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• W3043011806 abstract "The NMDA receptor antagonist dextromethorphan (DXM) and its metabolite dextrorphan (DXO) have been recommended for treatment of type 2 diabetes mellitus because of their beneficial effects on insulin secretion. This study investigates how different key points of the stimulus-secretion coupling in mouse islets and <i>β</i>-cells are influenced by DXM or DXO. Both compounds elevated insulin secretion, electrical activity, and [Ca²⁺]_c in islets at a concentration of 100 µM along with a stimulating glucose concentration. DXO and DXM increased insulin secretion approximately 30-fold at a substimulatory glucose concentration (3 mM). Patch-clamp experiments revealed that 100 µM DXM directly inhibited K_ATP channels by about 70%. Of note, DXM decreased the current through L-type Ca²⁺ channels about 25%, leading to a transient reduction in Ca²⁺ action potentials. This interaction might explain why elevating DXM to 500 µM drastically decreased insulin release. DXO inhibited K_ATP channels almost equally. In islets of K_ATP channel–deficient sulfonylurea receptor 1 knockout mice, the elevating effects of 100 µM DXM on [Ca²⁺]_c and insulin release were completely lost. By contrast, 100 µM DXO still increased glucose-stimulated insulin release around 60%. In summary, DXM-induced alterations in stimulus-secretion coupling of wild-type islets result from a direct block of K_ATP channels and are partly counteracted by inhibition of L-type Ca²⁺ channels. The stimulatory effect of DXO seems to be based on a combined antagonism on K_ATP channels and NMDA receptors and already occurs under resting conditions. Consequently, both compounds seem not to be suitable candidates for treatment of type 2 diabetes mellitus. <h3>SIGNIFICANCE STATEMENT</h3> This study shows that the use of dextromethorphan as an antidiabetic drug can cause unpredictable alterations in insulin secretion by direct interaction with K_ATP and L-type Ca²⁺ channels besides its actual target, the NMDA receptor." @default.
• W3043011806 created "2020-07-23" @default.
• W3043011806 creator A5064467348 @default.
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• W3043011806 date "2020-07-14" @default.
• W3043011806 modified "2023-09-24" @default.
• W3043011806 title "Dextromethorphan and Dextrorphan Influence Insulin Secretion by Interacting with K_ATPand L-type Ca²⁺Channels in Pancreatic<i>β</i>-Cells" @default.
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• W3043011806 doi "https://doi.org/10.1124/jpet.120.265835" @default.
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