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Diabetes and Vascular Disease

SAT-561 - Cysteine promotes islet α-cell glucagon secretion by limiting oxidative inhibition of voltage-gated sodium channels

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT
Disclosure(s):
SOMA BEHERA, PhD: No financial relationships to disclose
Cysteine serves as a robust α-cell secretagogue. Moreover, cysteine becomes elevated during the pathogenesis of type 2 diabetes and may contribute to hyperglucagonemia and hyperglycemia. However, the mechanisms of cysteine action on α-cell function have not been determined. In this study, we identify cysteine as a key regulator of islet glucagon secretion through redox control of α-cell electrical excitability. Short-term cysteine depletion (4-12hrs) markedly suppressed hypoglycemia-stimulated glucagon secretion from human (84 ±6.8%, P < 0.001) and mouse (71 ±14.6%, p< 0.05) islets. Moreover, cysteine depleted islets showed reduced α-cell Ca2+ influx (57.5 ±5.9%, P < 0.0001). Supplementation with cysteine rapidly restored glucagon secretion (428 ± 64%, P < 0.01) and Ca2+ entry (288 ±33%, P < 0.05). Cysteine depletion also reduced α-cell voltage-gated sodium channel (NaV) conductance and action potential amplitude (47 ±6 % at 10mV, P < 0.0001). Importantly, reducing agents restored NaV currents in cysteine depleted α-cells (dithiothreitol (400 ±132% at 10mV, P < 0.001), 3-mercaptopyruvate (3-MP; 245 ±54% at 10mV, P < 0.001); 3-MP also rescued glucose control of islet α-cell Ca2+ in cysteine depleted islets. These findings identify reductive amplification of NaVs 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.

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