Abstract

The NMDA receptor antagonist dextromethorphan (DXM) and its metabolite dextrorphan (DXO) have been recommended for treatment of type 2 diabetes mellitus because of 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 [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 SUR1 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 wildtype 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.