Notch-mediated Ephrin signaling disrupts islet architecture and β cell function

Area of Science:

• Endocrinology
• Cell Biology
• Developmental Biology

Background:

• Altered islet architecture is linked to beta cell dysfunction and type 2 diabetes (T2D).
• Molecular regulators of islet spatial organization are largely unknown.
• Notch signaling, known for regulating pancreatic development, was observed to be reactivated in beta cells of obese mice.

Purpose of the Study:

• To investigate the effects and reversibility of Notch signaling activation in postnatal beta cells.
• To identify molecular mechanisms underlying Notch-induced islet architectural changes and glucose intolerance.
• To explore the role of Notch and Ephrin signaling in T2D pathogenesis.

Main Methods:

• Generated doxycycline-dependent, beta cell-specific Notch gain-of-function mouse models.
• Assessed glucose-stimulated insulin secretion and glucose tolerance.
• Performed transcriptomic screening of islets.
• Examined the impact of Ephrin ligands on beta cell behavior and pseudoislet formation in vitro.
• Analyzed human T2D patient samples.

Main Results:

• Notch activation in postnatal beta cells impaired glucose tolerance and insulin secretion.
• Glucose intolerance persisted even after Notch activity cessation, linked to disrupted islet architecture.
• Transcriptomic analysis revealed increased Ephrin signaling in Notch-activated islets.
• Ephrin ligand exposure caused beta cell repulsion and impaired pseudoislet formation.
• Elevated Notch and Ephrin signaling were found in metabolically inflexible beta cells from T2D patients.

Conclusions:

• Beta cell Notch/Ephrin signaling can permanently alter islet architecture during a critical early-life developmental window.
• This signaling pathway represents a potential therapeutic target for preventing or treating T2D.
• Understanding these mechanisms is crucial for addressing beta cell dysfunction in T2D.