Glucagonotropic and Glucagonostatic Effects of KATP Channel Closure and Potassium Depolarization
Glucagonotropic and Glucagonostatic Effects of KATP Channel Closure and Potassium Depolarization
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DOI：
10.1210/endocr/bqaa136
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发表时间：
2021-01-01
期刊：
影响因子：
4.8
通讯作者：
Rustenbeck, Ingo
中科院分区：
文献类型：
--
作者：
Frueh, Eike;Elgert, Christin;Rustenbeck, Ingo
通过比较K-ATP通道阻断和高钾的影响，研究了去极化在胰高血糖素分泌的逆葡萄糖依赖性中的作用。同时测定灌流小鼠胰岛分泌胰高血糖素和胰岛素的能力。降低葡萄糖在降低胰岛素分泌之前增加胰高血糖素分泌，表明α细胞内在信号识别。升高葡萄糖同时影响胰高血糖素和胰岛素的分泌。然而，去极化甲苯磺丁脲，格列齐特，或15 mM氯化钾增加胰岛素分泌之前，胰高血糖素分泌消退。与精氨酸和KCl（15和40 mM）对单个α细胞的强大去极化作用相反，甲苯磺丁脲的疗效不同。只有在其他去极化剂之前应用时，甲苯磺丁脲才具有一致的去极化作用，并定期增加胞浆Ca 2+浓度。当测试由内而外的贴片时，甲苯磺丁脲对α细胞和β细胞一样有效。在1 μ M可乐定存在下，为了区分促胰岛素作用和促胰高血糖素作用，500 μ M甲苯磺丁脲和30 μ M格列齐特均显着但短暂地增加胰高血糖素分泌。与此相反，15或40 mM KCl的额外存在导致胰高血糖素分泌的显著和持久的增加。甲苯磺丁脲不增加SUR 1敲除胰岛的胰高血糖素分泌，而40 mM KCl的效率不变。总之，强烈和持续的去极化与显著和持续的胰高血糖素分泌相容。α细胞中的K-ATP通道关闭比β细胞中的K-ATP通道关闭更不容易实现，这可能解释了中度和短暂的促胰高血糖素作用。
The role of depolarization in the inverse glucose-dependence of glucagon secretion was investigated by comparing the effects of K-ATP channel block and of high potassium. The secretion of glucagon and insulin by perifused mouse islets was simultaneously measured. Lowering glucose raised glucagon secretion before it decreased insulin secretion, suggesting an alpha cell-intrinsic signal recognition. Raising glucose affected glucagon and insulin secretion at the same time. However, depolarization by tolbutamide, gliclazide, or 15 mM KCl increased insulin secretion before the glucagon secretion receded. In contrast to the robust depolarizing effect of arginine and KCl (15 and 40 mM) on single alpha cells, tolbutamide was of variable efficacy. Only when applied before other depolarizing agents had tolbutamide a consistent depolarizing effect and regularly increased the cytosolic Ca2+ concentration. When tested on inside-out patches tolbutamide was as effective on alpha cells as on beta cells. In the presence of 1 mu M clonidine, to separate insulinotropic from glucagonotropic effects, both 500 mu M tolbutamide and 30 mu M gliclazide increased glucagon secretion significantly, but transiently. The additional presence of 15 or 40 mM KCl in contrast led to a marked and lasting increase of the glucagon secretion.The glucagon secretion by SUR1 knockout islets was not increased by tolbutamide, whereas 40 mM KCl was of unchanged efficiency. In conclusion a strong and sustained depolarization is compatible with a marked and lasting glucagon secretion. K-ATP channel closure in alpha cells is less readily achieved than in beta cells, which may explain the moderate and transient glucagonotropic effect.