Bolaffi J L, Bruno L, Heldt A, Grodsky G M
Metabolic Research Unit, University of California San Francisco 94143.
Endocrinology. 1988 May;122(5):1801-9. doi: 10.1210/endo-122-5-1801.
This report has investigated desensitization of pancreatic B cell secretion, or diminution of the insulin response to chronic stimulation. Freshly isolated rat islets were continuously challenged with various secretagogues over 24 h either in batch incubation or in a computer-controlled, flow-through perifusion system. At various glucose concentrations, secretion rose to a peak level in the third hour, then dropped to a new desensitized secretory level which was 25% or less than that of the maximum rate. The amount of insulin secreted was glucose dependent although secretory kinetics were independent of the amount of hormone secreted. At all glucose concentrations the reduction in islet insulin content was not great enough to account for the observed degree of desensitization. Furthermore at hour 20, islets responded vigorously to an alternate stimulus, indicating insulin stores and islet secretory machinery were still capable of being stimulated. Addition of 3-isobutyl-1-methylxanthine or forskolin did not prevent glucose-induced desensitization. Insulin secretion desensitized similarly to nonglucose (alpha-ketoisocaproic acid) and nonfuel (phorbol ester) stimuli. Glucose potentiation of a terminal KIC response, although demonstrable after 20 h of chronic glucose, was diminished somewhat compared to that after 3 h of chronic glucose. Delaying glucose stimulation by 6 h reduced insulin secretion, yet desensitization persisted. Although insulin secretion entrained to a glucose signal which oscillated from 1.3-12.7 mM in sine wave pulses of 90-min frequency, desensitization was not prevented. Thus, desensitization occurred in response to glucose, nonglucose, and nonfuel stimuli and despite delayed or oscillating signals. We conclude that exhaustion of a finite insulin compartment is not the underlying defect in desensitized secretion and suggest that metabolic feedback or recruitment of multiple heterogeneous compartments may explain this phenomenon.
本报告研究了胰腺β细胞分泌的脱敏现象，即胰岛素对慢性刺激的反应减弱。将新鲜分离的大鼠胰岛在分批孵育或计算机控制的流通式灌流系统中，用各种促分泌剂连续刺激24小时。在不同的葡萄糖浓度下，分泌在第3小时升至峰值水平，然后降至新的脱敏分泌水平，该水平为最大速率的25%或更低。胰岛素分泌量依赖于葡萄糖，尽管分泌动力学与分泌的激素量无关。在所有葡萄糖浓度下，胰岛胰岛素含量的降低不足以解释观察到的脱敏程度。此外，在第20小时，胰岛对交替刺激有强烈反应，表明胰岛素储存和胰岛分泌机制仍能被刺激。添加3 -异丁基-1 -甲基黄嘌呤或福斯可林并不能阻止葡萄糖诱导的脱敏。胰岛素分泌对非葡萄糖（α-酮异己酸）和非燃料（佛波酯）刺激的脱敏情况类似。虽然在慢性葡萄糖刺激20小时后可证明末端KIC反应的葡萄糖增强作用，但与慢性葡萄糖刺激3小时后相比有所减弱。将葡萄糖刺激延迟6小时会降低胰岛素分泌，但脱敏现象仍然存在。尽管胰岛素分泌与频率为90分钟的正弦波脉冲中从1.3 - 12.7 mM振荡的葡萄糖信号同步，但脱敏现象并未被阻止。因此，脱敏现象发生在对葡萄糖、非葡萄糖和非燃料刺激的反应中，且不受延迟或振荡信号的影响。我们得出结论，有限的胰岛素池耗尽不是脱敏分泌的潜在缺陷，并提出代谢反馈或多个异质池的募集可能解释这一现象。
