Abstract
Adamantane derivatives were found to increase insulin release in vitro. Mouse islets were used to study the mechanisms and molecular requirements of that hitherto unrecognised property. At a non-stimulatory concentration of glucose (3 mM), 1-adamantanamine (1 mM) reversibly inhibited 86Rb efflux from islet cells, depolarized the beta-cell membrane, induced electrical activity, stimulated 45Ca uptake and efflux, and triggered insulin release. Omission of extracellular Ca2+ abolished the secretory response but only partially inhibited the acceleration of 45Ca efflux. At a stimulatory concentration of glucose (10 mM), 1-adamantanamine reversibly increased 86Rb efflux, potentiated electrical activity (lengthening of the slow waves with spikes), augmented 45Ca uptake and efflux, and increased insulin release. The effects of adamantanamine were dose-dependent, with a threshold concentration of 10 microM for stimulation release. 2-Adamantanamine was as potent as 1-adamantanamine. In contrast, substitution of the amino group by a carboxyl group (1-adamantanecarboxylic acid) decreased the effectiveness by about 65%, and substitution by a hydroxyl group (1-adamantanol) suppressed it. It is concluded that adamantane derivatives bearing an amino group decrease K+ permeability of the beta-cell membrane and thereby cause depolarization. This activates voltage-dependent Ca channels, permits Ca2+ influx and eventually stimulates insulin release. They may also mobilize cellular Ca2+, but this effect is not sufficient to cause release.