Henquin J C
I. Physiologisches Institut, University of Saarland, Homburg/Saar, Germany.
Endocrinology. 1992 Jul;131(1):127-31. doi: 10.1210/endo.131.1.1611991.
Stimulation of insulin release by glucose requires Ca2+ influx in pancreatic B-cells. This influx occurs during phases of electrical activity (slow waves of membrane potential with superimposed spikes) that can be monitored with intracellular microelectrodes. It has been suggested that closure of ATP-sensitive K+ channels contributes to the increase in electrical activity (and, hence, in Ca2+ influx and insulin release) produced by suprathreshold (greater than 7 mM) concentrations of glucose. If this is the sole mechanism of control, the decrease in electrical activity that follows a decrease in glucose concentration should be mimicked by opening these ATP-sensitive K+ channels. This was achieved by diazoxide, which selectively and directly acts at the channel level (without decreasing B-cell metabolism), and azide, which indirectly opens the channels by inhibiting mitochondrial ATP production. Stepwise lowering of the glucose concentration from 15 to 8 mM progressively decreased electrical activity in B-cells. This decrease was characterized by a shortening of the slow waves and a lengthening of the intervals between the slow waves, with little change in slow wave frequency. Similar changes followed the addition of azide (250-750 microM) to a medium containing 15 mM glucose. In contrast, in the presence of 15 mM glucose, diazoxide (5-20 microM) considerably increased the interval duration, but did not shorten the slow waves, thus causing a marked fall in slow wave frequency. In B-cells persistently depolarized by 30 mM glucose, diazoxide restored slow waves and intervals that were much longer than those recorded when the same cells were stimulated by 15 mM glucose. In conclusion, decreasing mitochondrial ATP production with azide is more able to reproduce the effects of a decrease in glucose concentration on electrical activity in B-cells than a direct pharmacological opening of ATP-sensitive K+ channels with diazoxide. This suggests that ionic channels other than ATP-sensitive K+ channels are under metabolic control and may contribute to the regulation of electrical activity by glucose.
葡萄糖刺激胰岛素释放需要胰腺β细胞内的Ca2+内流。这种内流发生在电活动阶段（膜电位的慢波叠加尖峰），可用细胞内微电极进行监测。有人提出，ATP敏感性钾通道的关闭有助于由阈上（大于7 mM）浓度的葡萄糖产生的电活动增加（进而导致Ca2+内流和胰岛素释放增加）。如果这是唯一的控制机制，那么葡萄糖浓度降低后电活动的降低应可通过打开这些ATP敏感性钾通道来模拟。这通过二氮嗪实现，它选择性地直接作用于通道水平（不降低β细胞代谢），还有叠氮化物，它通过抑制线粒体ATP生成间接打开通道。将葡萄糖浓度从15 mM逐步降至8 mM会使β细胞的电活动逐渐降低。这种降低的特征是慢波缩短以及慢波之间的间隔延长，慢波频率变化不大。向含有15 mM葡萄糖的培养基中添加叠氮化物（250 - 750 μM）后也出现类似变化。相反，在存在15 mM葡萄糖的情况下，二氮嗪（5 - 20 μM）显著增加了间隔持续时间，但没有缩短慢波，从而导致慢波频率明显下降。在被30 mM葡萄糖持续去极化的β细胞中，二氮嗪恢复了慢波和间隔，其长度远长于相同细胞被15 mM葡萄糖刺激时记录到的长度。总之，与用二氮嗪直接药理学打开ATP敏感性钾通道相比，用叠氮化物降低线粒体ATP生成更能重现葡萄糖浓度降低对β细胞电活动的影响。这表明除ATP敏感性钾通道外的离子通道受代谢控制，可能有助于葡萄糖对电活动的调节。
