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L-Cysteine Inhibits Insulin Release From the Pancreatic ß-Cell

Possible Involvement of Metabolic Production of Hydrogen Sulfide, a Novel Gasotransmitter

¹ Department of Pharmacology, Oita University Faculty of Medicine, Oita, Japan
² Department of Molecular Genetics, National Institute of Neuroscience, Tokyo, Japan

Address correspondence and reprint requests to Ichiro Niki, Department of Pharmacology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. E-mail: niki{at}med.oita-u.ac.jp

Abbreviations: -KIC, -ketoisocaproate; [Ca²⁺]_i, intracellular Ca²⁺ concentration; CBS, cystathionine ß-synthase; CSE, cystathionine -lyase; FCCP, calbonyl cyanide p-(trifluoromethoxy) phenyl hydrazone; GTPS, guanosine 5'-0-3-thiotriphosphate; K_ATP channel, ATP-sensitive K⁺ channel; SLO, streptolysin-O; TBST, Tris-buffered saline with Tween

Hydrogen sulfide (H₂S) was historically recognized as a toxic gas generated by natural resources. However, its enzymatic production from L-cysteine has recently been demonstrated in mammals. Cystathionine ß-synthase and cystathionine -lyase, both of which can produce H₂S, were expressed in mouse pancreatic islet cells and the ß-cell line, MIN6. L-Cysteine and the H₂S donor NaHS inhibited glucose-induced insulin release from islets and MIN6 cells. These inhibitory effects were reproduced when insulin release was stimulated by -ketoisocaproate, tolbutamide, or high K⁺. L-Cysteine and NaHS inhibited glucose-potentiated insulin release in the copresence of diazoxide and high K⁺. Real-time imaging of intracellular Ca²⁺ concentration ([Ca²⁺]_i) demonstrated that both L-cysteine and NaHS reversibly suppressed glucose-induced [Ca²⁺]_i oscillation in a single ß-cell without obvious changes in the mean value. These substances inhibited Ca²⁺- or guanosine 5'-0-3-thiotriphosphate–induced insulin release from islets permeabilized with streptolysin-O. L-Cysteine and NaHS reduced ATP production and attenuated glucose-induced hyperpolarization of the mitochondrial membrane potential. Finally, L-cysteine increased H₂S content in MIN6 cells. We suggest here that L-cysteine inhibits insulin release via multiple actions on the insulin secretory process through H₂S production. Because the activities of H₂S-producing enzymes and the tissue H₂S contents are known to increase under diabetic conditions, the inhibition may participate in the deterioration of insulin release in this disease.

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