Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion
Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion
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DOI：
10.1016/j.devcel.2016.10.003
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发表时间：
2016-11-07
影响因子：
11.8
通讯作者：
Kuruvilla, Rejji
中科院分区：
文献类型：
--
作者：
Houtz, Jessica;Borden, Philip;Kuruvilla, Rejji
胰岛β细胞分泌胰岛素对血糖稳态至关重要，而胰岛β细胞分泌反应迟钝是2型糖尿病的早期缺陷。在这里，我们揭示了葡萄糖招募血管源性神经营养因子来控制胰岛素分泌的调节机制。神经生长因子(NGF)是一种经典的神经细胞营养因子，在胰腺血管中表达，而其TrkA受体定位于胰岛β细胞。高糖迅速促进小鼠和人类胰岛神经生长因子的分泌和TrkA的磷酸化。组织特异性的NGF或TrkA缺失，或TrkA信号的急性中断，会损害小鼠的葡萄糖耐量和胰岛素分泌。我们发现内化的TrkA受体通过F-肌动蛋白重组促进胰岛素颗粒的胞吐。此外，NGF治疗增加了葡萄糖诱导的人胰岛胰岛素的分泌。这些发现揭示了神经营养因子的非神经性作用，并确定了一种新的胰岛素分泌调节途径，可以靶向改善β细胞功能障碍。
Insulin secretion by pancreatic islet beta cells is critical for glucose homeostasis, and a blunted beta cell secretory response is an early deficit in type 2 diabetes. Here, we uncover a regulatory mechanism by which glucose recruits vascular-derived neurotrophins to control insulin secretion. Nerve growth factor (NGF), a classical trophic factor for nerve cells, is expressed in pancreatic vasculature while its TrkA receptor is localized to islet beta cells. High glucose rapidly enhances NGF secretion and increases TrkA phosphorylation in mouse and human islets. Tissue-specific deletion of NGF or TrkA, or acute disruption of TrkA signaling, impairs glucose tolerance and insulin secretion in mice. We show that internalized TrkA receptors promote insulin granule exocytosis via F-actin reorganization. Furthermore, NGF treatment augments glucose-induced insulin secretion in human islets. These findings reveal a non-neuronal role for neurotrophins and identify a new regulatory pathway in insulin secretion that can be targeted to ameliorate beta cell dysfunction.