Desensitization of insulin secretion by depolarizing insulin secretagogues
Desensitization of insulin secretion by depolarizing insulin secretagogues
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DOI：
10.2337/diabetes.53.suppl_3.s140
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发表时间：
2004-12-01
期刊：
影响因子：
7.7
通讯作者：
Jörns, A
中科院分区：
文献类型：
--
作者：
Rustenbeck, I;Wienbergen, A;Jörns, A
去极化和 Ca2+ 流入对胰岛素分泌的长期刺激通常会导致对营养和非营养刺激的分泌反应性降低的可逆状态。这种状态被称为“脱敏”。脱敏可能会在暴露于去极化刺激后 1 小时内发生。通过接触磺酰脲类、咪唑啉类或奎宁类药物进行脱敏，可对其他 ATP 敏感的 K+ 通道（K-ATP 通道）阻断促分泌剂产生显着的交叉脱敏作用。然而，脱敏的 P 细胞不一定会表现出 K-ATP 通道活性或 Ca2+ 处理的变化。必须小心区分脱敏引起的信号变化与促分泌素持续存在的影响。去极化促分泌剂的脱敏主要伴随着免疫反应性胰岛素含量的减少和β细胞中分泌颗粒的显着减少。 4 小时后，咪唑啉依法罗生的体外脱敏作用几乎完全恢复。此时，颗粒含量的消耗部分逆转。显然，脱敏的恢复影响颗粒从生物发生到胞吐作用的整个寿命。然而，β细胞颗粒含量和分泌反应性之间没有直接关系。尽管分离的胰岛长时间暴露于去极化促分泌素通常与 β 细胞超微结构损伤的发生有关，但我们无法找到去极化和 Ca2+ 流入以及细胞凋亡或坏死 β 细胞死亡之间的有力联系。
Prolonged stimulation of insulin secretion by depolarization and Ca2+ influx regularly leads to a reversible state of decreased secretory responsiveness to nutrient and nonnutrient stimuli. This state is termed "desensitization." The onset of desensitization may occur within 1 h of exposure to depolarizing stimuli. Desensitization by exposure to sulfonylureas, imidazolines, or quinine produces a marked cross-desensitization against other ATP-sensitive K+ channel (K-ATP channel)-blocking secretagogues. However, desensitized P-cells do not necessarily show changes in K-ATP channel activity or Ca2+ handling. Care has to be taken to distinguish desensitization-induced changes in signaling from effects due to the persisting presence of secretagogues. The desensitization by depolarizing secretagogues is mostly accompanied by a reduced content of immunoreactive insulin and a marked reduction of secretory granules in the beta-cells. In vitro recovery from a desensitization by the imidazoline efaroxan was nearly complete after 4 h. At this time point the depletion of the granule content was partially reversed. Apparently, recovery from desensitization affects the whole lifespan of a granule from biogenesis to exocytosis. There is, however, no direct relation between the beta-cell granule content and the secretory responsiveness. Even though a prolonged exposure of isolated islets to depolarizing secretagogues is often associated with the occurrence of ultrastructural damage to beta-cells, we could not find a cogent link between depolarization and Ca2+ influx and apoptotic or necrotic beta-cell death.