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

1)NMU及其通过神经元信号的作用我们先前报道在β细胞中产生的NMU通过NMUR1及其下游信号GαI/O蛋白以自分泌/旁分泌的方式抑制GSI并导致GSI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条途径，我们假设NMU在从肠道分泌后可能起到衰老的作用。根据我们的结果，外周给予NMU增加了迷走神经节(NG)和孤束核中神经元激活标记FOS的表达。禁食24小时后，NMU在回肠和NG中表达上调。禁食期间，NMUR1在NG和胰岛中表达上调。禁食24小时可下调下丘脑NMUR2的表达。总的来说，感觉禁食的肠道增加了NMU的表达，并通过迷走神经将禁食信息传递到中枢神经系统。推测下丘脑对NMU的敏感性降低，NMU的厌食效应减弱。作为对禁食的反应，这些变化被认为是为了促进食欲，防止低血糖抑制胰岛素分泌，维持机体的动态平衡。2)NURP的表达及其胰岛素抑制作用。NMU前体相关肽(NURP)是由NMU的同一前体产生的，但我们证实它在胰腺α细胞中表达，在β细胞中抑制GSI。此外，NURP抑制钙内流并诱导线粒体功能障碍。

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.