Intrinsic islet heterogeneity and gap junction coupling determine spatiotemporal Ca²⁺ wave dynamics

Area of Science:

• Endocrinology
• Computational Biology
• Cell Biology

Background:

• Insulin release from pancreatic islets relies on synchronized intracellular calcium oscillations.
• These oscillations involve calcium waves mediated by Connexin36 (Cx36) gap junctions.
• Previous models suggested islet heterogeneity influences wave emergence.

Purpose of the Study:

• To investigate the role of beta-cell heterogeneity in calcium wave propagation within islets.
• To determine how gap junction coupling modulates spatiotemporal calcium dynamics under heterogeneous glucose stimulation.
• To refine computational models of islet function by incorporating electrochemical gradients.

Main Methods:

• Utilized microfluidic devices to apply defined glucose stimulation patterns across islets.
• Measured intracellular free calcium ([Ca(2+)]i) dynamics and calcium wave propagation.
• Modified computational islet models to include electrochemical gradients between beta-cells.

Main Results:

• Calcium waves originate in islet regions with higher beta-cell excitability, indicating intrinsic heterogeneity.
• Gap junction coupling is crucial for the extent of [Ca(2+)]i elevation across the islet.
• Gap junction coupling exhibits glucose dependence, influencing wave propagation.
• Computational models were enhanced to account for electrochemical gradients.

Conclusions:

• Islet beta-cell heterogeneity is a key determinant of spatiotemporal calcium dynamics.
• Cell-cell coupling via gap junctions is vital for regulating calcium waves and insulin release.
• Understanding these dynamics is critical for comprehending coordinated insulin secretion.