Regulation of α-cell function by the β-cell in isolated human and rat islets deprived of glucose:: the "switch-off" hypothesis
Regulation of α-cell function by the β-cell in isolated human and rat islets deprived of glucose:: the "switch-off" hypothesis
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DOI：
10.2337/diabetes.53.6.1488
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发表时间：
2004-06-01
期刊：
影响因子：
7.7
通讯作者：
Robertson, RP
中科院分区：
文献类型：
--
作者：
Hope, KM;Tran, POT;Robertson, RP
解释低血糖期间α细胞功能的β细胞调节的“关闭”假说先前尚未在分离的胰岛中进行评估，主要是因为它们特征性地不通过分泌胰高血糖素来响应葡萄糖剥夺。我们使用正常人和Wistar大鼠胰岛以及链脲佐菌素（STZ）给药的β细胞缺陷Wistar大鼠胰岛研究了这一假设。正如预期的那样，用葡萄糖和3-异丁酰基-1-甲基黄嘌呤灌注的胰岛对葡萄糖剥夺没有通过增加胰高血糖素分泌来响应。然而，如果正常大鼠胰岛首先用16.7 mmol/l葡萄糖灌注以增加内源性胰岛素分泌，随后停止葡萄糖灌注，则观察到胰高血糖素对葡萄糖剥夺的反应（关闭后10分钟内的峰值变化= 61 +/- 15 pg/ml [平均值+/-SE]，n = 6，P < 0.01）。还观察到使用相同实验设计的正常人胰岛的胰高血糖素反应。从β细胞耗尽的STZ诱导的糖尿病大鼠中观察到胰高血糖素反应（关闭后7分钟内的峰值变化= 31 +/-1 pg/ml，n = 3，P < 0.01），所述糖尿病大鼠的胰岛仍分泌少量胰岛素。然而，当这些胰岛首先用外源性胰岛素和16.7mmol/l葡萄糖灌注，然后关闭胰岛素和葡萄糖灌注液时，观察到显著更大（P < 0.05）的胰高血糖素反应（关闭后7分钟内的峰值变化= 71 +/-11 pg/ml，n = 4，P < 0.01）。如果当胰岛被剥夺葡萄糖时不关闭胰岛素灌流，或者当胰岛素被关闭而没有葡萄糖剥夺时，则没有观察到这种反应。这些数据独特地证明，正常的、分离的胰岛和来自STZ给药大鼠的胰岛如果首先被提供增加的内源性或外源性胰岛素，则可以通过释放胰高血糖素来响应葡萄糖剥夺。这些结果完全支持β细胞关闭假说作为α细胞对低血糖反应的关键机制。
The "switch-off" hypothesis to explain beta-cell regulation of alpha-cell function during hypoglycemia has not been assessed previously in isolated islets, largely because they characteristically do not respond to glucose deprivation by secreting glucagon. We examined this hypothesis using normal human and Wistar rat islets, as well as islets from streptozotocin (STZ)-administered beta-cell-deficient Wistar rats. As expected, islets perifused with glucose and 3-isobutryl-1-methylxanthine did not respond to glucose deprivation by increasing glucagon secretion. However, if normal rat islets were first perifused with 16.7 mmol/l glucose to increase endogenous insulin secretion, followed by discontinuation of the glucose perifusate, a glucagon response to glucose deprivation was observed (peak change within 10 min after switch off = 61 +/- 15 pg/ml [mean +/-SE], n = 6, P < 0.01). A glucagon response from normal human islets using the same experimental design was also observed. A glucagon response (peak change within 7 min after switch off = 31 +/- 1 pg/ml, n = 3, P < 0.01) was observed from beta-cell-depleted, STZ-induced diabetic rats whose islets still secreted small amounts of insulin. However, when these islets were first perifused with both exogenous insulin and 16.7 mmol/l glucose, followed by switching off both the insulin and glucose perifusate, a significantly larger (P < 0.05) glucagon response was observed (peak change within 7 min after switch off = 71 +/- 11 pg/ml, n = 4, P < 0.01). This response was not observed if the insulin perifusion was not switched off when the islets were deprived of glucose or when insulin was switched off without glucose deprivation. These data uniquely demonstrate that both normal, isolated islets and islets from STZ-administered rats can respond to glucose deprivation by releasing glucagon if they are first provided with increased endogenous or exogenous insulin. These results fully support the beta-cell switch-off hypothesis as a key mechanism for the alpha-cell response to hypoglycemia.