Carbon monoxide stimulates insulin release and propagates Ca2+ signals between pancreatic β-cells
Carbon monoxide stimulates insulin release and propagates Ca2+ signals between pancreatic β-cells
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DOI：
10.1152/ajpendo.00498.2002
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发表时间：
2003-11-01
影响因子：
5.1
通讯作者：
Hellman, B
中科院分区：
文献类型：
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作者：
Lundquist, I;Alm, P;Hellman, B
了解脉冲式胰岛素释放机制的一个关键问题是细胞质 Ca2+ 浓度 ([Ca2+](i)) 的潜在 β 细胞振荡如何在胰腺胰岛内部和胰岛之间同步。一氧化氮被认为可以通过沉淀 [Ca2+](i) 的瞬变来协调 β 细胞的活动。通过比较 ob/ob 小鼠和瘦对照小鼠，我们现在研究了一氧化碳 (CO) 的作用，一氧化碳 (CO) 是另一种对 cGMP 产生具有刺激作用的神经递质。在位于胰岛周围的神经节细胞和几乎所有胰岛内分泌细胞中发现了对产生 CO 的组成型血红素加氧酶 (HO-2) 具有很强的免疫反应性。 ob/ob 小鼠的胰岛产生的 CO（1 nmol.min(-1).mg 蛋白质(-1)）是瘦对照小鼠的六倍。这是其 NO 本质生成率的 100 倍。此外，ob/ob 小鼠的胰岛显示 HO-2 表达增加了三倍，并表达诱导型 HO (HO-1)。 ob/ob 小鼠中胰岛过度产生 CO，与暴露于 H2O 抑制剂 Zn-原卟啉 (10 muM) 的胰岛中葡萄糖刺激的胰岛素释放受到明显抑制相对应，并且其 β 细胞中 [Ca2+](i) 瞬变频率高出 16 倍。 H2O 的天然底物血红素（0.1 和 1.0 μM）促进了 [Ca2+](i) 瞬态的出现，10 μM H2O 抑制剂 Zn-原卟啉和 Cr-中卟啉对瞬态的激发及其同步具有抑制作用。结论是，胰岛 CO 产生增加导致 ob/ob 小鼠出现高胰岛素血症。 CO 除了作为葡萄糖刺激的胰岛素释放的正调节剂之外，还作为传播 Ca2+ 信号的信使，对 β 细胞节律性具有协调作用。
A key question for understanding the mechanisms of pulsatile insulin release is how the underlying beta-cell oscillations of the cytoplasmic Ca2+ concentration ([Ca2+](i)) are synchronized within and among the islets in the pancreas. Nitric oxide has been proposed to coordinate the activity of the beta-cells by precipitating transients of [Ca2+](i). Comparing ob/ob mice and lean controls, we have now studied the action of carbon monoxide (CO), another neurotransmitter with stimulatory effects on cGMP production. A strong immunoreactivity for the CO-producing constitutive heme oxygenase (HO-2) was found in ganglionic cells located in the periphery of the islets and in almost all islet endocrine cells. Islets from ob/ob mice had sixfold higher generation of CO ( 1 nmol.min(-1).mg protein(-1)) than the lean controls. This is 100-fold the rate for their constitutive production of NO. Moreover, islets from ob/ob mice showed a threefold increase in HO-2 expression and expressed inducible HO (HO-1). The presence of an excessive islet production of CO in the ob/ob mouse had its counterpart in a pronounced suppression of the glucose-stimulated insulin release from islets exposed to the HO inhibitor Zn-protoporhyrin (10 muM) and in a 16 times higher frequency of [Ca2+](i) transients in their beta-cells. Hemin (0.1 and 1.0 muM), the natural substrate for HO, promoted the appearance of [Ca2+](i) transients, and 10 muM of the HO inhibitors Zn-protoporphyrin and Cr-mesoporphyrin had a suppressive action both on the firing of transients and their synchronization. It is concluded that the increased islet production of CO contributes to the hyperinsulinemia in ob/ob mice. In addition to serving as a positive modulator of glucose-stimulated insulin release, CO acts as a messenger propagating Ca2+ signals with coordinating effects on the beta-cell rhythmicity.