Dynamics of glucose-induced insulin secretion in normal human islets
Dynamics of glucose-induced insulin secretion in normal human islets
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DOI：
10.1152/ajpendo.00251.2015
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发表时间：
2015-10-01
影响因子：
5.1
通讯作者：
Nenquin, Myriam
中科院分区：
文献类型：
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作者：
Henquin, Jean-Claude;Dufrane, Denis;Nenquin, Myriam
在2型糖尿病中，葡萄糖诱导的胰岛素分泌的双相模式改变。第一阶段的损害是β细胞功能障碍的早期迹象，但其潜在机制仍不清楚。通过体外比较来自糖尿病患者和对照受试者的胰岛来鉴定它们需要表征和定量正常胰岛的胰岛素分泌动力学。当灌流正常人胰岛刺激15 mmol/l葡萄糖（G15），胰岛素原/胰岛素分泌产物的比例迅速和可逆的下降（类似50%），并没有随着时间的推移而重新增加。从预刺激G3切换到G6-G30诱导双相胰岛素分泌，具有平坦但持续（2小时）的第二相。刺激指数达到6.7-和3.6-倍的第一和第二相诱导的G10。两个阶段的浓度依赖性相似，分别在G6.5和G15出现半最大和最大反应。G15-G30的第一时相反应在G6（与G3相比）的短时间（30-60分钟）预刺激下减弱，在G8的预刺激下消失，而第二时相不受影响。在G8（而不是G5）中培养1-2天后，胰岛实际上对G15无反应。在这两种情况下，短暂返回G3-G5或短暂忽略CaCl 2恢复双相胰岛素分泌。引人注目的是，甲苯磺丁脲和精氨酸引起胰岛素分泌的葡萄糖难治性胰岛立即。总之，我们定量分析了正常人胰岛中葡萄糖诱导的胰岛素分泌的动力学特征，并表明刺激前葡萄糖的轻微升高可逆地损害了第一阶段，这支持了2型糖尿病患者中类似损害可能部分是继发现象的观点。
The biphasic pattern of glucose-induced insulin secretion is altered in type 2 diabetes. Impairment of the first phase is an early sign of beta-cell dysfunction, but the underlying mechanisms are still unknown. Their identification through in vitro comparisons of islets from diabetic and control subjects requires characterization and quantification of the dynamics of insulin secretion by normal islets. When perifused normal human islets were stimulated with 15 mmol/l glucose (G15), the proinsulin/insulin ratio in secretory products rapidly and reversibly decreased (similar to 50%) and did not reaugment with time. Switching from prestimulatory G3 to G6-G30 induced biphasic insulin secretion with flat but sustained (2 h) second phases. Stimulation index reached 6.7- and 3.6-fold for the first and second phases induced by G10. Concentration dependency was similar for both phases, with half-maximal and maximal responses at G6.5 and G15, respectively. First-phase response to G15-G30 was diminished by short (30-60 min) prestimulation in G6 (vs. G3) and abolished by prestimulation in G8, whereas the second phase was unaffected. After 1-2 days of culture in G8 (instead of G5), islets were virtually unresponsive to G15. In both settings, a brief return to G3-G5 or transient omission of CaCl2 restored biphasic insulin secretion. Strikingly, tolbutamide and arginine evoked immediate insulin secretion in islets refractory to glucose. In conclusion, we quantitatively characterized the dynamics of glucose-induced insulin secretion in normal human islets and showed that slight elevation of prestimulatory glucose reversibly impairs the first phase, which supports the view that the similar impairment in type 2 diabetic patients might partially be a secondary phenomenon.