Beta-cell memory to insulin secretagogues: characterization of the time-dependent inhibitory control system in the isolated rat pancreas.

Most secretagogues, in addition to their acute stimulatory effect on insulin release, modify the responsiveness of the islet to subsequent stimulations. According to the nature and duration of the stimulus, the generated islet memory may either amplify [time-dependent potentiation, (TDP)] or diminish [time-dependent inhibition (TDI)] the responsiveness of the beta-cell. This work characterizes the kinetic parameters of TDI in the isolated rat pancreas. When subjected to a low dose (8.3 mmol/liter) glucose stimulus, maximal TDI was observed after 5 min of priming, while at a higher dose (16.7 mmol/liter) shorter exposures were sufficient. Longer periods of stimulation (10-40 min) resulted in the predominance of TDP, thus amplifying the release rate. TDI was not affected by previous generation of TDP; 40-min priming with 16.7 mmol/liter glucose markedly augmented the subsequent insulin responses to a pair of 6.9 mmol/liter stimuli, but the response to the second stimulus was inhibited, as in unprimed pancreas. Stimulation with arginine (5.0 mmol/liter) in the presence of basal (3.3 mmol/liter) glucose activated TDI only, and hence revealed monophasic insulin release. Tolbutamide (100 micrograms/ml), glucagon (5 micrograms/ml), and isobutylmethylxanthine (0.1 mmol/liter) also demonstrated TDI when given as a pair of 10-min stimuli; they all elicited monophasic insulin responses during prolonged stimulation. Arginine was chosen for detailed characterization of TDI because of its potency. Using identical concentrations of arginine for the generation and expression of TDI, a similar degree of inhibition (60-80%) was observed at all doses tested (0.5-5.0 mmol/liter). However, there existed competition between TDI and the acute secretory signal. Thus, TDI generated by 1.0 mmol/liter arginine had a minimal effect on insulin release induced by 2.0-5.0 mmol/liter amino acid, while it was fully inhibitory of the response to 1.0 mmol/liter arginine. Similarly, inhibition of the insulin response to 5.0 mmol/liter arginine was dependent on the dose (0.5-5.0 mmol/liter) of the priming pulse of arginine. The generation of TDI was unaffected by the insulin release rate during priming, since synergistic augmentation (combined arginine-glucose or arginine-isobutylmethylxanthine stimulation) or partial inhibition (arginine plus epinephrine) of the response had no effect on the subsequent expression of TDI. It is concluded that TDI and TDP are two distinct regulatory systems that independently control the rate of insulin release, most probably operating through different mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)