Nampt/PBEF/Visfatin regulates insulin secretion in β cells as a systemic NAD biosynthetic enzyme
Nampt/PBEF/Visfatin regulates insulin secretion in β cells as a systemic NAD biosynthetic enzyme
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DOI：
10.1016/j.cmet.2007.09.003
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发表时间：
2007-11-01
期刊：
影响因子：
29
通讯作者：
Imai, Shin-Ichiro
中科院分区：
文献类型：
--
作者：
Revollo, Javier R.;Koerner, Antje;Imai, Shin-Ichiro
胞内烟酰胺磷酸核糖转移酶(INampt)是NAD生物合成途径中的一个重要酶。这种蛋白质的胞外形式(ENampt)已被报道作为一种名为PBEF的细胞因子或一种名为visfatin的胰岛素类似激素，但其生理意义仍存在争议。在这里，我们表明，eNampt在体外或体内不发挥胰岛素模拟作用，而是显示出强大的NAD生物合成活性。NAMPT的单倍体缺陷和化学抑制导致体内和体外胰岛NAD生物合成和葡萄糖刺激的胰岛素分泌缺陷。这些缺陷可以通过注射NAMPT反应的产物烟酰胺单核苷酸(NMN)来纠正。小鼠血浆中存在较高浓度的NMN，而NAMPT杂合子雌性小鼠血浆eNampt和NMN水平降低。我们的结果表明，NAMPT介导的全身性NAD生物合成对β细胞功能至关重要，这表明它是调节葡萄糖稳态的重要框架。
Intracellular nicotinamide phosphoribosyltransferase (iNampt) is an essential enzyme in the NAD biosynthetic pathway. An extracellular form of this protein (eNampt) has been reported to act as a cytokine named PBEF or an insulin-mimetic hormone named visfatin, but its physiological relevance remains controversial. Here we show that eNampt does not exert insulin-mimetic effects in vitro or in vivo but rather exhibits robust NAD biosynthetic activity. Haplo-deficiency and chemical inhibition of Nampt cause defects in NAD biosynthesis and glucose-stimulated insulin secretion in pancreatic islets in vivo and in vitro. These defects are corrected by administration of nicotinamide mononucleotide (NMN), a product of the Nampt reaction. A high concentration of NMN is present in mouse plasma, and plasma eNampt and NMN levels are reduced in Nampt heterozygous females. Our results demonstrate that Nampt-mediated systemic NAD biosynthesis is critical for beta cell function, suggesting a vital framework for the regulation of glucose homeostasis.