Journal
CELL METABOLISM
Volume 6, Issue 5, Pages 363-375Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2007.09.003
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Funding
- NCRR NIH HHS [P41RR00945, C06RR015502] Funding Source: Medline
- NIA NIH HHS [R01 AG024150, AG024150, R01 AG024150-04] Funding Source: Medline
- NIDDK NIH HHS [P30 DK056341-06, P30 DK52574, P30 DK052574, P30 DK056341-07, P30 DK056341, DK56341] Funding Source: Medline
- NINDS NIH HHS [NS36358] Funding Source: Medline
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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.
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