Weigle D S, Goodner C J
Endocrinology. 1986 Apr;118(4):1606-13. doi: 10.1210/endo-118-4-1606.
We have reported that glucagon administered to perifused rat hepatocytes as a series of pulses at 15-min intervals is a more effective stimulus for hepatocyte glucose production (HGP) than is continuous glucagon infusion. To test whether the efficiency of HGP depends upon the frequency of pulsatile glucagon delivery, we administered glucagon to perifused rat hepatocytes as a series of pulses of fixed amplitude [922 +/- 30 (+/- SE) pg/ml] at eight separate pulse intervals ranging from 3-45 min. Compared to continuous infusion of the same total amount of hormone, pulsatile glucagon administration clearly enhanced HGP in a frequency-dependent fashion. At pulse intervals between 10 and 20 min, pulsatile HGP exceeded continuous HGP by a factor of 1.5-2. This range of optimal intervals compared favorably with the glucagon secretory period of 10 min observed in nonhuman primates and that of 13-20 min observed in humans. We noted a desensitization of the hepatocyte response to glucagon that was directly proportional to the log of the time-averaged hormone concentration. Since the magnitude of the desensitization elicited by pulsatile glucagon delivery exceeded the desensitization elicited by continuous hormone delivery regardless of pulse frequency, differential desensitization could not explain the frequency dependency of the pulse enhancement effect. A mathematical simulation of our data demonstrated that the asymmetry of the HGP waveform elicited by a brief glucagon pulse could account for the observed frequency dependency of HGP. Pulse to pulse summation and the desensitization phenomenon modulated both the magnitude of the pulse enhancement effect and the frequency range over which the effect was manifest. We conclude that the enhancement of HGP by glucagon pulses is a frequency-dependent phenomenon and that the physiological glucagon secretory period optimizes HGP.
我们曾报道，以15分钟的间隔对灌流大鼠肝细胞进行一系列脉冲式胰高血糖素给药，相较于持续输注胰高血糖素，是刺激肝细胞葡萄糖生成（HGP）更有效的方式。为了测试HGP的效率是否取决于脉冲式胰高血糖素给药的频率，我们以固定幅度[922±30（±标准误）pg/ml]的一系列脉冲，在3 - 45分钟的八个不同脉冲间隔对灌流大鼠肝细胞给予胰高血糖素。与持续输注相同总量的激素相比，脉冲式胰高血糖素给药明显以频率依赖的方式增强了HGP。在10至20分钟的脉冲间隔时，脉冲式HGP比持续HGP高出1.5 - 2倍。这个最佳间隔范围与在非人类灵长类动物中观察到的10分钟的胰高血糖素分泌期以及在人类中观察到的13 - 20分钟的分泌期相比具有优势。我们注意到肝细胞对胰高血糖素的反应存在脱敏现象，该现象与时间平均激素浓度的对数成正比。由于无论脉冲频率如何，脉冲式胰高血糖素给药引起的脱敏程度都超过了持续激素给药引起的脱敏程度，所以差异脱敏不能解释脉冲增强效应的频率依赖性。对我们数据的数学模拟表明，短暂的胰高血糖素脉冲引发的HGP波形不对称可以解释观察到的HGP的频率依赖性。脉冲间总和以及脱敏现象调节了脉冲增强效应的幅度和该效应显现的频率范围。我们得出结论，胰高血糖素脉冲对HGP的增强是一种频率依赖性现象，并且生理上的胰高血糖素分泌期使HGP达到最佳。
