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

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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.