Post-Inhibitory Rebound by δ-Cells Converts Inhibition into Excitation and Confers Islet Plasticity

Area of Science:

• Endocrinology
• Cellular Physiology
• Diabetes Research

Background:

• Pancreatic islet hormone secretion coordination is not fully understood.
• Somatostatin was traditionally viewed as a static inhibitor of insulin and glucagon.
• A paradox exists in type 2 diabetes with correlated insulin and somatostatin hypersecretion.

Purpose of the Study:

• To identify novel mechanisms regulating pancreatic islet hormone secretion.
• To investigate the role of δ-cells and somatostatin in islet physiology.
• To explain the correlated hypersecretion of insulin and somatostatin in type 2 diabetes.

Main Methods:

• Utilized cell-type-specific chemogenetics and optogenetics in mouse models.
• Performed high-resolution triple-hormone perifusion and Ca²⁺ imaging.
• Validated findings in human islets and in vivo islet grafts.

Main Results:

• Identified post-inhibitory rebound (PIR) as a fundamental islet signaling feature.
• Demonstrated that δ-cell inhibition/activation triggers rebound excitation in β- and α-cells.
• Showcased glucose-dependent, synchronized hormone oscillations mediated by somatostatin.

Conclusions:

• Somatostatin signaling encodes hormone output through temporal dynamics, not tonic inhibition.
• δ-cell-driven PIR converts inhibition into coordinated endocrine output.
• Established a revised framework for intra-islet paracrine crosstalk with implications for diabetes.