during autoimmune attack.

Purpose of the Study:

  • To investigate the role of Notch signaling in cytokine-induced pancreatic beta-cell dysfunction.
  • To determine how Notch pathway activation affects differentiated functions in beta-cells.

Main Methods:

  • Exposure of rat primary beta-cells and INS-1E cells to cytokines (interleukin-1beta + interferon-gamma).
  • Microarray analysis to assess gene expression changes.
  • Transfection with a constitutively active Notch receptor to study pathway activation.
  • Measurement of Pdx1 and insulin expression levels.

Main Results:

  • Cytokine exposure upregulated Notch receptors, ligands, and the target gene Hes1 in primary rat beta-cells.
  • Constitutively active Notch receptor activation downregulated Pdx1 and insulin expression in dividing INS-1E cells.
  • Notch activation did not affect Pdx1 and insulin expression in terminally differentiated primary rat beta-cells.

Conclusions:

  • Activation of the Notch signaling pathway is implicated in pancreatic beta-cell dysfunction.
  • Notch pathway activation inhibits differentiated functions in dividing beta-cells.
  • Terminally differentiated beta-cells are resistant to Notch-mediated inhibition of differentiated functions, suggesting a potential mechanism for beta-cell survival in type 1 diabetes.

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