Rustenbeck Ingo
Institute of Pharmacology and Toxicology, Technical University of Braunschweig, Mendelssohnstr. 1, D-38106, Braunschweig, Germany.
Biochem Pharmacol. 2002 Jun 1;63(11):1921-35. doi: 10.1016/s0006-2952(02)00996-6.
Desensitization of insulin secretion describes a reversible state of decreased secretory responsiveness of the pancreatic beta-cell, induced by a prolonged exposure to a multitude of stimuli. These include the main physiological stimulator, glucose, but also other nutrients like free fatty acids and practically all pharmacological stimulators acting by depolarization and Ca2+ influx into the beta-cell. Desensitization of insulin secretion appears to be an important step in the manifestation of type 2 diabetes and in the secondary failure of oral antidiabetic treatment. In this commentary, the basic concepts and the controversial issues in the field will be outlined. With regard to glucose-induced desensitization, two fundamentally opposing concepts have emerged. The first is that desensitization is the consequence of functional changes in the beta-cell that impair glucose-recognition. The second is that long-term increased secretory activity leads to a depletion of releasable insulin, often in spite of increased insulin synthesis. The latter concept is more appropriately termed beta-cell exhaustion. The same dichotomy applies to the desensitization evoked by pharmacological stimuli: again the relative contributions of a decreased insulin content versus alterations in signal transduction are in dispute. The action of tolbutamide on beta-cells may be an example of desensitization caused by a lack of releasable insulin since the signaling mechanisms are nearly unchanged, whereas the action of phentolamine, an imidazoline, induces a strong desensitization without reducing insulin content or secretory granules, apparently by abolishing Ca2+ influx. With pharmacological agents it seems that both, alterations in signal transduction and decreased availability of releasable insulin, can contribute to the desensitized state of the beta-cell, the relative contribution being variable depending upon the exact nature of the secretory stimulus.
胰岛素分泌脱敏描述了胰腺β细胞分泌反应性降低的一种可逆状态，这种状态是由长时间暴露于多种刺激所诱导的。这些刺激包括主要的生理刺激物葡萄糖，也包括其他营养物质如游离脂肪酸，以及实际上所有通过使β细胞去极化和钙离子内流起作用的药理刺激物。胰岛素分泌脱敏似乎是2型糖尿病发生及口服抗糖尿病治疗继发性失效过程中的一个重要步骤。在本评论中，将概述该领域的基本概念和有争议的问题。关于葡萄糖诱导的脱敏，出现了两种根本对立的概念。第一种观点认为，脱敏是β细胞功能变化导致葡萄糖识别受损的结果。第二种观点认为，长期增加的分泌活动会导致可释放胰岛素的耗竭，尽管胰岛素合成增加。后一种概念更恰当地称为β细胞耗竭。同样的二分法也适用于药理刺激引起的脱敏：胰岛素含量降低与信号转导改变的相对作用仍存在争议。甲苯磺丁脲对β细胞的作用可能是由于缺乏可释放胰岛素导致脱敏的一个例子，因为其信号转导机制几乎未变，而咪唑啉类药物酚妥拉明的作用则明显通过消除钙离子内流诱导强烈的脱敏，而不降低胰岛素含量或分泌颗粒。对于药理制剂，似乎信号转导改变和可释放胰岛素可用性降低都可能导致β细胞的脱敏状态，其相对作用因分泌刺激的确切性质而异。
