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Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion

Fabienne Billiard1, Sevasti Karaliota2, Bei Wang1

  • 1Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.

Cell Reports
|February 2, 2018
PubMed

Insights

Inhibiting Dll4-Notch signaling promotes insulin-producing beta-islet cell proliferation and differentiation. This approach offers potential for treating diabetes by enhancing insulin secretion and protecting against diabetes development.

Area of Science:

  • Endocrinology
  • Immunology
  • Cell Biology

Background:

  • Notch signaling is implicated in various diseases, but its role in pancreatic islets is unclear.
  • Understanding Notch signaling's impact on pancreatic islets is crucial for developing diabetes therapies.

Purpose of the Study:

  • To investigate the direct effects of Dll4-Notch signaling inhibition on pancreatic islet biology.
  • To explore the therapeutic potential of Dll4 blockade in diabetes.

Main Methods:

  • Assessed Notch signaling gene expression in pancreatic islets from diabetic NOD mice.
  • Treated mice with an anti-Dll4 antibody to inhibit Notch signaling.
  • Evaluated the impact of Notch inhibition on beta-islet cell proliferation, differentiation, and insulin secretion.
  • Studied STZ-induced diabetes models.

Main Results:

  • Confirmed elevated Notch signaling gene expression in diabetic islets.
  • Anti-Dll4 antibody treatment effectively abolished Notch pathway activation.
  • Notch inhibition promoted beta-islet cell proliferation and protected against STZ-induced diabetes.
  • Inhibition of Dll4 increased insulin secretion by enhancing beta-islet cell progenitor differentiation and insulin-secreting cell proliferation.

Conclusions:

  • Dll4-Notch signaling directly influences pancreatic islet biology, promoting beta-islet cell expansion and function.
  • Dll4 blockade presents a potential therapeutic strategy for diabetes, addressing inefficient insulin action.
Keywords:
delta-like liganddiabetesdifferentiationinsulin secretionnotch pathwayproliferationβ-cells

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