Ca2+-secretion coupling is impaired in diabetic Goto Kakizaki rats.
Ca2+-secretion coupling is impaired in diabetic Goto Kakizaki rats.
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DOI：
10.1085/jgp.200609604
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发表时间：
2007-06
期刊：
影响因子：
--
通讯作者：
Rupnik M
中科院分区：
文献类型：
--
作者：
Rose T;Efendic S;Rupnik M
后藤崎（GK）大鼠是广泛用于研究2型糖尿病（T2 D）中葡萄糖刺激的胰岛素释放缺陷的动物模型。与T2 D患者一样，在该模型中，参与含胰岛素的大致密核心囊泡的Ca 2+依赖性胞吐的几种蛋白质的表达失调。到目前为止，还不能证明胰岛素分泌后期步骤的缺陷。为了解决这一明显的矛盾，我们研究了急性胰腺组织切片中健康和GK大鼠β细胞的Ca 2+分泌偶联，通过高时间分辨率膜电容测量评估胞吐作用。我们发现GK大鼠β细胞对葡萄糖刺激的反应是胞浆Ca ~（2+）浓度正常增加。在去极化脉冲序列中，尽管GK大鼠β细胞的大小上调，电压激活的Ca 2+电流加倍，但其分泌活性是有缺陷的。在GK大鼠β细胞中，诱发的Ca 2+内流触发释放的效率显著低于非糖尿病对照组。这种损害既不是由于功能囊泡池大小的减少，也不是由于不同的动力学池再填充。用两个连续的去极化脉冲序列进行强刺激导致GK大鼠β细胞中显著的活性依赖性释放促进，而对照中的分泌不受影响。广谱抑制PKC可使GK大鼠β细胞内Ca 2+依赖性胞吐增敏，而抑制活性依赖性易化。我们的结论是GK大鼠β细胞对去极化诱发的Ca 2+内流的敏感性降低参与了葡萄糖刺激的胰岛素分泌缺陷。此外，我们讨论了糖尿病大鼠β细胞中一种或多种PKC同工酶活性组成性增加的作用。
The Goto Kakizaki (GK) rat is a widely used animal model to study defective glucose-stimulated insulin release in type-2 diabetes (T2D). As in T2D patients, the expression of several proteins involved in Ca2+-dependent exocytosis of insulin-containing large dense-core vesicles is dysregulated in this model. So far, a defect in late steps of insulin secretion could not be demonstrated. To resolve this apparent contradiction, we studied Ca2+–secretion coupling of healthy and GK rat β cells in acute pancreatic tissue slices by assessing exocytosis with high time-resolution membrane capacitance measurements. We found that β cells of GK rats respond to glucose stimulation with a normal increase in the cytosolic Ca2+ concentration. During trains of depolarizing pulses, the secretory activity from GK rat β cells was defective in spite of upregulated cell size and doubled voltage-activated Ca2+ currents. In GK rat β cells, evoked Ca2+ entry was significantly less efficient in triggering release than in nondiabetic controls. This impairment was neither due to a decrease of functional vesicle pool sizes nor due to different kinetics of pool refilling. Strong stimulation with two successive trains of depolarizing pulses led to a prominent activity-dependent facilitation of release in GK rat β cells, whereas secretion in controls was unaffected. Broad-spectrum inhibition of PKC sensitized Ca2+-dependent exocytosis, whereas it prevented the activity-dependent facilitation in GK rat β cells. We conclude that a decrease in the sensitivity of the GK rat β-cell to depolarization-evoked Ca2+ influx is involved in defective glucose-stimulated insulin secretion. Furthermore, we discuss a role for constitutively increased activity of one or more PKC isoenzymes in diabetic rat β cells.
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影响因子：
7.7
作者：
HAYEK, A;WOODSIDE, W
通讯作者：
WOODSIDE, W
大鼠胰腺B细胞中的Na通道和两种类型的Ca通道用反向溶血斑块测定法鉴定出来。
DOI：
10.1085/jgp.91.5.617
发表时间：
1988-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Hiriart M;Matteson DR
通讯作者：
Matteson DR
影响因子：
--
作者：
GIORDANO, E;CIRULLI, V;MEDA, P
通讯作者：
MEDA, P
影响因子：
2.2
作者：
GOTO, Y;KAKIZAKI, M;MASAKI, N
通讯作者：
MASAKI, N
影响因子：
7.7
作者：
Bergman, RN;Ader, M;Van Citters, G
通讯作者：
Van Citters, G