Diminished phosphodiesterase-8B potentiates biphasic insulin response to glucose
Diminished phosphodiesterase-8B potentiates biphasic insulin response to glucose
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DOI：
10.1210/en.2007-0968
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发表时间：
2008-02-01
期刊：
影响因子：
4.8
通讯作者：
Nesher, Rafael
中科院分区：
文献类型：
--
作者：
Dov, Avital;Abramovitch, Eva;Nesher, Rafael
cAMP 激活多种信号通路，对胰腺 β 细胞的功能和存活至关重要，并且是胰岛素释放的主要增强剂。磷酸二酯酶 (PDE) 家族终止 cAMP 信号。我们检查了大鼠 β 细胞中 PDE 的表达及其在调节胰岛素反应中的作用。使用 RT-PCR 和蛋白质印迹分析，我们鉴定了大鼠胰岛和 INS-1E 细胞中的 PDE3A、PDE3B、PDE4B、PDE4D 和 PDE8B 以及这些 PDE 的几种可能的剪接变体。用小干扰 (si) RNA (siPDE3A) 特异性去除 PDE3A 会导致 INS-1E 细胞中胰岛素对葡萄糖的反应小幅增加 (67%)，但大鼠胰岛则不会。 siPDE3A 对大鼠胰岛中胰高血糖素样肽-1 (10 nmol/升) 增强的胰岛素反应没有影响。使用类似技术 (siPDE8B) 减少大鼠胰岛中的 PDE8B 水平，可使胰岛素对葡萄糖的反应增加 70%，在第一阶段和第二阶段胰岛素释放期间，增强程度相似。当在葡萄糖刺激过程中加入胰高血糖素样肽-1 时，siPDE8B 增强的胰岛素反应进一步增加了 23%。总之，PDE8B在少数与葡萄糖或脂肪代谢无关的组织中表达。我们认为，PDE8B（一种 3-异丁基-1-甲基黄嘌呤不敏感的 cAMP 特异性磷酸二酯酶）可以证明是增强胰岛素反应的新靶标，影响参与控制胰岛素颗粒运输和胞吐作用的特定 cAMP 池。最后，我们讨论了胰腺 β 细胞中 cAMP 功能划分的证据。
cAMP activates multiple signal pathways, crucial for the pancreatic beta-cells function and survival and is a major potentiator of insulin release. A family of phosphodiesterases (PDEs) terminate the cAMP signals. We examined the expression of PDEs in rat beta-cells and their role in the regulation of insulin response. Using RT-PCR and Western blot analyses, we identified PDE3A, PDE3B, PDE4B, PDE4D, and PDE8B in rat islets and in INS-1E cells and several possible splice variants of these PDEs. Specific depletion of PDE3A with small interfering (si) RNA (siPDE3A) led to a small (67%) increase in the insulin response to glucose in INS-1E cells but not rat islets. siPDE3A had no effect on the glucagon-like peptide-1 (10 nmol/ liter) potentiated insulin response in rat islets. Depletion in PDE8B levels in rat islets using similar technology (siPDE8B) increased insulin response to glucose by 70%, the potentiation being of similar magnitude during the first and second phase insulin release. The siPDE8B-potentiated insulin response was further increased by 23% when glucagon-like peptide-1 was included during the glucose stimulus. In conclusion, PDE8B is expressed in a small number of tissues unrelated to glucose or fat metabolism. We propose that PDE8B, an 3-isobutyl-1-methylxanthine-insensitive cAMP-specific phosphodiesterase, could prove a novel target for enhanced insulin response, affecting a specific pool of cAMP involved in the control of insulin granule trafficking and exocytosis. Finally, we discuss evidence for functional compartmentation of cAMP in pancreatic beta-cells.