Cysteine promotes islet α-cell glucagon secretion by limiting oxidative inhibition of voltage-gated sodium channels

Cysteine serves as a robust α-cell secretagogue. While diabetes alters both plasma cysteine and glucagon levels, the mechanisms of α-cell cysteine action remain unclear. Here, we identified cysteine as a key regulator of islet glucagon secretion through redox control of α-cell electrical excitability. Short-term cysteine depletion markedly suppressed hypoglycemia-stimulated glucagon secretion from both human and mouse islets. Moreover, cysteine-depleted islets showed reduced hypoglycemia-stimulated α-cell calcium (Ca 2+ ) influx. Islet glucagon secretion and α-cell Ca 2+ influx rapidly normalized following cysteine restoration. Cysteine depletion also reduced α-cell voltage-gated sodium channel (Na V ) conductance and action potential amplitude. Importantly, reducing agents restored Na V currents and glucose control of α-cell Ca 2+ handling in islets without cysteine. Together, these findings identify reductive amplification of Na V channels as a key mechanism required for hypoglycemia-stimulated glucagon secretion, highlighting cysteine as a critical regulator of α-cell redox state, electrical excitability, and glucagon secretion.