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ニューロメジンUと関連ペプチドによるデクレチン効果と糖尿病病態との関連の解析

神经调节肽U及相关肽的降泌素作用与糖尿病病理的关系分析

基本信息

批准号：
22K06004
负责人：
張維東
金额：
$ 2.66万
依托单位：
University of Miyazaki
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2022
资助国家：
日本
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22K06004/
关键词：
インスリン分泌迷走神経インスリン

项目摘要

1) NMU and its action via neuronal signalingWe previously reported that NMU produced in β cells suppressed GSIS and caused β-cell failure via NMUR1 and its downstream signaling Gαi/o proteins in an antocrine/paracrine manner. However, vagus nerve has recently been considered another pathway that engages in the regulation of pancreatic function, and we hypothesized that NMU could act as a decretin after its secretion from the gut. From our results, peripheral administration of NMU to mice increased the expression of the neuronal activation marker FOS in the vagus nodose ganglion (NG) and the nucleus tractus solitarius. NMU was upregulated in the ileum and NG after 24h fasting. NMUR1 was upregulated in the NG and pancreatic islets during fasting. NMUR2 in hypothalamic was downregulated by 24h fasting. Collectively, the intestinal tract that senses fasting increases the expression of NMU and transmits fasting information to the central nervous system via the vagus nerve. It was presumed that the hypothalamic sensitivity to NMU was reduced in the hypothalamus, and the anorexic effect of NMU was reduced. In response to fasting, the changes are considered to promote appetite, prevent hypoglycemia from suppressing insulin secretion, and maintain the homeostasis of the body.2) NURP expression and its insulinostatic effect.NMU precursor-related peptide (NURP) is produced from the same precursor of NMU, but we confirmed that it expressed in pancreatic α cells and suppressed GSIS in β cells. Furthermore, NURP suppressed calcium influx and induced mitochondrial dysfunction.

1) NMU及其在神经元信号传导中的作用我们之前报道过β细胞中产生的NMU通过NMUR1及其下游信号g - αi/o蛋白以分泌/旁分泌的方式抑制GSIS并导致β细胞衰竭。然而，迷走神经最近被认为是参与胰腺功能调节的另一途径，我们假设NMU从肠道分泌后可以作为一种分泌素。从我们的研究结果来看，小鼠外周给药NMU增加了迷走神经结节神经节（NG）和孤束核中神经元激活标志物FOS的表达。禁食24h后，回肠和NG中NMU表达上调。禁食期间，NMUR1在NG和胰岛中表达上调。禁食24h后下丘脑NMUR2下调。总的来说，感知禁食的肠道增加NMU的表达，并通过迷走神经将禁食信息传递给中枢神经系统。推测下丘脑对NMU的敏感性降低，NMU的厌食作用减弱。在对禁食的反应中，这些变化被认为可以促进食欲，防止低血糖抑制胰岛素分泌，并维持身体的稳态。2) NURP表达及其胰岛素抑制作用。NMU前体相关肽（NURP）是由NMU的相同前体产生的，但我们证实它在胰腺α细胞中表达，并在β细胞中抑制GSIS。此外，NURP抑制钙内流并诱导线粒体功能障碍。