Dextromethorphan and Dextrorphan Influence Insulin Secretion by Interacting with K ATP and L-type Ca 2+ Channels in Pancreatic β -Cells.

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 β -cells are influenced by DXM or DXO. Both compounds elevated insulin secretion, electrical activity, and [Ca ²⁺ ] _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 Ca ²⁺ channels about 25%, leading to a transient reduction in Ca ²⁺ 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 [Ca ²⁺ ] _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 Ca ²⁺ 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. SIGNIFICANCE STATEMENT: 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 Ca ²⁺ channels besides its actual target, the NMDA receptor.
Competing Interests: The authors declare no conflict of interests.
(Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)