Nutrient control of insulin secretion in isolated normal human islets
Nutrient control of insulin secretion in isolated normal human islets
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DOI：
10.2337/db06-0868
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发表时间：
2006-12-01
期刊：
影响因子：
7.7
通讯作者：
Nenquin, Myriam
中科院分区：
文献类型：
--
作者：
Henquin, Jean-Claude;Dufrane, Denis;Nenquin, Myriam
从 16 个非糖尿病器官捐献者中分离胰岛，在 5 mmol/l 葡萄糖中培养大约 2 天后，进行灌注以表征人胰岛中营养诱导的胰岛素分泌。从 0 mmol/l 葡萄糖逐步增加到 30 mmol/l（8 个 30 分钟的步骤）会诱发浓度依赖性胰岛素分泌，阈值为 3-4 mmol/l 葡萄糖，K-m 为 6.5 mmol/l 葡萄糖，V-max 为 15 mmol/l 葡萄糖。葡萄糖从 1 mmol/l 增加到 15 mmol/l 会诱导双相胰岛素分泌，其中第一相显着（峰值增加约 18 倍），第二相持续平坦（约增加 10 倍），这两种情况均由毛喉素增强。 ATP 敏感的 K+ 通道在葡萄糖反应中的核心作用是通过二氮嗪消除胰岛素分泌和甲苯磺丁脲可逆恢复来确定的。用甲苯磺丁脲或 KCl（加二氮嗪）去极化可在 1 mmol/l 葡萄糖中引发快速胰岛素分泌。随后应用15 mmol/l葡萄糖进一步增加胰岛素分泌，表明放大途径是有效的。在对照培养基中，单独的谷氨酰胺无效，但其与亮氨酸或非代谢的2-氨基-双环[2,2,1]-庚烷-2-甲酸(BCH)的组合可引起快速胰岛素分泌。 BCH 在低血糖中的作用比在高血糖中更大。相反，葡萄糖或甲苯磺丁脲增强了对精氨酸或四种氨基酸混合物的胰岛素分泌反应。仅当超生理棕榈酸与白蛋白的比率为 5 时，棕榈酸才略微增加胰岛素分泌。肌苷和丙酮酸、谷氨酸或琥珀酸的膜渗透类似物在 3 mmol/l 和 10 mmol/l 葡萄糖中增加胰岛素分泌，而乳酸和丙酮酸则没有影响。总之，正常人胰岛中营养诱导的胰岛素分泌量比通常报道的要大。其特征与啮齿动物胰岛分泌胰岛素的特征总体相似，具有触发途径和放大途径。对葡萄糖的双相反应模式与小鼠胰岛的双相反应模式重叠，但浓度反应曲线向左移动，并且各种营养素，特别是氨基酸，在葡萄糖浓度的生理范围内影响胰岛素分泌。
Pancreatic islets were isolated from 16 nondiabetic organ donors and, after culture for similar to 2 days in 5 mmol/l glucose, were perifused to characterize nutrient-induced insulin secretion in human islets. Stepwise increases from 0 to 30 mmol/l glucose (eight 30-min steps) evoked concentration-dependent insulin secretion with a threshold at 3-4 mmol/l glucose, K-m at 6.5 mmol/l glucose, and V-max at 15 mmol/l glucose. An increase from 1 to 15 mmol/l glucose induced biphasic insulin secretion with a prominent first phase (peak increase of similar to 18-fold) and a sustained, flat second phase (similar to 10-fold increase), which were both potentiated by forskolin. The central role of ATP-sensitive K+ channels in the response to glucose was established by abrogation of insulin secretion by diazoxide and reversible restoration by tolbutamide. Depolarization with tolbutamide or KCl (plus diazoxide) triggered rapid insulin secretion in 1 mmol/l glucose. Subsequent application of 15 mmol/l glucose further increased insulin secretion, showing that the amplifying pathway is operative. In control medium, glutamine alone was ineffective, but its combination with leucine or nonmetabolized 2-amino-bicyclo [2,2,1]-heptane-2-carboxylic acid (BCH) evoked rapid insulin secretion. The effect of BCH was larger in low glucose than in high glucose. In contrast, the insulin secretion response to arginine or a mixture of four amino acids was potentiated by glucose or tolbutamide. Palmitate slightly augmented insulin secretion only at the supraphysiological palmitate-to-albumin ratio of 5. Inosine and membrane-permeant analogs of pyruvate, glutamate, or succinate increased insulin secretion in 3 and 10 mmol/l glucose, whereas lactate and pyruvate had no effect. In conclusion, nutrient-induced insulin secretion in normal human islets is larger than often reported. Its characteristics are globally similar to those of insulin secretion by rodent islets, with both triggering and amplifying pathways. The pattern of the biphasic response to glucose is superimposable on that in mouse islets, but the concentration-response curve is shifted to the left, and various nutrients, in particular amino acids, influence insulin secretion within the physiological range of glucose concentrations.