Nampt/PBEF/Visfatin Regulates Insulin Secretion in β Cells as a Systemic NAD Biosynthetic Enzyme

Abstract

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. Haplodeficiency 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.

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

“…Although the PBEF protein lacks a classic signal sequence for secretion, it is constitutively released and detected in conditioned medium from many cell types (12,13,(33)(34)(35)(36)(37). PBEF is detectable in serum and synovial fluid (1,6), and the levels of PBEF have been found to be increased in patients with rheumatoid arthritis, in whom it is clinically correlated with the Disease Activity Score in 28 joints and elevated C-reactive protein level (1,2,6).…”

“…Conversely, exogenous PBEF is also described as an adipocytokine (referred to as visfatin), and can regulate cellular processes via activation of transcriptional events through NF-B, phosphatidylinositol 3-kinase, and MAP kinase (6-8). Several groups have shown that PBEF interacts with the insulin receptor (8-10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).…”

“…Several groups have shown that PBEF interacts with the insulin receptor (8-10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).In vitro activation of signaling pathways by PBEF has been shown to regulate the expression of metalloproteinases, chemokines, and cytokines (6,7,(9)(10)(11)(12), but the in vivo contribution of this mediator of arthritis progression remains unclear. The recently developed small molecule inhibitor APO866 has been shown to act as a competitive inhibitor of PBEF/NAMPT activity by inhibiting binding of its natural substrate, nicotinamide (14,15).…”

“…Several groups have shown that PBEF interacts with the insulin receptor (8)(9)(10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).…”

“…In vitro activation of signaling pathways by PBEF has been shown to regulate the expression of metalloproteinases, chemokines, and cytokines (6,7,(9)(10)(11)(12), but the in vivo contribution of this mediator of arthritis progression remains unclear. The recently developed small molecule inhibitor APO866 has been shown to act as a competitive inhibitor of PBEF/NAMPT activity by inhibiting binding of its natural substrate, nicotinamide (14,15).…”