Purrello F, Rabuazzo A M, Anello M, Patanè G
Institute of Internal Medicine, Endocrinology and Metabolism, University of Catania, Ospedale Garibaldi, Italy.
Acta Diabetol. 1996 Dec;33(4):253-6. doi: 10.1007/BF00571559.
The prolonged exposure of pancreatic islets and isolated beta cells to elevated glucose concentrations induces a state of unresponsiveness to glucose (desensitization). However, an increased sensitivity to glucose (detected by a shift to the left of the dose-response curve of glucose-induced insulin release) has been also reported after chronic exposure to glucose, making the overall response less comprehensible. In vitro models have many theoretical and practical advantages in better understanding the effects of the prolonged glucose stimulation; moreover, they are also suitable for studying the mechanisms responsible of the observed alterations. We have performed a time-course study of the effect of the exposure to glucose at high concentration on the secretory behaviour of beta cells. Rat pancreatic islets exposed for 30 min to high glucose (300 mg/dl) showed increased basal insulin secretion (175 +/- 29 vs 44 +/- 8 pg/islet (per 30 min; n = 5, P < 0.002) was the only difference from control islets (exposed to 100 mg/dl). After 3 h exposure to high glucose, also increased sensitivity to glucose was observed, as indicated by a shift to the left of the glucose dose-response curve (EC50 123 +/- 10 and 177 +/- 11 mg/dl, respectively; n = 5, P < 0.05). After 6 h exposure to high glucose, besides the two alterations already described, also a decrease in glucose-induced insulin release was observed (688 +/- 104 vs 1184 +/- 34 pg/islet per 30 min; n = 5, P < 0.01). We studied the mechanism responsible for these alterations and we found that the "supersensitivity" to glucose may be related to alterations in the "glucose-sensing" mechanism of beta cells, in particular in glucose phosphorylation. In contrast, in islets desensitized to glucose our data suggest that ion flux and consequent membrane potential changes play a key role in determining the secretory defect. Since a normal response to glyburide was observed, a proximal signal defect for closure of potassium channels is more likely than an intrinsic defect in the channel. In conclusion, our data show what the prolonged stimulation of beta cells with glucose at high concentration induces a series of distinct secretory abnormalities, with a pattern of response that leads first to increased sensitivity and then to decreased responsiveness to glucose.
胰岛和分离的β细胞长时间暴露于升高的葡萄糖浓度会诱导出对葡萄糖无反应的状态（脱敏）。然而，也有报道称，在长期暴露于葡萄糖后，对葡萄糖的敏感性会增加（通过葡萄糖诱导的胰岛素释放剂量反应曲线向左移动来检测），这使得整体反应更难理解。体外模型在更好地理解长期葡萄糖刺激的影响方面具有许多理论和实际优势；此外，它们也适用于研究导致观察到的改变的机制。我们进行了一项时间进程研究，以探讨高浓度葡萄糖暴露对β细胞分泌行为的影响。大鼠胰岛暴露于高葡萄糖（300mg/dl）30分钟后，基础胰岛素分泌增加（每30分钟175±29对44±8pg/胰岛；n = 5，P < 0.002），这是与对照胰岛（暴露于100mg/dl）的唯一差异。在暴露于高葡萄糖3小时后，也观察到对葡萄糖的敏感性增加，如葡萄糖剂量反应曲线向左移动所示（EC50分别为123±10和177±11mg/dl；n = 5，P < 0.05）。在暴露于高葡萄糖6小时后，除了已经描述的两种改变外，还观察到葡萄糖诱导的胰岛素释放减少（每30分钟688±104对1184±34pg/胰岛；n = 5，P < 0.01）。我们研究了导致这些改变的机制，发现对葡萄糖的“超敏感性”可能与β细胞“葡萄糖感应”机制的改变有关，特别是在葡萄糖磷酸化方面。相比之下，在对葡萄糖脱敏的胰岛中，我们的数据表明离子通量和随之而来的膜电位变化在决定分泌缺陷中起关键作用。由于观察到对格列本脲的正常反应，钾通道关闭的近端信号缺陷比通道本身的内在缺陷更有可能。总之，我们的数据表明，高浓度葡萄糖对β细胞的长期刺激会诱导一系列不同的分泌异常，其反应模式首先导致敏感性增加，然后导致对葡萄糖的反应性降低。
