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The effects of theophylline and dibutyryl cyclic AMP on the membrane potential of mouse beta-cells were studied with micro-electrodes. They were compared to their effects on insulin release by perifused mouse islets. In 3 mM-glucose, theophylline (10 mM) depolarized the beta-cell membrane and stimulated insulin release, but did not induce electrical activity. Dibutyryl cyclic AMP (1 mM) was without effect. In 7 mM-glucose, theophylline (0.5-2 mM) and dibutyryl cyclic AMP (1 mM) slightly depolarized the beta-cell membrane, induced electrical activity in otherwise silent cells and increased insulin release. A higher concentration of theophylline (10 mM) hyperpolarized the beta-cell membrane, did not induce electrical activity, but also stimulated insulin release. In 10 mM-glucose, the membrane potential of beta-cells exhibited repetitive slow waves with bursts of spikes on the plateau. Under steady state, these slow waves were differently affected by low or high concentrations of theophylline. At 0.5-2 mM, theophylline shortened the intervals, lengthened the slow waves and slightly increased their frequency. On the other hand, 10 mM-theophylline markedly decreased the duration of both intervals and slow waves, and increased their frequency. The effects of 1 mM-dibutyryl cyclic AMP were similar to those of 2 mM-theophylline. With 2-10 mM-theophylline, two other effects were also observed: a transient hyperpolarization with suppression of electrical activity immediately after addition of the methylxanthine and an increase in electrical activity upon its withdrawal. Theophylline and dibutyryl cyclic AMP markedly potentiated insulin release induced by 10 mM-glucose. The magnitude of these changes did not correlate well with the importance of the changes in electrical activity. However, with 2-10 mM-theophylline the increase in release was also preceded by an initial transient inhibition, whereas withdrawal of the methylxanthine was accompanied by a further increase. When Ca influx was inhibited by D600, the slow waves were suppressed, the membrane was depolarized to the plateau level and only few spikes were present. Although theophylline markedly increased insulin release under these conditions, it did not affect the membrane potential. Several conclusions can be drawn from this study. Insulin release and electrical activity in beta-cells can be dissociated when intracellular Ca is used to trigger exocytosis. High concentrations of theophylline produce effects unrelated to cyclic AMP.(ABSTRACT TRUNCATED AT 400 WORDS)

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