<b>Dynorphin A inhibits insulin secretion through opioid receptor–dependent modulation of β-cell Ca²</b><b>⁺</b><b> dynamics</b>

Building on evidence that β-cells co-release dynorphin A with insulin, we show that applied dynorphin A inhibits insulin secretion during glucose stimulation. Dynorphin A dose-dependently suppresses glucose-stimulated insulin secretion in mouse and human islets while preserving insulin content and β-cell viability.

Under dynamic perifusion, dynorphin A attenuates both first- and second-phase insulin release. Mechanistically, dynorphin A slows glucose-stimulated β-cell Ca²⁺ oscillations in pancreatic slices, reducing oscillatory frequency while prolonging individual Ca²⁺ events. Notably, the receptor requirements for the inhibitory response to applied dynorphin A differ across species: μ-opioid receptor blockade or β-cell–specific deletion abolishes inhibition in mouse islets, whereas δ-opioid receptor antagonism prevents dynorphin A–mediated inhibition in human islets.